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Cognitive-Behavioral Treatments for Anxiety and Stress-Related Disorders

• Joshua E. Curtiss , Ph.D. ,
• Daniella S. Levine , B.A. ,
• Ilana Ander , B.A. ,
• Amanda W. Baker , Ph.D.

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Cognitive-behavioral therapy (CBT) is a first-line, empirically supported intervention for anxiety disorders. CBT refers to a family of techniques that are designed to target maladaptive thoughts and behaviors that maintain anxiety over time. Several individual CBT protocols have been developed for individual presentations of anxiety. The article describes common and unique components of CBT interventions for the treatment of patients with anxiety and related disorders (i.e., panic disorder, social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder, prolonged grief). Recent strategies for enhancing the efficacy of CBT protocols are highlighted as well.

Anxiety disorders are among the most prevalent of mental disorders and are associated with high societal burden ( 1 ). One of the most well-researched and efficacious treatments for anxiety disorders is cognitive-behavioral therapy (CBT). At its core, CBT refers to a family of interventions and techniques that promote more adaptive thinking and behaviors in an effort to ameliorate distressing emotional experiences ( 2 ). CBT differs from other therapeutic orientations in that it is highly structured and often manualized. CBT sessions often occur weekly for a limited period (e.g., 12–16 weeks), and a small number of booster sessions are sometimes offered subsequently to reinforce independent use of skills. A cognitive-behavioral conceptualization of anxiety disorders includes identification of dysfunctional thinking patterns, distressing feelings or physiological experiences, and unproductive behaviors. When each of these three components interact and mutually reinforce one another, distressing and impairing levels of anxiety can be maintained over time. Although there are several CBT interventions for different types of anxiety, some common techniques and treatment goals form the basis of the CBT philosophy.

Cognitive Interventions

One of the primary CBT strategies is cognitive intervention. In brief, CBT holds that one’s emotional experience is dictated by one’s interpretation of the events and circumstances surrounding that experience ( 2 , 3 ). Anxiety disorders are associated with negatively biased cognitive distortions (e.g., “I think it’s 100% likely I will lose my job, and no one will ever hire me again”). The objective of cognitive interventions is to facilitate more adaptive thinking through cognitive restructuring and behavioral experiments. Cognitive restructuring promotes more adaptive and realistic interpretations of events by identifying the presence of thinking traps. These cognitive traps are patterns of biased thinking that contribute to overly negative appraisals. For example, “black-and-white thinking” describes the interpretation of circumstances as either all good or all bad, without recognition of interpretations between these two extremes, and “overgeneralization” describes the making of sweeping judgments on the basis of limited experiences). Through identification of thinking traps, cognitive restructuring can be used to promote more balanced thinking, encouraging patients to consider alternative interpretations of circumstances that are more helpful and less biased by anxiety (e.g., “Maybe thinking the chance of losing my job is 100% is overestimating the likelihood that it will actually happen. And, it’s not a forgone conclusion that even if I lose my job, I will never find another one for the rest of my life.”). Similarly, behavioral experiments can be used to facilitate cognitive change. Behavioral experiments involve encouraging patients to empirically test maladaptive beliefs to determine whether there is evidence supporting extreme thinking. For example, if a patient believes that he/she/they is romantically undesirable and that asking someone on a date will cause the other person to react with disgust and disdain, then the patient would be encouraged to test this belief by asking someone on a date. Some combination of cognitive restructuring and behavioral experiments are often implemented in CBT across all anxiety disorders.

Behavioral Interventions

There are several behavioral strategies in CBT for anxiety disorders, yet the central behavioral strategy is exposure therapy. Exposure techniques rely on learning theory to explain how prolonged fear is maintained over time. Specifically, heightened anxiety and fear prompt individuals to avoid experiences, events, and thoughts that they believe will lead to catastrophic outcomes. Continued avoidance of feared stimuli and events contributes to the maintenance of prolonged anxiety. Consistent with the premises underlying extinction learning, exposure exercises are designed to encourage a patient to confront a feared situation without engaging in avoidance or subtle safety behaviors (i.e., doing something to make an anxiety-inducing situation less distressing). After repeated exposures to a feared situation (e.g., heights) without engaging in avoidance or safety behaviors (e.g., closing one’s eyes to avoid looking down), the patient will learn that such a situation is less likely to be associated with disastrous outcomes, and new experiences of safety will be reinforced. Similar to the behavioral experiments described in the cognitive intervention section above, which test whether a faulty thought is true or false, exposure exercises offer the opportunity for patients to test their negative beliefs about the likelihood of a bad outcome by exposing themselves to whatever situations they have been avoiding. Thus, cognitive approaches and exposure exercises are complementary techniques that can benefit individuals with anxiety disorders. In the following sections, different aspects of CBT will be explored and emphasized insofar as they relate to specific presentations of anxiety.

CBT for Specific Disorders

Panic disorder.

Panic disorder, as defined by the DSM-5 , is characterized by recurrent, unexpected panic attacks accompanied by worry and behavioral changes in relation to future attacks. Panic attacks are marked by acute, intense discomfort, with symptoms including heart palpitations, sweating, and shortness of breath. Individuals with panic disorder exhibit cognitive and behavioral symptoms, such as catastrophic misinterpretations of their symptoms as dangerous (e.g., “my heart pounding means I will have a heart attack”) and avoidance of situations or sensations that induce panic ( 4 ). Cognitive-behavioral treatments thus target these symptoms. For example, cognitive restructuring is used to help patients reinterpret their maladaptive thoughts surrounding panic (e.g., “if I get dizzy, I will go crazy”) to be more flexible (e.g., “if I get dizzy, it may just mean that I spun around too fast”). Behavioral treatments for panic include exposure to the situations (i.e., in-vivo exposure, which might include driving in traffic or riding the subway) and bodily sensations (i.e., interoceptive exposure, which would include physical exercises to bring on physical symptoms) that trigger panic in order to reduce the fear and anticipatory anxiety that maintain the symptoms. The aim of these exposures is to illustrate that the situations and sensations are benign and not indicative of danger.

Generalized Anxiety Disorder

Generalized anxiety disorder (GAD) is characterized by excessive and uncontrollable worry about several life domains (e.g., finances, health, career, the future in general). Treatment for GAD involves a wholesale approach to target excessive worry with a combination of cognitive and behavioral strategies ( 5 ). Although cognitive restructuring exercises are indeed emphasized throughout the treatment to target dysfunctional thoughts, usually further cognitive treatments are included to address worry behavior in addition to thought content. Individuals with GAD rarely achieve complete remission after restructuring only one of their negative thoughts. The CBT conceptualization of worry describes worry as a mental behavior or process, characterized by repetitive negative thinking about catastrophic future outcomes. To target worrying as a process, cognitive techniques, such as mindfulness, are emphasized. Rather than targeting the content of worry (e.g., “I think I will definitely lose my job if I do not prepare for this meeting”), mindfulness exercises target the worry behavior by promoting the opposite of repetitive negative thinking (i.e., nonjudgmental and nonreactive present moment awareness), thereby facilitating greater psychological distance from negative thoughts. Exposure therapy is often implemented as imaginal exposures for GAD, because individuals with GAD rarely have an external object that is feared. Such imaginal exposures will encourage patients with GAD to write a detailed narrative of their worst-case scenario or catastrophic outcome and then imagine themselves undergoing such an experience without avoiding their emotions. Cognitive restructuring and imaginal exposure exercises can benefit patients with GAD by targeting their tendency to give catastrophic interpretations to their worries, whereas mindfulness can be helpful in targeting worry as a mental behavior itself ( 5 ).

Social Anxiety Disorder

Social anxiety disorder involves a fear of negative evaluation in social situations and is accompanied by anxiety and avoidance of interpersonal interactions and performance in front of others. The primary treatment approach for social anxiety disorder consists of exposure exercises to feared social situations ( 6 ). Cognitive restructuring is used in conjunction with exposure exercises to reinforce the new learning and shift in perspective occurring through exposure therapy. Typically, exposure exercises for social anxiety disorder come in two stages ( 6 ). The first stage of exposures often targets patients’ overestimation that something bad will happen during a social interaction. For instance, patients with this disorder may fear that they will make many verbal faux pas (e.g., saying “uh” more than 30 times) during a conversation. An exposure exercise may consist of recording the patient having a 2-minute conversation and listening to the recording afterward to see whether the feared outcome actually occurred. The second stage of exposure exercises (i.e., social cost exposures) consists of having patients directly making their worst-case social anxiety scenario come true to determine how bad and intolerable it actually is. Such a social cost exposure might involve encouraging a patient to embarrass her- or himself on purpose by singing “Twinkle, Twinkle Little Star” in a crowded public street. After fully confronting a social situation that the patient predicted would be very embarrassing, the patient can then determine whether such a situation is as devastating and intolerable as predicted. After repeated social cost exposures, patients with social anxiety disorder experience less anxiety in embarrassing social situations and are more willing to adopt less catastrophic beliefs about the meaning of making mistakes in social situations.

Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is characterized by obsessions (i.e., unwanted thoughts or images that are intrusive in nature) and compulsions (i.e., actions or mental behaviors that are performed in a rule-like manner to neutralize the obsession). A CBT conceptualization of OCD considers compulsions as a form of emotional avoidance. Although both cognitive interventions and exposure exercises are helpful for individuals with OCD, the latter are often emphasized. The gold-standard CBT treatment for OCD is exposure and ritual prevention therapy ( 7 ). The primary idea underlying exposure and ritual prevention is to expose individuals with OCD to the feared circumstance associated with the obsession and prevent them from performing the compulsive ritual that gives them comfort through avoidance. For example, patients who experience frequent obsessions about whether their doors are locked or their appliances are off (e.g., “If my door is unlocked, then my house might be robbed or something bad might happen.”) will often feel compelled to perform a compulsion (e.g., ritualistic checking) to avoid the likelihood of having their obsession come true. Exposure and ritual prevention would be used to expose such patients to a feared situation, such as leaving their door unlocked on purpose, and resisting the compulsion to check the door or to lock it. During these exposures, the patients would be asked to embrace the uncertainty surrounding the possibility of the feared outcome coming true (i.e., someone entering the house). Repeated sessions of exposure and ritual prevention will facilitate corrective learning about the likelihood that feared outcomes will occur.

Posttraumatic Stress Disorder

As defined by the DSM-5 , posttraumatic stress disorder (PTSD) can arise after a traumatic event in which an individual directly experiences, witnesses, or learns about the actual or threatened death, serious injury, or sexual violence toward a loved one. After the traumatic stressor event, an individual with PTSD may experience intrusion symptoms (e.g., upsetting dreams or flashbacks of the event), avoidance of reminders of the event, changes in cognitions and affect (e.g., distorted beliefs about oneself, others, and the world), and changes in physiological arousal (e.g., jumpiness, irritability) ( 4 ). Gold-standard treatments for PTSD involve targeting the cognitive and behavioral symptoms that maintain the disorder ( 8 ). PTSD treatments target negative changes in cognition by restructuring the thoughts and beliefs surrounding the traumatic event. For example, evidence-based treatments alter persistent negative beliefs about the world (e.g., “I was assaulted; therefore, the world is dangerous”) to be more flexible (e.g., “even though I was assaulted, there are safe places for me to be”). In challenging these beliefs, the patient may be better able to foster flexible thinking, positive affect, trust, and control in their lives. PTSD treatments are also designed to help patients confront the upsetting memories and situations associated with the traumatic event. Through in-vivo exposures (i.e., approaching situations that are reminders of the trauma) and imaginal exposures (i.e., confronting upsetting memories of the trauma), the patient can begin to behaviorally approach, rather than avoid, reminders of the event to overcome their fears of the trauma and the associated symptoms.

Prolonged Grief Disorder

After losing a loved one, many individuals experience grief symptoms, such as thoughts (e.g., memories of the deceased, memories of the death), emotions (e.g., yearning, emotional pain), and behaviors (e.g., social withdrawal, avoidance of reminders). For most bereaved individuals, these symptoms decrease over time; however, some individuals experience a debilitating syndrome of persistent grief called prolonged grief disorder. This disorder is a direct consequence of the loss, thereby differentiating it from depression and PTSD. Evidence-based and efficacious treatment options for prolonged grief disorder draw from interpersonal therapy, CBT, and motivational interviewing, with additional psychoeducation components ( 9 ). These treatments aim to facilitate the natural bereavement process as individuals accept and integrate the loss. Strategies can be either loss-related or restoration-related. Specific loss-related strategies that draw from CBT include imaginal and situational revisiting (e.g., retelling the story of the loss, going to places that have been avoided since the loss) and a grief monitoring diary. Restoration-related strategies include short- and long-term planning, self-assessment and self-regulation, and rebuilding interpersonal connections.

Transdiagnostic Approaches to CBT for Anxiety Disorders

Throughout the past several decades, there has been a proliferation of CBT approaches that have been individualized to specific anxiety disorder presentations (e.g., panic disorder, specific phobias, social anxiety disorder). Each disorder-specific treatment manual is written to consider unique applications of CBT strategies for the presenting disorder. However, in recent years, there has been increased interest in considering transdiagnostic approaches to the treatment of anxiety and related disorders ( 10 ). The commonalities among individual anxiety disorders and the high levels of comorbidity have contributed to the rationale for a unified CBT approach that can target transdiagnostic mechanisms underlying all anxiety disorders. The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) has been the most studied transdiagnostic treatment for anxiety disorders, and recent evidence ( 10 ) corroborates the equivalent efficacy of the UP relative to disorder-specific treatment protocols for individual anxiety disorders.

The UP consists of five core modules that target transdiagnostic mechanisms of emotional disorders, particularly neuroticism and emotional avoidance, underlying all anxiety disorders. Specifically, the modules are mindfulness of emotions, cognitive flexibility, identifying and preventing patterns of emotion avoidance, increasing tolerance of emotion-related physical sensations, and interoceptive and situational emotion-focused exposures ( 10 ). Each module may be used flexibly for individual patients. The first two modules are more cognitive in nature, whereas the latter modules are more behavioral and emphasize the treatment of avoidance. The first module emphasizes mindfulness of emotions, which consists of allowing oneself to fully and nonjudgmentally experience emotions and allow them to come and go while remaining focused on the present. The second module fosters cognitive flexibility by identifying thinking traps that lead to overly negative thoughts and interpretations and by teaching restructuring strategies to generate alternative interpretations of circumstances that are less biased and more adaptive. The third module promotes the identification of emotion-driven behaviors (i.e., actions that a given emotion compels a person to do, such as avoidance behaviors in response to fear) and the adoption of alternative actions (i.e., behaviors that are different from or the opposite of the emotion-driven behavior). For example, if social anxiety prompts an individual to avoid eye contact as an emotion-driven behavior, then an alternative action would be to intentionally maintain eye contact with another speaker to counteract this subtle form of avoidance. The final two modules consist of exposure exercises to develop better tolerance of unwanted physical symptoms produced by anxiety (e.g., increased heart rate) and to reduce fear in anxiety-provoking situations.

Because the UP contains many of the core components of disorder-specific protocols and has demonstrated equivalent efficacy, such a treatment approach may reduce the need for excessive reliance on disorder-specific protocols ( 10 ). Furthermore, the UP can be extended to other emotional disorders, such as depression.

Complementary Approaches for CBT

Mindfulness.

Mindfulness-based interventions function both as transdiagnostic adjunctive treatments to CBT for patients with anxiety and stress disorders as well as stand-alone treatments. Mindfulness is the practice of nonjudgmental awareness of the present moment experience. The aim of these interventions is to reduce emotional dysregulation and reactivity to stressors. Common mindfulness-based interventions include manualized group skills training programs called mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy ( 11 ). MBSR involves eight, 2–2.5-hour sessions with an instructor, in conjunction with a daylong retreat, weekly homework assignments, and practice sessions. Modules are designed to train participants in mindful meditation, interpersonal communication, sustained attention, and recognition of automatic stress reactivity. Mindfulness-based cognitive therapy has a structure similar to MBSR but includes cognitive therapy techniques to train participants to recognize and disengage from negative automatic thought patterns ( 12 ). These interventions omit aspects of traditional CBT (e.g., cognitive restructuring). Mindfulness-based interventions have been explored as both brief and Internet-delivered interventions and have been integrated into other evidence-based practices (e.g., dialectical behavior therapy and acceptance and commitment therapy).

Pharmacotherapy

There has been much interest in determining whether combination strategies of CBT and pharmacotherapy yield greater efficacy than either one alone for individuals with anxiety disorders. A comprehensive meta-analysis ( 13 ) examining this combination strategy suggested that adding pharmacotherapy to CBT may produce short-term benefit, yet such improvements diminished during 6-month follow-up. This combination strategy was more efficacious for individuals with panic disorder or GAD than for individuals with other presentations of anxiety. Moreover, the meta-analysis ( 13 ) indicated that the effect size for CBT combined with benzodiazepines was significantly greater than that for CBT combined with serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants. Another important consideration for pharmacotherapy in the treatment of individuals with anxiety disorders is to ensure that anxiolytic medications, such as benzodiazepines, are administered carefully in the context of exposure therapy. Anxiolytic medications taken to temporarily reduce anxiety may undermine quality exposure therapy sessions by preventing patients from fully learning whether they can tolerate fear without resorting to avoidance behaviors. Thus, although pharmacotherapy appears to improve outcomes in combination with CBT for patients with anxiety disorders, further research is needed to determine the durability of these effects.

D-Cycloserine in Conjunction With Exposures

One approach for improving patient outcomes is to target the extinction learning process underlying exposure exercises. There has been recent interest in cognitive enhancers, such as d-cycloserine (DCS) or methylene blue, as pharmacological adjuncts to exposure therapy ( 14 , 15 ). In preclinical studies, DCS has demonstrated evidence as a cognitive enhancer, consolidating new learning during extinction training. Specifically, the efficacy associated with DCS depends on the efficacy of the exposure exercise. For instance, during a successful exposure exercise, in which anxiety levels decrease substantially, the administration of DCS may confer additional benefit by consolidating this learning. However, if an exposure exercise was unsuccessful and fear levels never decreased, then DCS might consolidate the fear memory, thereby exacerbating the severity of the anxiety disorder ( 14 ). Recently, however, there has been evidence ( 16 ) suggesting that the efficacy of cognitive enhancers, such as DCS, has been declining, possibly because of changes in dose and dose timing. More research needs to be undertaken to understand under what circumstances (e.g., length of exposure session, amount of fear reduction, timing of dose) DCS would offer the greatest therapeutic effect in conjunction with exposure therapy.

Novel Delivery Methods

Internet-delivered CBT (I-CBT) is an alternative modality for the delivery of CBT for patients with anxiety and related disorders. I-CBT is a scalable alternative to in-person treatment, with the Internet used as an accessible and cost-effective method of delivery for evidence-based treatment. In I-CBT, CBT modules are delivered via computer or an application on a mobile device, with the support of a therapist or through a self-guided system. I-CBT has been shown ( 17 – 19 ) to be superior to waitlist and placebo conditions in the treatment of adults with a range of anxiety and trauma disorders, including anxiety and PTSD. Results ( 18 ) have indicated that I-CBT is similarly effective at reducing panic disorder symptoms as face-to-face CBT. The results of another trial ( 20 ) have indicated that I-CBT is also effective at reducing symptoms of OCD and social anxiety disorder.

In addition to Internet and mobile application platforms for CBT, virtual reality technology offers novel avenues to access cognitive-behavioral interventions ( 21 ). One key advantage is that recent advances in the sensory vividness of virtual reality platforms have facilitated more meaningful exposure exercises. For example, virtual reality flight simulators can be leveraged to expose a patient with flight phobia to several flight conditions with enhanced sensory detail (e.g., sounds of liftoff or landing, vibrations, images of clouds through a window, images of in-cabin atmosphere). This technology could obviate the need to purchase several expensive flights to participate in exposure exercises, thereby permitting more frequent exposure opportunities.

Conclusions

CBT is an effective, gold-standard treatment for anxiety and stress-related disorders. CBT uses specific techniques to target unhelpful thoughts, feelings, and behaviors shown to generate and maintain anxiety. CBT can be used as a stand-alone treatment, may be combined with standard medications for the treatment of patients with anxiety disorders (e.g., selective serotonin reuptake inhibitors), or used with novel interventions (e.g., mindfulness). Furthermore, this treatment is flexible in terms of who may benefit from it. Overall, whenever a patient is experiencing some form of emotional psychopathology (e.g., an anxiety or depression disorder) or distressing emotions that do not meet disorder threshold but cause distress or interference in daily activities, referral to a CBT provider is indicated to pursue a course of treatment to actively address such symptoms and problems.

The authors report no financial relationships with commercial interests.

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Case Study 1: A 55-Year-Old Woman With Progressive Cognitive, Perceptual, and Motor Impairments

• Scott M. McGinnis , M.D. ,
• Andrew M. Stern , M.D., Ph.D. ,
• Jared K. Woods , M.D., Ph.D. ,
• Matthew Torre , M.D. ,
• Mel B. Feany , M.D., Ph.D. ,
• Michael B. Miller , M.D., Ph.D. ,
• David A. Silbersweig , M.D. ,
• Seth A. Gale , M.D. ,
• Kirk R. Daffner , M.D.

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CASE PRESENTATION

A 55-year-old right-handed woman presented with a 3-year history of cognitive changes. Early symptoms included mild forgetfulness—for example, forgetting where she left her purse or failing to remember to retrieve a take-out order her family placed—and word-finding difficulties. Problems with depth perception affected her ability to back her car out of the driveway. When descending stairs, she had to locate her feet visually in order to place them correctly, such that when she carried her dog and her view was obscured, she had difficulty managing this activity. She struggled to execute relatively simple tasks, such as inserting a plug into an outlet. She lost the ability to type on a keyboard, despite being able to move her fingers quickly. Her symptoms worsened progressively for 3 years, over which time she developed a sad mood and anxiety. She was laid off from work as a nurse administrator. Her family members assumed responsibility for paying her bills, and she ceased driving.

Her past medical history included high blood pressure, Hashimoto’s thyroiditis with thyroid peroxidase antibodies, remote history of migraine, and anxiety. Medications included mirtazapine, levothyroxine, calcium, and vitamin D. She had no history of smoking, drinking alcohol, or recreational drug use. There was no known family history of neurologic diseases.

What Are Diagnostic Considerations Based on the History? How Might a Clinical Examination Help to Narrow the Differential Diagnosis?

Insidious onset and gradual progression of cognitive symptoms over the course of several years raise concern for a neurodegenerative disorder. It is helpful to consider whether or not the presentation fits with a recognized neurodegenerative clinical syndrome, a judgment based principally on familiarity with syndromes and pattern recognition. Onset of symptoms before age 65 should prompt consideration of syndromes in the spectrum of frontotemporal dementia (FTD) and atypical (nonamnesic) presentations of Alzheimer’s disease (AD) ( 1 , 2 ). This patient’s symptoms reflect relatively prominent early dysfunction in visual-spatial processing and body schema, as might be observed in posterior cortical atrophy (PCA), although the history also includes mention of forgetfulness and word-retrieval difficulties. A chief goal of the cognitive examination would be to survey major domains of cognition—attention, executive functioning, memory, language, visual-spatial functioning, and higher somatosensory and motor functioning—to determine whether any domains stand out as more prominently affected. In addition to screening for evidence of focal signs, a neurological examination in this context should assess for evidence of parkinsonism or motor neuron disease, which can coexist with cognitive changes in neurodegenerative presentations.

The patient’s young age and history of Hashimoto’s thyroiditis might also prompt consideration of Hashimoto’s encephalopathy (HE; also known as steroid-responsive encephalopathy), associated with autoimmune thyroiditis. This syndrome is most likely attributable to an autoimmune or inflammatory process affecting the central nervous system. The time course of HE is usually more subacute and rapidly progressive or relapsing-remitting, as opposed to the gradual progression over months to years observed in the present case ( 3 ).

The patient’s mental status examination included the Montreal Cognitive Assessment (MoCA), a brief global screen of cognition ( 4 ), on which she scored 12/30. There was evidence of dysfunction across multiple cognitive domains ( Figure 1 ). She was fully oriented to location, day, month, year, and exact date. When asked to describe a complex scene from a picture in a magazine, she had great difficulty doing so, focusing on different details but having trouble directing her saccades to pertinent visual information. She likewise had problems directing her gaze to specified objects in the room and problems reaching in front of her to touch target objects in either visual field. In terms of other symptoms of higher order motor and somatosensory functioning, she had difficulty demonstrating previously learned actions—for example, positioning her hand correctly to pantomime holding a brush and combing her hair. She was confused about which side of her body was the left and which was the right. She had difficulty with mental calculations, even relatively simple ones such as “18 minus 12.” In addition, she had problems writing a sentence in terms of both grammar and the appropriate spacing of words and letters on the page.

FIGURE 1. Selected elements of a 55-year-old patient’s cognitive examination at presentation a

a BNT-15=Boston Naming Test (15-Item); MoCA=Montreal Cognitive Assessment.

On elementary neurologic examination she had symmetrically brisk reflexes, with spread. She walked steadily with a narrow base, but when asked to pass through a doorway she had difficulty finding her way through it and bumped into the door jamb. Her elemental neurological examination was otherwise normal, including but not limited to brisk, full-amplitude vertical eye movements, normal visual fields, no evidence of peripheral neuropathy, and no parkinsonian signs such as slowness of movement, tremor, or rigidity.

How Does the Examination Contribute to Our Understanding of Diagnostic Considerations? What Additional Tests or Studies Are Indicated?

The most prominent early symptoms and signs localize predominantly to the parietal association cortex: The patient has impairments in visual construction, ability to judge spatial relationships, ability to synthesize component parts of a visual scene into a coherent whole (simultanagnosia or asimultagnosia), impaired visually guided reaching for objects (optic ataxia), and most likely impaired ability to shift her visual attention so as to direct saccades to targets in her field of view (oculomotor apraxia or ocular apraxia). The last three signs constitute Bálint syndrome, which localizes to disruption of dorsal visual networks (i.e., dorsal stream) with key nodes in the posterior parietal and prefrontal cortices bilaterally ( 5 ). She has additional salient symptoms and signs suggesting left inferior parietal dysfunction, including ideomotor limb apraxia and elements of Gerstmann syndrome, which comprises dysgraphia, acalculia, left-right confusion, and finger agnosia ( 6 ). Information was not included about whether she was explicitly examined for finger agnosia, but elements of her presentation suggested a more generalized disruption of body schema (i.e., her representation of the position and configuration of her body in space). Her less prominent impairment in lexical-semantic retrieval evidenced by impaired confrontation naming and category fluency likely localizes to the language network in the left hemisphere. Her impairments in attention and executive functions have less localizing value but would plausibly arise in the context of frontoparietal network dysfunction. At this point, it is unclear whether her impairment in episodic memory mostly reflects encoding and activation versus a rapid rate of forgetting (storage), as occurs in temporolimbic amnesia. Regardless, it does not appear to be the most salient feature of her presentation.

This localization, presenting with insidious onset and gradual progression, is characteristic of a PCA syndrome. If we apply consensus clinical diagnostic criteria proposed by a working group of experts, we find that our patient has many of the representative features of early disturbance of visual functions plus or minus other cognitive functions mediated by the posterior cerebral cortex ( Table 1 ) ( 7 ). Some functions such as limb apraxia also occur in corticobasal syndrome (CBS), a clinical syndrome defined initially in association with corticobasal degeneration (CBD) neuropathology, a 4-repeat tauopathy characterized by achromatic ballooned neurons, neuropil threads, and astrocytic plaques. However, our patient lacks other suggestive features of CBS, including extrapyramidal motor dysfunction (e.g., limb rigidity, bradykinesia, dystonia), myoclonus, and alien limb phenomenon ( Table 1 ) ( 8 ).

TABLE 1. Clinical features and neuropathological associations of posterior cortical atrophy and corticobasal syndrome

a Consensus diagnostic criteria for posterior cortical atrophy per Crutch et al. ( 7 ) require at least three cognitive features and relative sparing of anterograde memory, speech-nonvisual language functions, executive functions, behavior, and personality. Diagnostic criteria for probable corticobasal syndrome per Armstrong et al. ( 8 ) require asymmetric presentation of at least two motor features and at least two higher cortical features. AD=Alzheimer’s disease; CBD=corticobasal degeneration; FDG-PET=[ 18 ]F-fluorodexoxyglucose positron emission tomography; JCD=Jakob-Creutzfeldt disease; LBD=Lewy body disease; PSP=progressive supranuclear palsy; SPECT=single-photon emission computed tomography; TDP=TDP–43 proteinopathy.

TABLE 1. Clinical features and neuropathological associations of posterior cortical atrophy and corticobasal syndrome a

In addition to a standard laboratory work-up for cognitive impairment, it is important to determine whether imaging of the brain provides evidence of neurodegeneration in a topographical distribution consistent with the clinical presentation. A first step in most cases would be to obtain an MRI of the brain that includes a high-resolution T 1 -weighted MRI sequence to assess potential atrophy, a T 2 /fluid-attenuated inversion recovery (FLAIR) sequence to assess the burden of vascular disease and rule out less likely etiological considerations (e.g., infection, autoimmune-inflammatory, neoplasm), a diffusion-weighted sequence to rule out subacute infarcts and prion disease (more pertinent to subacute or rapidly progressive cases), and a T 2 *-gradient echo or susceptibility weighted sequence to examine for microhemorrhages and superficial siderosis.

A lumbar puncture would serve two purposes. First, it would allow for the assessment of inflammation that might occur in HE, as approximately 80% of cases have some abnormality of CSF (i.e., elevated protein, lymphocytic pleiocytosis, or oligoclonal bands) ( 9 ). Second, in selected circumstances—particularly in cases with atypical nonamnesic clinical presentations or early-onset dementia in which AD is in the neuropathological differential diagnosis—we frequently pursue AD biomarkers of molecular neuropathology ( 10 , 11 ). This is most frequently accomplished with CSF analysis of amyloid-β-42, total tau, and phosphorylated tau levels. Amyloid positron emission tomography (PET) imaging, and most recently tau PET imaging, represent additional options that are approved by the U.S. Food and Drug Administration for clinical use. However, insurance often does not cover amyloid PET and currently does not reimburse tau PET imaging. [ 18 ]-F-fluorodeoxyglucose (FDG) PET and perfusion single-photon emission computed tomography imaging may provide indirect evidence for AD neuropathology via a pattern of hypometabolism or hypoperfusion involving the temporoparietal and posterior cingulate regions, though without molecular specificity. Pertinent to this case, a syndromic diagnosis of PCA is most commonly associated with underlying AD neuropathology—that is, plaques containing amyloid-β and neurofibrillary tangles containing tau ( 12 – 15 ).

The patient underwent MRI, demonstrating a minimal burden of T 2 /FLAIR hyperintensities and some degree of bilateral parietal volume loss with a left greater than right predominance ( Figure 2A ). There was relatively minimal medial temporal volume loss. Her basic laboratory work-up, including thyroid function, vitamin B 12 level, and treponemal antibody, was normal. She underwent a lumbar puncture; CSF studies revealed normal cell counts, protein, and glucose levels and low amyloid-β-42 levels at 165.9 pg/ml [>500 pg/ml] and elevated total and phosphorylated tau levels at 1,553 pg/ml [<350 pg/ml] and 200.4 pg/ml [<61 pg/ml], respectively.

FIGURE 2. MRI brain scan of the patient at presentation and 4 years later a

a Arrows denote regions of significant atrophy.

Considering This Additional Data, What Would Be an Appropriate Diagnostic Formulation?

For optimal clarity, we aim to provide a three-tiered approach to diagnosis comprising neurodegenerative clinical syndrome (e.g., primary amnesic, mixed amnesic and dysexecutive, primary progressive aphasia), level of severity (i.e., mild cognitive impairment; mild, moderate or severe dementia), and predicted underlying neuropathology (e.g., AD, Lewy body disease [LBD], frontotemporal lobar degeneration) ( 16 ). This approach avoids problematic conflations that cause confusion, for example when people equate AD with memory loss or dementia, whereas AD most strictly describes the neuropathology of plaques and tangles, regardless of the patient’s clinical symptoms and severity. This framework is important because there is never an exclusive, one-to-one correspondence between syndromic and neuropathological diagnosis. Syndromes arise from neurodegeneration that starts focally and progresses along the anatomical lines of large-scale brain networks that can be defined on the basis of both structural and functional connectivity, a concept detailed in the network degeneration hypothesis ( 17 ). It is important to note that neuropathologies defined on the basis of specific misfolded protein inclusions can target more than one large-scale network, and any given large-scale network can degenerate in association with more than one neuropathology.

The MRI results in this case support a syndromic diagnosis of PCA, with a posteriorly predominant pattern of atrophy. Given the patient’s loss of independent functioning in instrumental activities of daily living (ADLs), including driving and managing her finances, the patient would be characterized as having a dementia (also known as major neurocognitive disorder). The preservation of basic ADLs would suggest that the dementia was of mild severity. The CSF results provide supportive evidence for AD amyloid plaque and tau neurofibrillary tangle (NFT) neuropathology over other pathologies potentially associated with PCA syndrome (i.e., CBD, LBD, TDP-43 proteinopathy, and Jakob-Creutzfeldt disease) ( 13 , 14 ). The patient’s formulation would thus be best summarized as PCA at a level of mild dementia, likely associated with underlying AD neuropathology.

The patient’s symptoms progressed. One year after initial presentation, she had difficulty locating the buttons on her clothing or the food on her plate. Her word-finding difficulties worsened. Others observed stiffness of her right arm, a new symptom that was not present initially. She also had decreased ability using her right hand to hold everyday objects such as a comb, a brush, or a pen. On exam, she was noted to have rigidity of her right arm, impaired dexterity with her right hand for fine motor tasks, and a symmetrical tremor of the arms, apparent when holding objects or reaching. Her right hand would also intermittently assume a flexed, dystonic posture and would sometime move in complex ways without her having a sense of volitional control.

Four to 5 years after initial presentation, her functional status declined to the point where she was unable to feed, bathe, or dress herself. She was unable to follow simple instructions. She developed neuropsychiatric symptoms, including compulsive behaviors, anxiety, and apathy. Her right-sided motor symptoms progressed; she spent much of the time with her right arm flexed in abnormal postures or moving abnormally. She developed myoclonus of both arms. Her speech became slurred and monosyllabic. Her gait became less steady. She underwent a second MRI of the brain, demonstrating progressive bilateral atrophy involving the frontal and occipital lobes in addition to the parietal lobes and with more left > right asymmetry than was previously apparent ( Figure 2B ). Over time, she exhibited increasing weight loss. She was enrolled in hospice and ultimately passed away 8 years from the onset of symptoms.

Does Information About the Longitudinal Course of Her Illness Alter the Formulation About the Most Likely Underlying Neuropathological Process?

This patient developed clinical features characteristic of corticobasal syndrome over the longitudinal course of her disease. With time, it became apparent that she had lost volitional control over her right arm (characteristic of an alien limb phenomenon), and she developed signs more suggestive of basal ganglionic involvement (i.e., limb rigidity and possible dystonia). This presentation highlights the frequent overlap between neurodegenerative clinical syndromes; any given person may have elements of more than one syndrome, especially later in the course of a disease. In many instances, symptomatic features that are less prominent at presentation but evolve and progress can provide clues regarding the underlying neuropathological diagnosis. For example, a patient with primary progressive apraxia of speech or nonfluent-agrammatic primary progressive aphasia could develop the motor features of a progressive supranuclear palsy (PSP) clinical syndrome (e.g., supranuclear gaze impairment, axial rigidity, postural instability), which would suggest underlying PSP neuropathology (4-repeat tauopathy characterized by globose neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies).

If CSF biomarker data were not suggestive of AD, the secondary elements of CBS would substantially increase the likelihood of underlying CBD neuropathology presenting with a PCA syndrome and evolving to a mixed PCA-CBS. But the CSF amyloid and tau levels are unambiguously suggestive of AD (i.e., very low amyloid-β-42 and very high p-tau levels), the neuropathology of which accounts for not only a vast majority of PCA presentations but also roughly a quarter of cases presenting with CBS ( 18 , 19 ). Thus, underlying AD appears most likely.

NEUROPATHOLOGY

On gross examination, the brain weighed 1,150 g, slightly less than the lower end of normal at 1,200 g. External examination demonstrated mild cortical atrophy with widening of the sulci, relatively symmetrical and uniform throughout the brain ( Figure 3A ). There was no evidence of atrophy of the brainstem or cerebellum. On cut sections, the hippocampus was mildly atrophic. The substantia nigra in the midbrain was intact, showing appropriate dark pigmentation as would be seen in a relatively normal brain. The remainder of the gross examination was unremarkable.

FIGURE 3. Mild cortical atrophy with posterior predominance and neurofibrillary tangles, granulovacuolar degeneration, and a Hirano body a

a Panel A shows the gross view of the brain, demonstrating mild cortical atrophy with posterior predominance (arrow). Panel B shows the hematoxylin and eosin of the hippocampus at high power, demonstrating neurofibrillary tangles, granulovacuolar degeneration, and a Hirano body.

Histological examination confirmed that the neurons in the substantia nigra were appropriately pigmented, with occasional extraneuronal neuromelanin and moderate neuronal loss. In the nucleus basalis of Meynert, NFTs were apparent on hematoxylin and eosin staining as dense fibrillar eosinophilic structures in the neuronal cytoplasm, confirmed by tau immunohistochemistry (IHC; Figure 4 ). Low-power examination of the hippocampus revealed neuronal loss in the subiculum and in Ammon’s horn, most pronounced in the cornu ammonis 1 (CA1) subfield, with a relatively intact neuronal population in the dentate gyrus. Higher power examination with hematoxylin and eosin demonstrated numerous NFTs, neurons exhibiting granulovacuolar degeneration, and Hirano bodies ( Figure 3B ). Tau IHC confirmed numerous NFTs in the CA1 region and the subiculum. Amyloid-β IHC demonstrated occasional amyloid plaques in this region, less abundant than tau pathology. An α-synuclein stain revealed scattered Lewy bodies in the hippocampus and in the amygdala.

FIGURE 4. Tau immunohistochemistry demonstrating neurofibrillary tangles (staining brown) in the nucleus basalis of Meynert, in the hippocampus, and in the cerebral cortex of the frontal, temporal, parietal, and occipital lobes

In the neocortex, tau IHC highlighted the extent of the NFTs, which were very prominent in all of the lobes from which sections were taken: frontal, temporal, parietal and occipital. Numerous plaques on amyloid-β stain were likewise present in all cortical regions examined. The tau pathology was confined to the gray matter, sparing white matter. There were no ballooned neurons and no astrocytic plaques—two findings one would expect to see in CBD ( Table 2 ).

TABLE 2. Neuropathological features of this case compared with a case of corticobasal degeneration

a AD=Alzheimer’s disease; CBD=corticobasal degeneration; CBS=corticobasal syndrome; PCA=posterior cortical atrophy.

TABLE 2. Neuropathological features of this case compared with a case of corticobasal degeneration a

The case was designated by the neuropathology division as Alzheimer’s-type pathology, Braak stage V–VI (of VI), due to the widespread neocortical tau pathology, with LBD primarily in the limbic areas.

Our patient had AD neuropathology presenting atypically with a young age at onset (52 years old) and a predominantly visual-spatial and corticobasal syndrome as opposed to prominent amnesia. Syndromic diversity is a well-recognized phenomenon in AD. Nonamnesic presentations include not only PCA and CBS but also the logopenic variant of primary progressive aphasia and a behavioral-dysexecutive syndrome ( 20 ). Converging lines of evidence link the topographical distribution of NFTs with syndromic presentations and the pattern of hypometabolism and cortical atrophy. Neuropathological case reports and case series suggest that atypical AD syndromes arise in the setting of higher than normal densities of NFTs in networks subserving the functions compromised, including visual association areas in PCA-AD ( 21 ), the language network in PPA-AD ( 22 ), and frontal regions in behavioral-dysexecutive AD ( 23 ). In a large sample of close to 900 cases of pathologically diagnosed AD employing quantitative assessment of NFT density and distribution in selected neocortical and hippocampal regions, 25% of cases did not conform to a typical distribution of NFTs characterized in the Braak staging scheme ( 24 ). A subset of cases classified as hippocampal sparing with higher density of NFTs in the neocortex and lower density of NFTs in the hippocampus had a younger mean age at onset, higher frequency of atypical (nonamnesic) presentations, and more rapid rate of longitudinal decline than subsets defined as typical or limbic-predominant.

Tau PET, which detects the spatial distribution of fibrillary tau present in NFTs, has corroborated postmortem work in demonstrating distinct patterns of tracer uptake in different subtypes of AD defined by clinical symptoms and topographical distributions of atrophy ( 25 – 28 ). Amyloid PET, which detects the spatial distribution of fibrillar amyloid- β found in amyloid plaques, does not distinguish between typical and atypical AD ( 29 , 30 ). In a longitudinal study of 32 patients at early symptomatic stages of AD, the baseline topography of tau PET signal predicted subsequent atrophy on MRI at the single patient level, independent of baseline cortical thickness ( 31 ). This correlation was strongest in early-onset AD patients, who also tended to have higher tau signal and more rapid progression of atrophy than late-onset AD patients.

Differential vulnerability of selected large-scale brain networks in AD and in neurodegenerative disease more broadly remains poorly understood. There is evidence to support multiple mechanisms that are not mutually exclusive, including metabolic stress to key network nodes, trophic failure, transneuronal spread of pathological proteins (i.e., prion-like mechanisms), and shared vulnerability within network regions based on genetic or developmental factors ( 32 ). In the case of AD, cortical hub regions with high intrinsic functional connectivity to other regions across the brain appear to have high metabolic rates across the lifespan and to be foci of convergence of amyloid-β and tau accumulation ( 33 , 34 ). Tau NFT pathology appears to spread temporally along connected networks within the brain ( 35 ). Patients with primary progressive aphasia are more likely to have a personal or family history of developmental language-based learning disability ( 36 ), and patients with PCA are more likely to have a personal history of mathematical or visuospatial learning disability ( 37 ).

This case highlights the symptomatic heterogeneity in AD and the value of a three-tiered approach to diagnostic formulation in neurodegenerative presentations. It is important to remember that not all AD presents with amnesia and that early-onset AD tends to be more atypical and to progress more rapidly than late-onset AD. Multiple lines of evidence support a relationship between the burden and topographical distribution of tau NFT neuropathology and clinical symptomatology in AD, instantiating network-based neurodegeneration via mechanisms under ongoing investigation.

The authors report no financial relationships with commercial interests.

Supported by NIH grants K08 AG065502 (to Dr. Miller) and T32 HL007627 (to Dr. Miller).

The authors have confirmed that details of the case have been disguised to protect patient privacy.

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• Jeffrey Maneval , M.D. ,
• Kirk R. Daffner , M.D. ,
• Scott M. McGinnis , M.D.
• Seth A. Gale , M.A., M.D. ,
• C. Alan Anderson , M.D. ,
• David B. Arciniegas , M.D.

• Posterior Cortical Atrophy
• Corticobasal Syndrome
• Atypical Alzheimer Disease
• Network Degeneration

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Journal of Depression and Therapy

Current Issue Volume No: 1 Issue No: 2

Cognitive Behavior Therapy in The School Setting: A Case Study of A Nine Year Old Anxious Boy with Extreme Blushing

Francine c. jellesma  1  .

1 Research Institute Child Development and Education

Within the field of school psychology there is a gap between research and practice, caused by difficulties in translating the programs from research to the realities of the school setting. Illustrations of real-life cases may help school psychologists gain insight into the application of interventions. The purpose of this study was to describe an example of small group cognitive behavior therapy in the school setting. It concerned test anxiety with extreme blushing. A single subject case study of a nine year old Dutch boy was described. Interviews, observations and questionnaires were used for evaluation, as well as a standard national achievement test. The results indicate that the test anxiety and blushing decreased and on the achievement test three years later, performance was good.  As it concerns a case study, the results are discussed tentatively. It was concluded that the intervention was successful without alterations to the program. This study provides an illustration of research put into practice.

Author Contributions

Academic Editor: Addo Boafo, Royal Institute of mental health research

Checked for plagiarism: Yes

Review by: Single-blind

Copyright ©  2017 Francine C.Jellesma,et al.

The authors have declared that no competing interests exist.

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Introduction

This article describes a successful intervention for a nine year old boy presenting emerging test anxiety and extreme blushing. The treatment consisted of a group-based cognitive therapy (CBT) in the school setting. This case-study illustrates how CBT can be applied within primary school addressing test anxiety when the concern is not only on the level of an emerging mental health problem, but also on a specific symptom. Mental health problems are a major concern in primary education because they negatively affect socio-emotional as well as academic school functioning. Within the ecological context perspective of Bronfenbrenner schools represent a key component of the child’s microsystem: they are one of the most proximal influences on a child, and understandably, represent the primary setting where children show impairment due to mental health problems 1 . Research demonstrates that school-based cognitive-behavioral interventions that focus on small groups or individual students yield improvements in emotional, behavioral, social, and academic functioning 2 . Nevertheless, within the field of school psychology there is a gap between research and practice that seems to be caused by difficulties in translating the programs from research to the realities of the school setting 3 . Illustrations of real-life cases may help school psychologists gain insight into the application of interventions.

Test anxiety refers to feeling tense, fearful, and worried in evaluative situations 4 . It has formally been defined by Dusek as an “unpleasant feeling or emotional state that has physiological and behavioral concomitants and that is experienced in formal testing or other evaluative situations” (p.88) 5 . It has been estimated that between 10% to 40% of all students suffer from various levels of test anxiety 6 . In the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; 7 ), test anxiety is included indirectly as: “Individuals with Social Phobia often underachieve in school due to test anxiety(…)”. Bögels et al. argue that pervasive test anxiety is a form of social phobia (or social anxiety disorder), if fear of negative evaluation by others is the core issue, as was true for the current case 8 . Test anxiety poses students at risk for underperformance on achievement tests, poor grades, repeating a grade and school drop-out 9 , 10 , 11 , 12 . As such, it is important for schools to reduce test anxiety in their students effectively 13 .

Blushing can be one of the symptoms of test anxiety 7 . According to the communicative account of blushing, blushing has a remedial function. It communicates to observers that one is sensitive to their judgment 14 . Experimental research shows that blushing causes others to make more favorable appraisals. A blushing person is considered to be more trustworthy, less responsible for violating a norm and more friendly compared to a person that does not blush, but for example only shows shame 15 . Despite these positive effects, blushing is involuntary and uncontrollable and signals to others the presence of emotions that a person perhaps would like to suppress. The social blushing theory states that blushing occurs when a person receives undesired social attention 16 . Particularly in young people, blushing is a bodily symptom that can occur in situations of increased self-consciousness 17 , and these situations are common for children with test anxiety. Further, it is important to note that blushing is not only an especially salient physiological reaction (feeling warm cheeks), it is also clearly observable to others. As blushing often occurs in situations where one would rather not increase the attention of others, blushing can be highly aversive and for anxious individuals it can become a source of shame and anxiety in its own right 18 .

In the case presented in this article, a nine year old boy was referred to the school psychologist because the teacher noticed that his learning was impaired by a fear of failure. Whereas the teacher felt it was important for him to be able to concentrate on learning; the boy and his family concentrated on the experienced worries, fears, nervousness and extreme blushing. In other words, the important outcomes were: reduction of test anxiety, blushing and the more indirect outcome of school achievement. An important question of the case study was whether the blushing would be reduced by a CBT that was focused on test anxiety. This was the expectation because, not only is CBT one of the interventions that is recommended for treating test anxiety 13 , 19 ; Drummond and Su argue that anxiety management strategies in clinical settings reduce fear of blushing and blushing itself 20 . They demonstrated that social anxiety rather than expected or perceived blushing can increase facial blood flow during embarrassment. Therefore, reduction of anxiety should also lead to subsiding of the blushing.

Importance of this Study

In general, case studies are important because they help make something being discussed more realistic for teachers, school boards, and others. Case studies help people to see that what they have learned or read about a subject is not purely theoretical but instead can serve to create practical solutions to real dilemmas. With respect to interventions in schools, there is discussion about the use of existing programs because people sometimes reason that those problems are unlikely to be successful for a specific case or child 3 . The thought is that the child is an individual that in some aspects departs from the population of children for which the program was developed. Protocols and programs are seen as cookie-cutter approaches that in practice are unfit. With the current study, an example of a program put into practice for a specific child that departs from peers with test anxiety because of the extreme blushing, provides a clear example that CBT can be followed effectively and can meet specific individual needs.

Case Representation

Tim was a nine year old boy from a two-parent family of average social economic status. He lived with his parents and younger brother near his school in a small town in the Netherlands. Tim had entered school at age 4, which is common in the Netherlands where kindergarten and primary school are integrated.

Referral Information

The fourth grade teacher referred Tim to the care coordinator (CC) of the school because she noticed that he displayed clear signs of distress (frequent, visible blushing and expressions of worry) and that his learning progress was unexpectedly low. The CC discussed the referral with Tim’s parents who confirmed that Tim seemed to be bothered a lot by fear of failure and associated distress. The parents agreed for Tim to be seen by the school psychologist (i.e., author of the paper). In order to remain objectively, all assessments and observations were discussed with a second person, a social worker, who also co-observed the second last session of the therapy.

Tim and his parents were interviewed separately from each other using a semi-structured interview. Tim explained that he was very nervous at school before and during tests, and when speaking in front of the class or several classmates. His major concern was that he blushed frequently. According to Tim: “It happens all the time and I get really embarrassed”. Tim said that he would like to show more initiative in certain situations, such as playing a game, but that his shyness and nervousness withheld him from doing so. With concern to his school work, Tim often felt unable to concentrate and had many worries (“I think I will fail”, “I feel uncertain about the task”, “I think I might not be smart enough”).

Tim’s parents showed great involvement and his mother recognized some of the anxiety symptoms from her own youth. The parents confirmed that Tim was bothered frequently by his anxiety and felt helpless in not being able to reassure him. Tim’s parents knew that he blushed a lot at school whereas at home he was much more relaxed. The parents were discussing repetition of the fourth grade with the CC because of the little progress that Tim made during the school year. They thought that their son was “a sweet, open and bright boy”, but that his fears interfered with his ability to learn. They thought that Tim not only had low test scores, but also had actually learned less than he would have done when he had not been anxious. The symptoms seemed to have developed over a period of one year. The onset of test anxiety at this age falls within the normal range.

Tim completed two self-confidence subscales of the School Attitudes Questionnaire (SAQ; 21): expressive skills and self-confidence in examinations. The SAQ is a psychometrically sound and well-accepted diagnostic tool in the Dutch educational system. Each of the SAQ items consisted of a proposition, and the participant is asked to judge if the proposition is applicable to himself or herself on a short Likert-type response scale that has three options: that is the case , I don’t know , and that is not the case . Construct validity and reliability of these scales are good 21 . In comparison to the norm scores, Tim showed confidence well below the average (stanine 3) on the self-confidence in examinations scale (an example of an item is: During a school test I am usually calm and able to work with concentration ) and extremely low (stanine 1) on the expression scale (an example of an item is: I get shy when everyone in the classroom suddenly looks at me ).

Treatment Plan

In this study, a Dutch program was used entitled “Je kunt meer dan je denkt” (literally translated to “You can do more than you think”, a Dutch expression meaning that you shouldn’t underestimate your abilities). It is a program for small groups of children aged 6-12. It consists of eight sessions and one booster session. The sessions took place in the two months prior to summer vacation and the booster session was given in the second week of the new school year. The intervention was given on Mondays directly after school, in the remedial teaching classroom of the school. Besides Tim, five other children participated: four girls (one of which was from the same classroom) and one boy, which was Tim’s nephew, who was in the third grade.

The core components of CBT are: teaching children to identify and label irrational thoughts and to replace them with positive self-statements or modify them by challenging their veracity (cognitive component); exposure and relaxation training (behavioral components) 22 . These components were integrated in each session, that consisted of: a summary of the last session, discussion of the homework, introduction of a new topic, relaxation exercises, exposure, a game, complimenting oneself (the children wrote down something that they were proud of), and reviewing the session. The exposure consisted of the children taking turns to stand in a puppet theater and talk about a predefined topic. The children were allowed to choose for how long they would talk and could choose to hide in the puppet theater. The games intended to allow children practice group presentations in a fun way. After each session, the children received a letter with a summery and a homework assignment.

Course of Treatment

In the first session, the psychologist introduced herself with a collage, then talked with the children about why they were in the intervention group and what they would like to learn. Tim said that he would like to become less anxious and that he wanted to ‘stop blushing so frequently’. He said: “I hate it when it happens. I feel it and I just know that my face is all red”. A story was told about a child with test anxiety and afterwards the children discussed what they recognized. Tim recognized the emotional, cognitive and physical symptoms that were included in the story. The rules were made together with the children. They were formulated positively (e.g., we are quiet when another person is talking, we are kind to each other). The children then did a game pretending animals in duo’s and the others had to guess. Tim complimented himself on making a rule. In reviewing the session, it was clear that Tim had experienced some nervousness, but nevertheless also felt sufficiently safe. While talking, Tim blushed several times.

The children had to introduce themselves with a collage that they had made as a homework assignment. Tim was clearly nervous when doing so, but the positive responses of the other children seemed to reassure him. The breathing exercise went really well. The exposure exercise was more difficult. Tim choose to present himself, and used two sentences. He was blushing. Afterwards a game with different types of moving (e.g., running, jumping) was played. Tim anxiously observed the behavior of the others, but during the game did become a bit more brave in his behavioral expression. He complimented himself on doing all the exercises.

Tim had successfully worked with the homework assignment (repeating the relaxation exercised). The topic explained and discussed was emotions. The children then played a game pretending they entered a bus, and each time all the passengers would show the same emotional expression as the child who entered. Tim really enjoyed the game. He asked if it could be repeated, which was done after the session was officially finished. The relaxation went well and during the exposure exercise Tim showed slightly more fun, although was still blushing. He answered a question of one of the girls. An exercise was done in which the children had to walk to the belonging emotion labels that were spread around the room while the psychologist mentioned short situations. Tim was able to explain his answers and showed emotional insight. Tim complimented himself on being kind. During the session Tim asked the other children whether he was blushing. He had to smile when one of the others told him that he did, but that it was cute.

Tim had spent a lot of work on his homework assignment collecting pictures from newspapers and magazines with emotions on them. The cognitive model of emotional response was explained and practiced using the smart board with several examples. After the relaxation and exposure exercise, the children also role-played several situations, thoughts and feelings according to the model. Tim again asked the other children whether he was blushing and opened up about his feelings of embarrassment when classmates laughed about him at moments of blushing. The more positive responses from his peers in the group seemed to help. He further was stimulated to try the relaxation techniques (which was homework again) at times when he felt he would blush. Tim complimented himself on cooperating so well.

This session, the children learned to discriminate between positive, helping thoughts and negative thoughts. Tim was quite able to make this distinction, but found it very hard to think of positive thoughts that he could use for his real-life examples. He accepted help from the other children. As a game, the children had to act crazy. Tim tried a few odd dancing steps, but mainly laughed which seemed to be his way to escape out of a situation he found uncomfortable. Nevertheless, during this session Tim did not blush. Tim complimented himself on getting hot chocolate for everyone at the start of the session.

In this session, the children further worked on replacing their negative thoughts. In the relaxation exercise, not only breathing and bodily techniques were used, but also dreaming about positive events. The game of the second session was repeated, but this time the children were asked to move in a way that corresponded with certain thoughts (e.g., I can do this!). Tim had worked on altering his thoughts and showed improvement in finding positive thoughts. Tim volunteered to be second in the exposure exercise. He complimented himself on being more present in the group. Tim had blushed only during the game.

The children learned that it is OK to make mistakes. Tim had also heard this message before by his parents and teacher and was very willing to share experiences with the other children. In the game children had to move objects in a circle without using their hands. The exposure went really well. Tim took several minutes. During the relaxation exercise, Tim was laughing with one of the girls. Tim had not blushed during this session. He complimented himself for helping others.

The topic was finding solutions for problems. Tim participated well. In the game the children worked together in two teams getting across the room in different ways and Tim showed some initiative, that he later complimented himself on. The exposure exercise went as well as the previous session. Tim felt sorry that it was the last session. Tim had not blushed.

End of program

After the eight sessions, the parents were given information about Tim’s progress. They also received advice on how to help Tim with relaxation and changing negative thoughts into helpful thoughts. In the booster session, the children received a reminder of all the techniques that they had learned. Tim enjoyed this session and made a relaxed impression.

Observations

Observations during the sessions revealed decreases in Tim’s anxiety and blushing. The parents were interviewed after the eight sessions and they felt that there was a significant decrease in Tim’s fear of failure. They still agreed that it would be best for Tim to repeat the fourth grade and had more faith that he would make progression now.

Interview with Tim

On the booster session, Tim was interviewed during the booster session. He was happy to share some positive experiences.. He said that he felt that although it was exciting to be in a class full of new children, he felt more secure than in the past and had already made some new friends. This was an expected improvement, as in the last session, Tim had explained that even thought his confidence in expression was low, he felt that he would be able to become more experienced and he seemed highly motivated to show more social initiative. Further, Tim now thought he blushed much less frequently and he explained that: “I now also know that a lot of children do not think it is stupid when I blush”. With schoolwork he found it easier to concentrate and he thought that he would become one of the brightest students of his classroom now he felt more confident.

Questionnaire

On the SAQ, Tim had shown an increase in confidence directly after the eight sessions: his self-confidence in examinations had become average (stanine 6) and his confidence on the expression scale had grown, but was still low (stanine 2). At the second post-intervention assessment (booster session), his confidence on both scales was above average (stanine 8 and 9 respectively). For a picture of the whole group improvement, the graphs of the raw scores of all children are presented in Figure 1

As can be seen, all children showed improvement on at least one of the two scales.

The reliable change index is a statistic that we can use to work out whether a change in an individual’s score is statistically significant, based on how reliable the measure is. It is defined as the change in a client’s score divided by the standard error of the difference for the test(s) being used. If the RCI is 1.96 or greater, then the difference is statistically significant (1.96 equates to the 95% confidence interval). For the scores of Tim, the improvement in self-confidence in examinations was significant on both occasions: RCI 1 = 5.22 and RCI 2 = 7.14, when compared to the pre-intervention measurement. The improvement between the first and second post-intervention assessment was significant as well (RCI = 2.24). Similarly, for Tim’s confidence on the expression scale, although the short time improvement was clinically small (from a stanine 1 to a stanine 2), it was significant (RCI 1 = 3.08) and the improvement on the second post-intervention assessment was also significant RCI 2 = 10.77. The improvement between the first and second post-intervention assessment of expression confidence was significant as well (RCI = 7.69).

Interview with the Teacher

For the long term evaluation of Tim’s success, Tim’s sixth grade teacher was interviewed three years later. This is the last grade of primary school in the Netherlands. Tim’s teacher said that she knew Tim as a very gentle and kind boy. He did not seem anxious and there were no signs of test anxiety or social inhibition. According to the teacher: “Tim can sometimes feel a bit shy in new, social situations, but then he is able to discuss this.” The teacher did not notice any blushing in Tim anymore.

School Advice

For the final outcome, Tim’s academic success, we looked at his performance on the official national test that children take in the sixth and that is used to inform the parents and the school about the child’s appropriate high school level (in combination with the impression that the school has formed). On this test, Tim received advice to go to senior general secondary education (HAVO) , which qualifies students to enter higher professional education (HBO).

In this study, it was investigated what the effects of a small group CBT were for a case of test anxiety with extreme blushing. The current paper described the improvements of Tim during a program that was given in weekly sessions. Multiple informants and methods provided information that supported that the program was sufficient for both the anxiety as well as the blushing. The positive effect on the school achievement was also supported. The findings therefore confirmed our hypotheses.

With respect to the blushing, it was found that no adjustments to the program needed to be made. The blushing was, however, given attention to in response to initiatives of Tim to share his feelings on this topic. Within the small group CBT there it was possible for all children to share their thoughts and feelings and specific concerns. This may be a factor that is essential to meet the specific needs of all children in a group based program. For this purpose, it seems essential to create a therapeutic environment that feels safe and secure 23 . The relationship with the psychologist 24 , but also feelings of safety and friendship between the children should be fostered as these aspects are an important precondition for emotional disclosure in school-aged children 25 . Making positive rules together with the children (e.g., ‘We listen to each other’) and verbally reinforcing prosocial behavior are concrete examples of how this can be established.

The improvement in Tim’s confidence in expressing himself in the presence of others showed a ‘sleeper effect’ (i.e., a delayed effect of treatment) 26 . This effect might have occurred because Tim needed more practice and positive experiences before an increase in confidence could be achieved. During the treatment, Tim already showed great improvement in the exposure exercise, but there are many different situations in which expression oneself for an audience is needed (e.g., getting a turn in class or being invited for a social event). What is interesting is that Tim already expressed self-assurance in using the learned techniques in order to become more confident directly after the program. When the results of an intervention seem to be disappointing, it therefore might be informative to ask children about their faith in further improvement and to monitor this.

In conclusion, this case study is an illustrative example of how small group CBT can be applied in the school setting. The gap between research and practice needs to be narrowed because the school setting can have a great impact on a child and is also an important setting where children present mental health problems. The current problem of test anxiety is a clear example of this. The success of the intervention supports the possibilities of schools in fostering a healthy socio-emotional development in children.

Acknowledgements

With thanks to the child, parents and school to give their permissions. There were no conflicts of interest for the author of this paper. She was working on a voluntary basis.

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Assessment and Case Formulation in Cognitive Behavioural Therapy

• Sarah Corrie
• Michael Townend - University of Derby, UK
• Adrian Cockx - Community Psychiatric Nurse
• Description

Offering a unique philosophical, theoretical and process-focused introduction to one of the cornerstones of CBT: assessment and case formulation. Updated and expanded to take account of the vast developments in the field of CBT since its first publication, this second edition follows a clear two part structure:  - Part One introduces trainees to the key theory, practice and processes of assessment and case formulation  - Part Two provides practical illustrations of the theory through 12 extended case studies, considering both ‘simple’ and ‘complex’ presenting issues. Each of these chapters follows a set structure to enable easy comparison.

Offering all they need to know about this crucial part of their training, this is essential reading for trainees on any CBT course. 

See what’s new to this edition by selecting the Features tab on this page. Should you need additional information or have questions regarding the HEOA information provided for this title, including what is new to this edition, please email [email protected] . Please include your name, contact information, and the name of the title for which you would like more information. For information on the HEOA, please go to http://ed.gov/policy/highered/leg/hea08/index.html .

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This book offers clear but comprehensive explanations and guidance of the assessment process and the essential components of case conceptualizations. It provides useful and easy to follow case formulations, illustrated with realistic case studies. A very useful book for all CBT therapist and a must have for all CBT trainees.

Very relevant to practitioner training. Good resource for guiding decision making around formulation of client problems.

One I have used extensively when researching for our CBT course. Accessible and informative, giving examples which help illustrate the points raised, Essential.

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Cognitive Behaviour Therapy Case Studies

• Mike Thomas - University of Chester, UK
• Mandy Drake - University of Chester, UK
• Description

This distinctive practical format is ideal in showing how to put the principles of CBT and stepped care into effect. As well as echoing postgraduate level training, it provides an insight into the experiences the trainee will encounter in real-world practice. Each chapter addresses a specific client condition and covers initial referral, presentation and assessment, case formulation, treatment interventions, evaluation of CBT strategies and discharge planning. Specific presenting problems covered include:

- First onset and chronic Depression

- Social Phobia

- Obsessive-Compulsive Disorder

- Generalised Anxiety Disorder (GAD)

- Chronic Bulimia Nervosa and Anorexia nervosa

- Alcohol Addiction

- Personality Disorder

'This text is more than a cook book representation of CBT - it shows how some real-world creative work can be done'. - Michael Worrell, Consultant Clinical Psychologist & Programme Director CBT Training Programmes, CNWL Foundation Trust and Royal Holloway University of London

The contributors describe therapy experiences with people with problems ranging from depression and specific anxiety problems to personality disorder, and offer reflections on progress, as well as learning exercises and tips for clinical practice. 

Great resource for use in skills sessions. Provides more in-depth case studies that we can use across a number of courses.

This book helped my studetns explore real case and debate real solutions.

Excellent case studies for teaching, diverse range of clients and issues.

This is a good book for students to be aware of, when looking at the interventions for working with people with mental health problems.

This is an excellent text book, it gives a step by step guide for lecturers and students alike and is a must for every CBT practitioner.

Great text with well illustrated case examples for a range of different disorders.

As a lecturer I have found it's material useful in case discussions, formulations and role plays for students.

This is a good book. Being a researcher myself in the writings of case studies according to the CBT framework, I find this book essential for my students for they will be able to grasp not only the basics of how to write a CBT case study, but also to comprehend the elements which such research is constituted by

This is an excellent resource. Professor Thomas' in-depth knowledge of CBT enables him to present realistic case-studies. The introductory chapters provide a contemporary view of CBT before we are provided with detailed and varied case histories. I particularly liked the addition of a critique of each case study.

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A Counselling Case Study Using CBT

Jocelyn works as a Human Resources Manager for a large international organisation. She is becoming more and more stressed at work as the company is constantly changing and evolving. It is a requirement of her job that she keeps up with this change by implementing new strategies as well as ensuring focus is kept on her main role of headhunting new employees.

She finds that she is working twelve-hour days, six days a week and doesn’t have time for her friends and family. She has started yelling at staff members when they ask her questions and when making small mistakes in their work. Concerned about her stress levels, Jocelyn decided to attend a counselling session.

Below is an extract from Jocelyn’s first session with her counsellor:

Transcript from counselling session

Counsellor: So Jocelyn, let’s spend a few minutes talking about the connection between your thoughts and your emotions. Can you think of some times this week when you were frustrated with work? Jocelyn : Yes, definitely. It was on Friday and I had just implemented a new policy for staff members. I had imagined that I would get a lot of phone calls about it because I always do but I ended up snapping at people over the phone. Counsellor : And how were you feeling at that time? Jocelyn : I felt quite stressed and also annoyed at other staff members because they didn’t understand the policy. Counsellor : And what was going through your mind? Jocelyn : I guess I was thinking that no-one appreciates what I do. Counsellor : Okay. You just identified what we call an automatic thought. Everyone has them. They are thoughts that immediately pop to mind without any effort on your part. Most of the time the thought occurs so quickly you don’t notice it but it has an impact on your emotions. It’s usually the emotion that you notice, rather than the thought. Often these automatic thoughts are distorted in some way but we usually don’t stop to question the validity of the thought. But today, that’s what we are going to do?

The counsellor proceeds to work through the cognitive behaviour process with Jocelyn as follow:

Step 1 – Identify the automatic thought

Together, the counsellor and Jocelyn identified Jocelyn’s automatic thought as: “No-one appreciates what I do”.

Step 2 – Question the validity of the automatic thought

To question the validity of Jocelyn’s automatic thought, the counsellor engages in the following dialogue:

Counsellor : Tell me Jocelyn, what is the effect of believing that ‘no-one appreciates you?’ Jocelyn : Well, it infuriates me! I feel so undervalued and it puts me in such a foul mood. Counsellor : Okay, now I’d just like you to think for a moment what could be the effect if you changed that way of thinking Jocelyn: You mean, if I didn’t think that ‘no-one appreciates me’? Counsellor : Yes. Jocelyn : I guess I’d be a lot happier in my job. Ha, ha, I’d probably be nicer to be around. I’d be less snappy, more patient.

Step 3 – Challenge core beliefs

To challenge Jocelyn’s core belief, the counsellor engages in the following dialogue:

Counsellor : Jocelyn, I’d like you to read through this list of common false beliefs and tell me if you relate to any of them (hands Jocelyn the list of common false beliefs). Jocelyn : (Reads list)Ah, yes,I can see how I relate to number four, ‘that it’s necessary to be competent and successful in all those things which are attempted’.That’s so true for me. Counsellor : The reason these are called “false beliefs” is because they are extreme ways of perceiving the world. They are black or white and ignore the shades of grey in between.

Applications of CBT

Cognitive approaches have been applied as means of treatment across a variety of presenting concerns and psychological conditions. Cognitive approaches emphasise the role of thought in the development and maintenance of unhelpful or distressing patterns of emotion or behaviour.

Beck originally applied his cognitive approach to the treatment of depression. Cognitive therapy has also been successfully used to treat such conditions as anxiety disorders, obsessive disorders, substance abuse, post-traumatic stress, eating disorders, dissociative identity disorder, chronic pain and many other clinical conditions. In addition, it has been widely utilised to assist clients in enhancing their coping skills and moderating extremes in unhelpful thinking.

• March 18, 2010
• Case Study , CBT , Counselling , Workplace
• Case Studies , Counselling Therapies , Workplace Issues

Comments: 11

I recently had a call (lifeline) from a young person with similar issues as Jocelyn so it was interresting to me to see that I was on the right track helping my client to change her thinking.

I am employed as a counselling psychologist in the dept. of professional studies for graduate students, it’s the way i had been challenging irrational beliefs students hold about themselves, & CBT helps a lot in improving their academic achievement, & helps my counselling to gain ground successfully.

it was a good case study helped a lot I as a student studying about case study on CBT patients !! thanks a lot

Thank you very much. it helped me as I am a student of basic counselling course.

I think the way the process is explained is very helpful.

It’s a very good article.Therapist explicitly challenged the automatic thought and could elicit it very well. CBT is more realistic and genuine. Great case study. Expect more such case details. Thanks.

I concur many students don’t fail exams because they don’t work hard but lack of confidence and negative self talk like I can never pass cbt is powerful in replacing the negative self talk

This type of case study is useful to know about the basic job awareness and what kind of stress the employee has. Mainly useful to know about the lot of information about counseling knowledge.

I am preparing for my internship in counseling and looking for case studies. I found this case study helpful and useful in how to utilize the CBT techniques when working with my potential clients. Thanks

what psychological theory would best help understand the client’s problems and how therapy from that theoretical standpoint will help them?

Cognitive Theory Behaviorism – Operant Conditioning Behaviorism – Classic Conditioning Psychoanalytic Theory Object Relations/Attachment Theory Existential Theory Humanistic Theory

As a psychology student this case study helped me alot in understanding the core values of CBT as well as how important of a role it is in counseling. Thank you!

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• Article Information

All HRs are adjusted for education, income, cohabitation, hypertension, diabetes, and thyroid disease at index date. “Never use” comprised women who had never received estrogen-progestin hormone treatment, including vaginal estrogen treatment, or progestin-only treatment (including the levonorgestrel-releasing intrauterine device) from aged 45 to 55 years until index date.

a For the comparison of different routes of administration and daily doses, only estradiol use was considered. Estradiol use composed approximately 90% of person-time with estrogen-only therapy.

eTable. Data Sources and Definitions

eReferences.

Data Sharing Statement

• Estrogen-Only Hormone Therapy and Dementia—Reply JAMA Comment & Response May 14, 2024 Nelsan Pourhadi, MD; Lina S. Mørch, PhD; Amani Meaidi, PhD
• Estrogen-Only Hormone Therapy and Dementia JAMA Comment & Response May 14, 2024 Madeline Wood Alexander, BA; Gillian Einstein, PhD; Jennifer S. Rabin, PhD, CPsych
• Estrogen-Only Hormone Therapy and Dementia JAMA Comment & Response May 14, 2024 Sarah Glynne, MBBS, MSc

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Pourhadi N , Mørch LS , Holm EA , Torp-Pedersen C , Meaidi A. Dementia in Women Using Estrogen-Only Therapy. JAMA. 2024;331(2):160–162. doi:10.1001/jama.2023.23784

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Dementia in Women Using Estrogen-Only Therapy

• 1 Danish Dementia Research Centre, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark
• 2 Cancer Surveillance and Pharmacoepidemiology, Danish Cancer Institute, Copenhagen, Denmark
• 3 Department of Medicine, Zealand University Hospital, Køge, Denmark
• 4 Department of Cardiology, Nordsjællands Hospital, Hillerød, Denmark
• Comment & Response Estrogen-Only Hormone Therapy and Dementia—Reply Nelsan Pourhadi, MD; Lina S. Mørch, PhD; Amani Meaidi, PhD JAMA
• Comment & Response Estrogen-Only Hormone Therapy and Dementia Madeline Wood Alexander, BA; Gillian Einstein, PhD; Jennifer S. Rabin, PhD, CPsych JAMA
• Comment & Response Estrogen-Only Hormone Therapy and Dementia Sarah Glynne, MBBS, MSc JAMA

Conjugated equine estrogen was associated with increased dementia risk in a randomized clinical trial of women who had undergone hysterectomy, aged 65 years and older in 1996 to 1999. 1 These findings are less relevant in contemporary clinical settings, where hormone therapy for vasomotor symptoms is initiated near menopause and short term. 2

We assessed association between estrogen-only use and dementia.

Using national Danish registers, we performed a nested case-control study of women with hysterectomy, aged 50 to 60 years in 2000, and without previous dementia, oophorectomy, or contraindications for menopausal hormone therapy (eTable in Supplement 1 ). Women were followed from January 1, 2000, until December 31, 2018, death, emigration, or an exclusion criterion.

In Denmark, dementia is typically diagnosed in hospital memory clinics, 3 although it can be diagnosed in primary care. Outcome was first-time diagnosis of all-cause dementia or prescription redemption of antidementia medication, the latter allowing identification of patients treated in primary care (eTable in Supplement 1 ). On date of dementia (index date), each case patient was incidence-density matched by birth year to 5 dementia-free control participants.

Estrogen-only use was assessed through prescriptions from 1995 until 2 years before index date to diminish potential reverse causation bias. Based on individual-level data on time, amount, route, and type of estrogen-only therapy, cumulative duration of use (≤5 years; >5 years) and mean daily dose (<2 mg; 2-<3 mg; ≥3 mg) were computed.

Conditional logistic regression was used to assess associations between cumulative duration of estrogen-only therapy and between dose and route of estradiol and incident dementia. The latter models included only estradiol because estrogens’ potencies vary. Reference group constituted never users of any hormone therapy.

Subanalyses assessed women solely exposed at aged 55 years or younger to assess current recommendations for hormone therapy use near menopause 2 and cases with specifically Alzheimer disease diagnosis. Models included age, education, income, cohabitation, thyroid disease, hypertension, and diabetes as potential confounders (eTable in Supplement 1 ).

Linear trend tests were performed to assess associations between dose and dementia 4 ; 95% CIs not crossing 1 and 2-sided P  < .05 defined statistical significance. R statistical software (R Core Team, 2020) was used. The Danish Data Protection Agency and The Danish Health Data Authority approved the study. Danish register-based studies do not require ethics approval or patient consent.

We followed 29 104 women with hysterectomy for 500 000 person-years. Median age at hysterectomy was 43 years (IQR, 39-47 years). During follow-up, 541 women developed dementia (Alzheimer disease, 92) and were matched to 2705 controls; 13.9% were identified only by use of antidementia medication. Median age at diagnosis was 70 years (IQR, 66-73 years) ( Table ). Estrogen-only users constituted 53.2% of cases and 45.0% of controls; users aged 55 years or younger constituted 15.6% and 12.3%, respectively. Median age at treatment initiation was 53 years (IQR, 51-54 years). Median treatment duration among users was 5.4 years (IQR, 1.3-8.8 years) for cases and 5.1 years (IQR, 1.7-8.6 years) for controls. Estradiol use composed 94% (9266 of 9858 person-years) of person-time with estrogen-only therapy, and of this, 81% (7487 person-years) was oral and 19% (1779 person-years) transdermal.

Estrogen-only vs never use was associated with increased dementia rate (hazard ratio [HR], 1.55; 95% CI, 1.25-1.93); HR was 1.49 (95% CI, 1.15-1.93) for 5 years use or less and 1.62 (95% CI, 1.25-2.09) for greater than 5 years’ use. Increasing daily estradiol dose yielded increasing HRs ( P trend < .003) ( Figure ). Oral estradiol HR was 1.62 (95% CI, 1.28-2.05); and transdermal, 1.39 (95% CI, 0.97-1.99).

The association persisted in women using estrogen only until a maximum of aged 55 years (HR, 1.58; 95% CI, 1.06-2.35). Alzheimer disease HR was 1.79 (95% CI, 0.99-3.23).

Estrogen-only use was associated with increased dementia rate even in women exposed near menopause, confirming findings from the large randomized clinical trial 1 but in a more contemporary population reflecting actual use.

Limitations include that residual confounding, including confounding by indication, could occur. Numbers of women receiving transdermal estradiol and higher doses were small. Alzheimer disease was underregistered because unspecific dementia diagnoses tended to be used during the study. An unknown number of patients with diagnoses and treatment by primary care without medications were missed, although these should not be differentially distributed among estrogen users and nonusers.

Studies are warranted to ascertain whether findings represent a causal link between estrogen-only use and dementia risk or predisposition among women needing therapy.

Accepted for Publication: October 28, 2023.

Published Online: December 18, 2023. doi:10.1001/jama.2023.23784

Corresponding Author: Nelsan Pourhadi, MD, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, Blegdamsvej 9, 2100 København Ø, Denmark ( [email protected] ).

Author Contributions: Drs Pourhadi and Meaidi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Pourhadi, Mørch, Torp-Pedersen, Meaidi.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Pourhadi, Meaidi.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Pourhadi, Torp-Pedersen, Meaidi.

Administrative, technical, or material support: Pourhadi, Torp-Pedersen, Meaidi.

Supervision: Mørch, Holm, Torp-Pedersen, Meaidi.

Conflict of Interest Disclosures: Dr Mørch reported receiving grants from Health Insurance “Denmark,” the Danish Cancer Society Scientific Committee, and Novo Nordisk outside the submitted work; and reported being vice chair of the Danish Society for Pharmacoepidemiology and a representative for the Nordic PharmacoEpidemiological Network. Dr Torp-Pedersen reported receiving grants from Bayer for a randomized study and grants from Novo Nordisk for an epidemiologic study outside the submitted work. No other disclosures were reported.

Data Sharing Statement: See Supplement 2 .

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• Cognitive rehab tied to MRI changes in cognition-linked brain regions

Findings may help explain why rehab leads to gains for some MS patients

by Lindsey Shapiro, PhD | June 12, 2024

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A three month cognitive rehabilitation program, with or without aerobic exercise, increased tissue volume and activity in brain regions linked to cognition among people with progressive forms of multiple sclerosis (MS), clinical trial data suggests.

The MRI findings offer potential biological explanations about why cognitive rehabilitation leads to cognitive gains for some MS patients, the researchers said in “ Cognitive rehabilitation effects on grey matter volume and Go-NoGo activity in progressive multiple sclerosis: results from the CogEx trial ,” which was published in the Journal of Neurology, Neurosurgery, & Psychiatry .

Cognitive impairment is common in MS and is thought to affect up to 65% of patients . But people with progressive types of MS often have more severe cognitive dysfunction than those with a relapsing-remitting disease course.

Both cognitive rehabilitation, involving activities to strengthen or restore cognitive abilities, and physical exercise have each been linked to cognitive improvements in MS patients, although their exact benefits are still being explored.

The CogEx trial (NCT03679468) examined the possible cognitive benefits of a combined cognitive rehabilitation and aerobic exercise approach among more than 300 people with progressive forms of MS, ages 25-65, who had existing impairments in information processing speed, a common type of cognitive issue in MS.

Healthy Connections in Brain May Be Needed for Cognitive Rehab

Cognitive rehab’s effect on gray matter.

The participants were randomly assigned to receive cognitive rehabilitation, aerobic exercise, cognitive rehabilitation with aerobic exercise, or neither, which they performed for 12 weeks and returned for another follow-up six months after stopping the intervention.

Cognitive rehabilitation involved computer-based brain tasks. In groups where cognitive rehabilitation wasn’t performed, patients performed a sham exercise involving basic internet searches/computer use. Aerobic exercise involved a step machine. The groups not assigned to aerobic exercise performed balance and stretching activities as a sham intervention.

The trial’s primary analysis showed that combining cognitive rehabilitation with aerobic exercise failed to improve cognitive performance relative to either intervention alone. A substantial number of patients did see improvements in information processing speed, however.

A subgroup of 104 participants also underwent MRI scans to look at changes in brain tissue volume and connectivity. The recent publication reports findings from that substudy.

Here, as in the broader study population, no differences were seen in cognitive performance between the different groups.

While most structural findings on MRI scans also didn’t differ by intervention, the volume of gray matter, which is brain tissue containing mainly nerve cell bodies, showed significant differences among the groups. These differences were largely driven by an increased gray matter volume over time in those who performed only cognitive rehabilitation.

Those who performed cognitive rehabilitation with or without aerobic exercise showed significant increases in gray matter volume across multiple brain regions relevant for cognition after 12 weeks. That contrasted with the groups that didn’t involve cognitive rehabilitation, where a general decrease in gray matter volume was observed. Gray matter is relevant for cognition and studies show its loss is associated with cognitive worsening in MS. For this reason, an increase “might be beneficial for cognitive performances,” the researchers said.

Indeed, in the groups performing cognitive rehabilitation, increased gray matter volume correlated with an improved performance in a test of verbal learning and memory.

Functional MRI scans were also performed to look at differences in brain activation and connectivity with the various interventions.

Cognitive rehabilitation was associated with increased activation of a brain region called the insula relative to groups that performed the sham computer activities at week 12. The insula is involved in attention and information processing, and its dysfunction has been linked to cognitive problems in MS.

While the study shows no “synergistic effect” of cognitive rehabilitation and aerobic exercise on cognitive performance or its MRI correlates, the findings do highlight that cognitive rehabilitation itself might lead to beneficial changes in brain regions linked to cognition that may explain cognitive improvements in some patients.

“Future studies exploring insular connectivity in this cohort may provide additional insights into changes taking place in the insular network post rehabilitation,” the researchers said.

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• > Volume 13
• > Integrating CBT and CFT within a case formulation approach...

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Integrating cbt and cft within a case formulation approach to reduce depression and anxiety in an older adult with a complex mental and physical health history: a single case study.

Published online by Cambridge University Press:  12 October 2020

Depression and anxiety are major contributors to growing healthcare costs in the UK, particularly with an increasingly ageing population. However, identification of mental health needs in older adults has been overshadowed by a tendency to focus on physical health issues, despite the established co-morbidity of depression, anxiety and physical health conditions. When older adults seek psychological support, treatment options may vary and may be time limited, either because of protocol guidance or due to the resource constraints of psychology services. Time-limited treatment, common in many adult services, may not best meet the needs of older adults, whose physical, cognitive and emotional needs alter with age. It is, therefore, important to identify treatments that best meet the needs of older adults who seek psychological support, but who may arrive with complex mental and physical health histories. This paper aims to explore how a case formulation-driven approach that draws on the theoretical underpinnings of cognitive behavioural therapy (CBT) and compassion-focused therapy (CFT) can be used to reduce anxiety and depression in an older adult with a complex multi-morbid mental and physical health history. This study employs a single-case (A–B) experimental design [assessment (A), CBT and CFT intervention (B)] over 28 sessions. Results suggest the greatest reductions in depression and anxiety (as measured using PHQ-9 and GAD-7) occurred during the CFT phase of the intervention, although scores failed to drop below subclinical levels in any phase of the intervention. This case highlights the value of incorporating CFT with CBT in case formulation-driven interventions.

(1) To consider the value of using case formulation approaches in older adult populations.

(2) To demonstrate flexibility in balancing evidence-based interventions with service user needs by incorporating CBT and CFT to treat anxiety and depression in an older adult.

(3) To present a clinical case to identify how assessment, formulation and treatment of anxiety and depression are adapted to best meet the needs of older adults with complex co-morbid mental and physical health conditions.

(4) To appreciate the impact of contextual factors, such as austerity measures, on therapeutic work with individuals with long-standing mental and physical health difficulties.

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• Nicola Birdsey (a1)
• DOI: https://doi.org/10.1017/S1754470X20000410

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• Indian J Psychiatry
• v.62(Suppl 2); 2020 Jan

Cognitive Behavioral Therapy for Depression

Manaswi gautam.

Consultant Psychiatrist Gautam Hospital and Research Center, Jaipur, Rajasthan, India

Adarsh Tripathi

1 Department of Psychiatry, King George's Medical University, Lucknow, Uttar Pradesh, India

Deepanjali Deshmukh

2 MGM Medical College, Aurangabad, Maharashtra, India

Manisha Gaur

3 Consultant Psychologist, Gaur Mental Health Clinic, Ajmer, Rajasthan, India

INTRODUCTION

Depressive disorders are one of the most common psychiatric disorders that occur in people of all ages across all world regions. Although it may present at any age however adolescence to early adults is the most common age of onset, and females are affected two times more in comparison to the males. Depressive disorders can occur as heterogeneous conditions in clinical scenario ranging from transient minor symptoms to severe and debilitating clinical conditions, causing severe social and occupational impairments. Usually, it presents with constellations of cognitive, emotional, behavioral, physiological, interpersonal, social, and occupational symptoms. The illness can be of various severities, and a significant proportion of the patients can have recurrent illness. Depression is also highly comorbid with several psychiatric and medical illnesses such as anxiety disorders, substance use, obsessive–compulsive disorder, diabetes, hypertension, and cardiovascular illnesses.

Major depressive disorders accounted for around 8.2% global years lived with disability (YLD) in 2010, and it was the second leading cause of the YLDs. In addition, they also contribute to the burden of several other disorders indirectly such as suicide and ischemic heart disease.[ 1 ]

EVIDENCE BASE FOR COGNITIVE BEHAVIORAL THERAPY IN DEPRESSION

Cognitive behavioral therapy (CBT) is one of the most evidence-based psychological interventions for the treatment of several psychiatric disorders such as depression, anxiety disorders, somatoform disorder, and substance use disorder. The uses are recently extended to psychotic disorders, behavioral medicine, marital discord, stressful life situations, and many other clinical conditions.

A sufficient number of researches have been conducted and shown the efficacy of CBT in depressive disorders. A meta-analysis of 115 studies has shown that CBT is an effective treatment strategy for depression and combined treatment with pharmacotherapy is significantly more effective than pharmacotherapy alone.[ 2 ] Evidence also suggests that relapse rate of patient treated with CBT is lower in comparison to the patients treated with pharmacotherapy alone.[ 3 ]

Treatment guidelines for the depression suggest that psychological interventions are effective and acceptable strategy for treatment. The psychological interventions are most commonly used for mild-to-moderate depressive episodes. As per the prevailing situations of India with regards to significant lesser availability of trained therapist in most of the places and patients preferences, the pharmacological interventions are offered as the first-line treatment modalities for treatment of depression.

Indication for Cognitive behavior therapy as enlisted in table 1 .

Indications for cognitive behavioral therapy (situations that can call for preferred use of the psychological interventions) are

CONTRAINDICATIONS FOR COGNITIVE BEHAVIORAL THERAPY

There is no absolute contraindication to CBT; however, it is often reported that clients with comorbid severe personality disorders such as antisocial personality disorders and subnormal intelligence are difficult to manage through CBT. Special training and expertise may be needed for the treatment of these clients.

Patient with severe depression with psychosis and/or suicidality might be difficult to manage with CBT alone and need medications and other treatment before considering CBT. Organicity should be ruled out using clinical evaluation and relevant investigations, as and when required.

There are many advantages of CBT in depression as given in table 2

Advantages of cognitive behavioral therapy in depression

CHOICE OF TREATMENT SETTINGS

CBT can be done on an Out Patient Department (OPD) basis with regular planned sessions. Each session lasts for about 45 min–1 h depending on the suitability for both patients and therapists. In specific situations, the CBT can be delivered in inpatient settings along with treatment as usual such as adjuvant treatment in severe depression, high risk for self-harm or suicidal patients, patients with multiple medical or psychiatric comorbidities and in patients hospitalized due to social reasons.

ASSESSMENT AND EVALUATION FOR THE THERAPY

A detail diagnostic assessment is needed for the assessment of psychopathology, premorbid personality, diagnosis, severity, presence of suicidal ideations, and comorbidities. Baseline assessment of severity using a brief scale will be helpful in mutual understanding of severity before starting therapy and also to track the progress. Clients during depressive illness often fail to recognize early improvement and undermine any positive change. Objective rating scale hence helps in pointing out the progress and can also help in determining agenda during therapy process. Beck Depression Inventory (A. T. Beck, Steer, and Brown, 1996), the Depression Anxiety Stress Scales (Lovibond and Lovibond, 1995), Montgomery-Asberg Depression Rating Scale, Hamilton Rating Scale for Depression are useful rating scales for this purpose. The assessment for CBT in depression is, however, different from diagnostic assessment.

THE USE OF COGNITIVE BEHAVIORAL THERAPY ACCORDING TO SEVERITY OF DEPRESSION

Various trials have shown the benefit of combined treatment for severe depression.

Combined therapy though costlier than monotherapy it provides cost-effectiveness in the form of relapse prevention.

Number of sessions depends on patient responsiveness.

Booster sessions might be required at the intervals of the 1–12 th month as per the clinical need.

A model for reference is given in table 3

The use of cognitive behavioral therapy according to the severity of depression

The general outline of CBT for depression has been discussed in table 4

Overview of cognitive behavioral therapy for depression

CBT – Cognitive behavioral therapy

COGNITIVE MODEL FOR DEPRESSION

Cognitive theory conceptualizes that people are not influenced by the events rather the view they take of the events. It essentially means that individual differences in the maladaptive thinking process and negative appraisal of the life events lead to the development of dysfunctional cognitive reactions. This cognitive dysfunction is in turn is responsible for the rest of the symptoms in affective and behavioral domains.

Aaron beck proposed a cognitive model of depression, and it is detailed in Figure 1 . Cognitive dysfunctions are of the following categories.

Cognitive behavioral therapy model of depression

• Schema - stable internal structure of information usually formed during early life, also include core belief about self
• information processing and intermediate belief are usually interpreted as rules of living and usually expressed in terms of “if and then” sentences
• Automatic thoughts - proximally related to everyday events and in depression, often reflects cognitive triad, i.e., negative view of oneself, world, and future.

Negative cognitive triad of depression as given beck is as following:

• I am helpless (helplessness)
• The future is bleak (hopelessness)
• I am worthless (worthlessness).

CHOICE OF THE PATIENT

Patient-related factors that facilitated response are.

• Psychological mindedness of patients: Patients who are able to understand and label their feelings and emotions generally respond better to CBT. Although some patients in the course of treatment learn those skills during treatment
• Intellectual level of the patient might also affect the overall effectiveness of the treatment
• Willingness and motivation on the part of patients: Although it is not prerequisite, patients who are motivated to analyze their feelings and ready to undergo various homework show a better response to treatment
• Patient preference is single most important factor: After initial assessment of the patient those who prefer psychological treatment can be offered CBT alone or in combination depending on type of depression
• Those with mild to moderate depression CBT can be recommended as a first line of treatment
• Patients with severe depression might need combination of both CBT and medications (and or other treatments)
• Special situations such as children and adolescents, pregnancy, lactation, female in fertile age group planning for pregnancy, medical comorbidities
• Inability to tolerate psychopharmacological treatment
• The presence of significant psychosocial factors, intrapsychic conflicts, and interpersonal difficulties.

Therapist related factors

• Availability of cognitive behavioral therapist/psychiatrist
• The ability of therapist to form therapeutic alliance with the patient.

CLINICAL INTERVIEW FOR COGNITIVE BEHAVIORAL THERAPY

Symptoms and associated cognitions.

Negative automatic thoughts both trigger and enhance depression. It might be helpful to identify unhealthy automatic thoughts associated with symptoms of depression.

Some common symptoms and associated automatic thoughts are given in table 5 .

Symptoms of depression and associated cognitions

Impact on functioning

it is important to know the extent and effect of depression on the overall functioning and interpersonal relationships.

Coping strategies

Sometimes patients with depression might have adapted a coping strategies which make them feel good for short duration (e.g., alcohol consumption) but might be unhealthy in long term.

Onset of current symptoms

Patient's perception about the situation at the onset of symptoms might provide useful information about underlying cognitive distortions.

Background information

Detailed history of patient is necessary, including patients premorbid personality.

The therapist should be able to do the cognitive case conceptualization for the patient as given in Figure 2 .

Case conceptualization for the cognitive model of depression

MANAGING TREATMENT

An outline of the breakup of typical session of CBT is given in table 6 .

Session structure of cognitive behavioral therapy

Starting treatment

First treatment interview has mainly four objectives:

• To establish a warm collaborative therapeutic alliance
• To list specific problem set and associated goals
• To psycho-educate patient regarding the cognitive model and vicious cycle that maintains the depression
• Give the patient idea about further treatment procedures.

CBT can be explained in the following headings

• Behavioral interventions

Working with negative automatic thoughts

• Ending session.

The first treatment interview has four main objectives:

• To establish a warm, collaborative therapeutic alliance
• To list specific problems and associated goals, and select a first problem to tackle
• To educate the patient about the cognitive model, especially the vicious circle that maintains depression
• To give the patient first-hand experience of the focused, workman-like, empirical style of CBT.

These convey two important messages: (1) It is possible to make sense of depression; (2) there is something the patient can do about it. These messages directly address hopelessness and helplessness.

• Identifying problems and goals:-The various problems faced by patients should be included in a list which can include symptoms of depression or social problems (e.g., family conflict). Developing this list at the end of the first session helps in planning treatment goals
• Introducing cognitive model of depression:- In the first session at least a basic idea about how our cognitions affect our emotions and behavior is taught to the patient. The data provided by patient can be used to give insight into behaviors
• Where to start:-Common treatment goal is agreed upon by patient and therapist, therapeutic alliance is of key importance in CBT. Appropriate homework assignment should be given to patient according to predecided goal.

Behavioural interventions

Reducing ruminations.

It has been seen that depressed patients spend a significant amount of time and attention focusing on their shortcomings. Making patient aware of those negative ruminations and consciously diverting attention toward certain positive aspects can be taught to patients.

Monitoring activities

Loss of interest in day to day activities is central to the depression. It has been seen that early behavioral intervention has been increased sense of autonomy in the patients.

Patients are taught to record each and every activity hour by hour on the activity schedule. Each activity is rated 0–10 for Pleasure (P) and Mastery (M). P ratings indicate how enjoyable the activity was, and M ratings how much of an achievement it was. Mostly depressed patients feel low on achievement all the time. Hence, M should be explained as “achievement how you felt at the time of doing.” Patients are instructed to rate activities immediately and not retrospectively.

Example of activity schedule is

Activity Chart Write in each box, activity performed and depression rating from 0-100% (0-minimal, 100-maximum)

Planning activities

Once the patient learns to self-monitor activities each day is planned in advance.

This helps patients by:

• This provides a structure and helps with setting priorities
• This avoids the need to keep making decisions about what to do next
• This changes perception from chaos to manageable tasks
• This increases the chances that activities will be carried out
• This enhances patients’ sense of control.

A plan for activities is made in such a way that both pleasure and mastery are balanced (e.g., ironing cloths followed by listening to music). The tasks which are generally avoided by patient can be divided into graded tasks.

The patient is taught to evaluate each and every day in detail also encouraged to keep the record of unhelpful negative thoughts regarding tasks.

Other important behavioral activities are:-

• Mindfulness meditation: Helps people stay grounded in the present by keeping away from ruminations
• Successive approximation: Breaking larger tasks into smaller tasks which are easy to accomplish
• Visualizing the best part of the day
• Pleasant activity scheduling.

Scheduling an activity in near future which one can look on with mastery and with sense of achievement.

The main tool for this negative automatic thought record.

Thought Record -1

Thought Record – 2

Identifying negative automatic thoughts

Patients learn to record upsetting incidents as soon as possible after they occur (delay makes it difficult to recall thoughts and feelings accurately). They learn:

• To identify unpleasant emotions (e.g., despair, anger, guilt), signs that negative thinking is present. Emotions are rated for intensity on a 0–100 scale. These ratings (though the patient may initially find them difficult) help to make small changes in emotional state obvious when the search for alternatives to negative thoughts begins. This is important since change is rarely all-or-nothing, and small improvements may otherwise be missed
• To identify the problem situation. What was the patient doing or thinking about when the painful emotion occurred (e.g., “waiting at the supermarket checkout,” “worrying about my husband being late home”)?
• To identify negative automatic thoughts associated with the unpleasant emotions. Sessions direct the therapist towards asking: “And what went through your mind at that moment?” Patients become aware of thoughts, images, or implicit meanings that are present when emotional shifts occur, and record. Belief in each thought is also rated on a 0%–100%.

Questioning negative automatic thoughts

Therapist can help patient to discover dysfunctional automatic thoughts through “guided discovery.”

• What is evidence?
• What are alternative views?
• What are advantages and disadvantages of this way of thinking?
• What are my thinking biases?

Common cognitive distortions are

• Black– and– white (also called all– or– nothing, polarized, or dichotomous thinking): Situations viewed in only two categories instead of on a continuum. Example: “If I don’t top the exams. I’m a failure”
• Fortune-telling (also called catastrophizing): Future is predicted negatively without considering other possible, more likely outcomes. Example: “I ll be so upset, i won’t be able to function at all”
• Disqualifying or discounting the positive: The person unreasonably tell oneself that positive experiences, deeds, or qualities do not count. Example: “I cracked the examl, but that doesn’t mean I’m competent; It was a fluke”
• Emotional reasoning: One thinks something must be true because he/she “feels” (actually believe) it so strongly, ignoring or discounting evidence to the contrary. Example: “I know I successfully complete most of my tasks, but I still feel like I’ m incompetent”
• Labeling: One puts a fixed, global label on oneself or others without considering that the evidence might more reasonably lead to a less disastrous conclusion. Example: “I’m a failure. He's not good enough”
• Magnification/minimization: When one evaluates oneself, another person, or a situation, one unreasonably magnifies the negative and/or minimizes the positive. Example: “Getting a C Grade in exams proves how mediocre I am. Getting high marks doesn’t mean I’m smart”
• Selective abstraction (also called mental filter): One pays undue attention to one's negative detail instead of seeing the whole picture. Example: “Because I got just passing marks in one subject in my examinations (which also contained distinctions in other subjects) it means I’m not a good student”
• Mind reading: One believes that he/she knows what others are thinking, failing to consider other, more likely possibilities. Example: “He assumes that his boss thinks that he is a novice for this assignment”
• Overgeneralization: One makes a negative conclusion that goes far beyond the current situation. Example: “(Because I felt uncomfortable at the meeting) I don’t have what it takes to be a group leader”
• Personalization: O ne believes others are behaving negatively because of him/her, without exploring alternative explanations for their behavior. Example: “The watchman didn’t smile at me because I did something wrong”
• Imperatives (also called “Should” and “must” statements): One has a precise, fixed idea of how one or others should behave, and they overestimate how bad it is that these expectations are not met with. Example: “It's terrible that I sneeze as I am a Gym Trainer”
• Tunnel vision: One only views the negative aspects of a situation. Example: “My subordinate can’t do anything right. He's callous, casual and insensitive towards his job.”

Testing negative automatic thoughts: What can I do now?

It is important that cognitive changes that are brought out by questioning are consolidated by behavior experiments.

Ending the treatment

CBT is time-limited goal-directed form of therapy. Hence, the patient is made aware about end of treatment in advance. This can be done through the following stages.

Dysfunctional assumptions identification

Consolidating learning blueprint.

• Preparation for the setback.

Once the patient is able to identify negative automatic thoughts. Before ending treatment patient patients should be made aware about dysfunctional assumptions.

• Where did this rule come from? Identifying the source of a dysfunctional assumption (e.g., parental criticism) often helps to encourage distance by suggesting that its development is understandable, though it may no longer be relevant or useful
• In what ways is the rule unrealistic? Dysfunctional assumptions do not fit the way the world works. They operate by extremes, which are reflected in their language (always/never rather than some of the time; must/should/ought rather than want/prefer/would like)
• In what ways is the rule helpful? Dysfunctional assumptions are not usually wholly negative in their effects. For example, perfectionism may lead to genuine, high-quality performance. If such advantages are not recognized and taken into account when new assumptions are formulated, the patient may be reluctant to move forward
• In what ways is the rule unhelpful? The advantages of dysfunctional assumptions are normally outweighed by their costs. Perfectionism leads to rewards, but it also undermines satisfaction with achievements and stops people learning from constructive criticism
• What alternative rule might be more realistic and helpful? Once the old assumption has been undermined, it is helpful to formulate an explicit alternative (e.g., "It is good to do things well, but I am only human-sometimes I make mistakes"). This provides a new guideline for living, rather than simply undermining the old system
• What needs to be done to consolidate the new rule? As with negative automatic thoughts, re-evaluation is best made real through experience: Behavioral experiments.

The patient should be able to summarize whatever he has learned throughout the sessions.

The following questions might help to set the framework:

• How did my problems develop? (unhelpful beliefs and assumptions, the experiences that led to their formation, events precipitating onset)
• What kept them going? (maintenance factors)
• What did I learn from therapy that helped? Techniques (e.g., activity scheduling) and Ideas (e.g., "I can do something to influence my mood")
• What were my most unhelpful negative thoughts and assumptions? What alternatives did I find to them? (summarized in two columns)
• How can I build on what I have learned? (a solid, practical, clearly specified action plan).

Preparation for the setback

Since depression is recurring illness patient should be made aware about the possibility of relapse.

• What might lead to a setback for me? For example, future losses (e.g., children leaving home) and stresses (e.g., financial difficulties), i.e., events which impinge on patients’ vulnerabilities and are thus liable to be interpreted negatively
• What early warning signs do I need to be alert for?
• Feelings, behaviors, and symptoms that might indicate the beginning of another depression are identified and listed
• If I notice that I am becoming depressed again, what should I do? Clear simple instructions, which will make sense despite low mood, are needed here. Specific ideas and techniques summarized earlier in the blueprint should be referred to.

Financial support and sponsorship

Conflicts of interest.

There are no conflicts of interest.

PTSD Treatments

APA’s Clinical Practice Guideline strongly recommends four interventions for treating posttraumatic stress disorder, and conditionally recommends another four.

The information below about the recommended interventions is intended to provide clinicians with a basic understanding of the specific treatment approach. Clinicians are encouraged to become familiar with each of the different interventions to determine which of these might be consistent with their practice, to develop a plan for additional training and professional development, and to become informed about the range of evidence-based treatment options in order to help patients with decision making and any necessary referrals. The information contained herein is not sufficient to enable one to become proficient in delivering these treatments. Clinicians are encouraged to pursue training opportunities and, to become fully competent in new interventions, receive consultation or supervision while first delivering the intervention.

Strongly Recommended

Four interventions are strongly recommended, all of which are variations of cognitive behavioral therapy (CBT). The category of CBT encompasses various types and elements of treatment used by cognitive behavioral therapists, while Cognitive Processing Therapy, Cognitive Therapy and Prolonged Exposure are all more specialized treatments that focus on particular aspects of CBT interventions.

Cognitive Behavioral Therapy (CBT) »

Cognitive behavioral therapy focuses on the relationships among thoughts, feelings and behaviors; targets current problems and symptoms; and focuses on changing patterns of behaviors, thoughts and feelings that lead to difficulties in functioning.

Cognitive behavioral therapy notes how changes in any one domain can improve functioning in the other domains. For example, altering a person’s unhelpful thinking can lead to healthier behaviors and improved emotion regulation.  It is typically delivered over 12-16 sessions in either individual or group format.

Case Example

Jill, a 32-year-old Afghanistan War veteran

Treating PTSD with Cognitive-Behavioral Therapies: Interventions That Work

Cognitive Processing Therapy (CPT) »

Cognitive processing therapy is a specific type of cognitive behavioral therapy that helps patients learn how to modify and challenge unhelpful beliefs related to the trauma.

CPT is generally delivered over 12 sessions and helps patients learn how to challenge and modify unhelpful beliefs related to the trauma. In so doing, the patient creates a new understanding and conceptualization of the traumatic event so that it reduces its ongoing negative effects on current life.

Case Examples

Several published CPT case examples exist in the literature, but many find the one in this chapter to be very helpful: Monson, C. M., Resick, P. A., & Rizvi, S. L. (2014). Posttraumatic stress disorder . In D. H. Barlow (Ed.), Clinical handbook of psychological disorders (5th ed. pp 80-113). Guilford Press.   

Additional CPT case examples include

Difede, J., & Eskra, D. (2002). Cognitive Processing Therapy for PTSD in a Survivor of the World Trade Center Bombing: A Case Study . Journal of Trauma Practice, 1 (3-4), 155-165.

König, J. (2014). Thoughts and Trauma – Theory and Treatment of Posttraumatic Stress Disorder from a Cognitive Behavioral Therapy Perspective . Intervalla: platform for intellectual exchange, 2 , 13- 19.

Wachen, J. S., Dondanville, K. A., Pruiksma, K. E., Molino, A., Carson, C. S., Blankenship, A. E, Wilkinson, C., Yarvis, J. S., & Resick, P. A. (2016). Implementing Cognitive Processing Therapy for Posttraumatic Stress Disorder With Active Duty U.S. Military Personnel: Special Considerations and Case Examples . Cognitive and Behavioral Practice, 23 (2), 133-147. 

Waltman, S. H. (2015). Functional Analysis in Differential Diagnosis: Using Cognitive Processing Therapy to Treat PTSD . Clinical Case Studies, 14 (6), 422-433.   

• Cognitive Processing Therapy Course : An overview of CPT, including the research support and information about delivering the treatment, produced by the VA. No CE credit. 
• Cognitive Processing Therapy for PTSD: A Comprehensive Manual : A Guilford Press publication, by Patricia A. Resick, PhD, Candice M. Monson, PhD, and Kathleen M. Chard, PhD. 

Cognitive Therapy »

Derived from cognitive behavioral therapy, cognitive therapy entails modifying the pessimistic evaluations and memories of trauma, with the goal of interrupting the disturbing behavioral and/or thought patterns that have been interfering in the person’s daily life.

Treatment entails modifying the pessimistic evaluations and memories of trauma, with the goal of interrupting the disturbing behavioral and/or thought patterns that have been interfering in the person’s daily life. It is typically delivered in weekly sessions over three months individually or in groups.

Philip, a 60-year-old who was in a traffic accident  (PDF)

A Cognitive Model of Posttraumatic Stress Disorder

A Randomized Controlled Trial of 7-day Intensive and Standard Weekly Cognitive Therapy for PTSD and Emotion-focused Supportive Therapy

Prolonged Exposure »

Prolonged exposure is a specific type of cognitive behavioral therapy that teaches individuals to gradually approach trauma-related memories, feelings and situations. By facing what has been avoided, a person presumably learns that the trauma-related memories and cues are not dangerous and do not need to be avoided.

Typically provided over a period of about three months with weekly individual sessions. Sixty- to 120-minute sessions are usually needed in order for the individual to engage in exposure and sufficiently process the experience.

Terry, a 42-year-old earthquake survivor

Prolonged Exposure Therapy for PTSD: Emotional Processing of Traumatic Experiences, Therapist Guide

Conditionally Recommended

Brief eclectic psychotherapy ».

Brief eclectic psychotherapy combines elements of cognitive behavioral therapy with a psychodynamic approach. It focuses on changing the emotions of shame and guilt and emphasizes the relationship between the patient and therapist.

As conducted in research studies, treatment consists of 16 individual sessions, each lasting between 45 minutes and one hour. Sessions are typically scheduled once per week. Each of the 16 sessions has a specific objective. This intervention is intended for individuals who have experienced a single traumatic event. 

Evidence-based treatments for trauma-related psychological disorders  

Effects of Brief Eclectic Psychotherapy in patients with PTSD: Randomized clinical trial

Eye Movement Desensitization and Reprocessing (EMDR) Therapy »

A structured therapy that encourages the patient to briefly focus on the trauma memory while simultaneously experiencing bilateral stimulation (typically eye movements), which is associated with a reduction in the vividness and emotion associated with the trauma memories.

EMDR is an individual therapy typically delivered 1-2 times per week for a total of 6-12 sessions. It differs from other trauma-focused treatments in that it does not include extended exposure to the distressing memory, detailed descriptions of the trauma, challenging of beliefs, or homework assignments. 

Mike, a 32-year-old Iraq War veteran

Eye Movement Desensitization and Reprocessing (EMDR) Therapy: Basic Principles, Protocols, and Procedures, Third Edition

Narrative Exposure Therapy (NET) »

Narrative exposure therapy helps individuals establish a coherent life narrative in which to contextualize traumatic experiences. It is known for its use in group treatment for refugees.

NET is distinct from other treatments in its explicit focus on recognizing and creating an account or testament of what happened, in a way that serves to recapture the patient’s self-respect and acknowledges their human rights. Often, small groups of individuals receive four to 10 sessions of NET together, although it also can be provided individually.

Summary & Case Example

Eric, a 24-year-old Rwandan refugee living in Uganda  (PDF, 27KB)

Narrative Exposure Therapy: A Short Term Treatment for Traumatic Stress Disorders, Second Edition

Medications »

Four medications received a conditional recommendation for use in the treatment of PTSD: sertraline, paroxetine, fluoxetine and venlafaxine. 

Currently only the SSRIs sertraline (Zoloft) and paroxetine (Paxil) are FDA-approved for the treatment of PTSD. While SSRIs are typically the first class of medications used in PTSD treatment, exceptions may occur for patients based upon their individual histories of side effects, response, comorbidities, and personal preferences.

Efficacy and safety of paroxetine treatment for chronic PTSD: A fixed-dose, placebo-controlled study

Efficacy and safety of sertraline treatment of posttraumatic stress disorder: A randomized controlled trial  (PDF, 239KB)

This website is for informational and educational purposes only. It does not render individual professional advice or endorse any particular treatment for any individuals. APA recommends that individuals consult with a mental health professional in order to obtain an accurate diagnosis and to discuss various treatment options. When you meet with a professional, be sure to work together to establish clear treatment goals and to monitor progress toward those goals. Even treatments that have scientific support will not work for everyone, and carefully monitoring your progress will help you and your mental health professional decide if a different approach should be tried. Feel free to print information from this website and take it with you to discuss with your mental health professional.

• Open access
• Published: 03 June 2024

Systematic review of fatigue severity in ME/CFS patients: insights from randomized controlled trials

• Jae-Woong Park 1 ,
• Byung-Jin Park 1 ,
• Jin-Seok Lee 4 , 5 ,
• Eun-Jung Lee 2 ,
• Yo-Chan Ahn 3 &
• Chang-Gue Son   ORCID: orcid.org/0000-0002-2034-7429 4 , 5  

Journal of Translational Medicine volume  22 , Article number:  529 ( 2024 ) Cite this article

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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating illness medically unexplained, affecting approximately 1% of the global population. Due to the subjective complaint, assessing the exact severity of fatigue is a clinical challenge, thus, this study aimed to produce comprehensive features of fatigue severity in ME/CFS patients.

We systematically extracted the data for fatigue levels of participants in randomized controlled trials (RCTs) targeting ME/CFS from PubMed, Cochrane Library, Web of Science, and CINAHL throughout January 31, 2024. We normalized each different measurement to a maximum 100-point scale and performed a meta-analysis to assess fatigue severity by subgroups of age, fatigue domain, intervention, case definition, and assessment tool, respectively.

Among the total of 497 relevant studies, 60 RCTs finally met our eligibility criteria, which included a total of 7088 ME/CFS patients (males 1815, females 4532, and no information 741). The fatigue severity of the whole 7,088 patients was 77.9 (95% CI 74.7–81.0), showing 77.7 (95% CI 74.3–81.0) from 54 RCTs in 6,706 adults and 79.6 (95% CI 69.8–89.3) from 6 RCTs in 382 adolescents. Regarding the domain of fatigue, ‘cognitive’ (74.2, 95% CI 65.4–83.0) and ‘physical’ fatigue (74.3, 95% CI 68.3–80.3) were a little higher than ‘mental’ fatigue (70.1, 95% CI 64.4–75.8). The ME/CFS participants for non-pharmacological intervention (79.1, 95% CI 75.2–83.0) showed a higher fatigue level than those for pharmacological intervention (75.5, 95% CI 70.0–81.0). The fatigue levels of ME/CFS patients varied according to diagnostic criteria and assessment tools adapted in RCTs, likely from 54.2 by ICC (International Consensus Criteria) to 83.6 by Canadian criteria and 54.2 by MFS (Mental Fatigue Scale) to 88.6 by CIS (Checklist Individual Strength), respectively.

Conclusions

This systematic review firstly produced comprehensive features of fatigue severity in patients with ME/CFS. Our data will provide insights for clinicians in diagnosis, therapeutic assessment, and patient management, as well as for researchers in fatigue-related investigations.

Introduction

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating illness characterized by core symptoms of chronic fatigue lasting for more than 6 months, unrefreshing sleep, post-exertional malaise (PEM), and cognitive dysfunction [ 1 ]. This disorder affects approximately 1% of the global population across all ages, races, and ethnic backgrounds [ 2 ]. Also, about 25 to 29% of CFS patients are in a house- or bed-bound state [ 3 ], and they have a sixfold higher risk of suicide compared to healthy subjects [ 4 ].

Indeed, besides CFS, fatigue is one of the most common morbidities even in the general population, affecting approximately 20% [ 5 ]. Additionally, for certain diseases, fatigue is a critical feature of the representative symptoms with high prevalence, for example, 50% in cancer [ 6 ], 80% in fibromyalgia [ 7 ], and 90% in major depressive disorder (MDD) [ 8 ], respectively. Then, CFS has been identified as the most severe form of medically unexplained fatigue and much more severe than other fatigue-associated diseases. Also, CFS patients appeared to have the lowest quality of life (QoL) comparing to subjects suffering from other diseases [ 9 ].

On the other hand, fatigue-related medical issues depend on the duration of the fatigue and its severity [ 10 ]. Since fatigue is a subjective symptom, the assessment of fatigue severity is a key factor for both patients and physicians [ 11 ]. To date, in order to objectify the severity of fatigue among CFS patients, an abundance of questionnaires and assessment tools have been developed, such as the Chalder Fatigue Questionnaire (CFQ), Multidimensional Fatigue Inventory (MFI), and Fatigue Impact Scale (FIS) [ 12 , 13 , 14 ]. Nevertheless, for many healthcare professionals including general practitioners who care for patients with ME/CFS, the difficult process of assessing exact fatigue-related status including, in particular, the severity of fatigue is a clinical challenge due to the lack of standardized global information [ 15 ]. Although there have been numerous studies to define the characteristics of CFS, there is no data showing comprehensive features and quantified information on fatigue severity in ME/CFS patients.

Therefore, we aimed to systematically produce the features of fatigue severity and its characteristics using data from randomized controlled trials (RCTs) targeting ME/CFS patients.

Data sources and search terms

In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [ 16 ], a systematic literature survey was performed using four electronic literature databases, PubMed, Cochrane Library, Web of Science, and CINAHL, throughout January 2024. The search keywords was ‘chronic fatigue syndrome’ [MeSH term]. The search terms were “randomised controlled trial” [All Fields] OR “RCT” [All Fields]) AND “chronic fatigue syndrome” [Title] OR “CFS” [Title] in PubMed, while “chronic fatigue syndrome [Record title] AND randomized controlled trial [Title abstract keyword]” in the Cochrane Library. In Web of Science, the search terms were “Randomized Controlled Trial OR RCT [All Fields] and chronic fatigue syndrome OR CFS [All Fields]”, while in CINAHL, it was (“Chronic Fatigue Syndrome” OR “CFS”) AND (“Randomized Controlled Trial” OR “RCT”). The trial type was limited to RCTs, and only the English language was included.

Eligibility criteria

Articles were screened according to the following inclusion criteria: (1) RCTs or randomized controlled trials, (2) patients with ME/CFS, (3) studies that evaluate the efficacy of ME/CFS intervention, (4) studies that used fatigue-specialized measurements (CFQ; Chalder Fatigue Questionnaire, CIS; Checklist Individual Strength, MFI; Multidimensional Fatigue Inventory-20, FSS; Fatigue Severity Scale, FIS; Fatigue Impact Scale, MFS; Mental Fatigue Scale). The exclusion criteria were as follows: (1) articles with no full text, (2) articles where the number of participants was less than 20, (3) studies without detailed characteristics of patients, (4) studies that did not use fatigue-specialized measurements (CFQ, CIS, FSS, FIS, MFI, MFS).

Review process and data extraction

The authors conducted a search of databases to identify potentially eligible studies. Subsequently, the full texts of potentially eligible studies were independently screened and crosschecked by the authors. In line with our study's objective to analyze fatigue severity in ME/CFS patients, we included data from all participants in both the intervention and control groups at the initial enrollment time point of each RCT. We extracted the following data from each study: number of ME/CFS patients, sex information, age, ME/CFS diagnostic case definitions, fatigue assessment tools, mean and standard deviations of baseline fatigue scores derived from each assessment tool and 3 different types of fatigue domain (physical fatigue, mental fatigue, and cognitive fatigue). Also we noted details regarding treatment type and duration, publication year, and country where each study was conducted.

Assessment of study quality, heterogeneity and publication bias

To evaluate the study quality, we used the Cochrane Risk of Bias tool 2 (RoB2), which examines five key areas: the randomization process, deviations from planned interventions, missing outcome data, outcome measurement, and the selection of reported results [ 17 ]. The results are reported in Additional file 2 : Fig. S2. In cases of high risk of bias, a sensitivity analysis was applied (Additional file 6 : Table S3). This analysis removed high-risk bias studies to affirm the stability of our meta-analysis findings, in line with the guidelines provided by the Cochrane RoB2.

For assessing heterogeneity between studies, we employed the I 2 statistic to evaluate variability among each item. Subsequently, we chose the DerSimonian and Laird method to implement a random-effects model when heterogeneity within each item exceeded 50%, and a fixed-effects model for data showing less than 50% heterogeneity [ 18 ]. This model was chosen for its capability to account for both within-study and between-study variability in the overall analysis. Publication and reporting bias potential was evaluated through the utilization of funnel plots and Egger’s test. The results are shown in Additional file 1 : Fig. S1 and Additional file 5 : Table S2 [ 19 ]. Also, we used the PRISMA checklist to assist reviewers in understanding how the review was conducted (Additional file 8 ).

Meta-analysis for assessment of fatigue severity in ME/CFS patients

For easy and intuitive presentation of fatigue severity, baseline fatigue scores of ME/CFS patients were converted into a scale of 0 to 100 points based on the characteristics of each assessment tool (Additional file 4 : Table S1). To obtain converted scores, we first computed the mean and standard deviations of the raw scores for each treatment and control group. We then normalized these means to a scale of minimum 0 to maximum 100 points, aligning them with the scoring of each assessment tool. We used only baseline fatigue scores of the treatment and control groups because our study focused on investigating the fatigue features of ME/CFS patients rather than assessing the effectiveness of treatment. After this process, we conducted a meta-analysis, calculating and analyzing the mean and 95% confidence interval (CI) of baseline fatigue scores of ME/CFS patients by age, fatigue domain, intervention type, case definitions, weighting them based on sample size (Table  2 ). We constructed a linear mixed effect model for understanding the correlation between fatigue severity and others factors such as age, continent, assessment tool, case definition and intervention (Fig.  2 C, D and Additional file 7 : Table S4). To assess the robustness of synthesized results, we also conducted an additional meta-analysis according to the results of quality assessment and publication bias. The results are in Additional file 5 : Table S2 and Additional file 6 : Table S3. All statistical analyses were performed using the “meta” package (by Guido Schwarzer) in R version 4.2.1. All analyses applied p < 0.05 for statistical significance.

General characteristics of the selected RCTs

A total of 629 articles were firstly identified from 4 database (PubMed, Cochrane databases, Web of Science, and CINAHL) and 60 articles met the inclusion criteria of this review (Fig.  1 ). In 60 RCTs, 7088 patients with ME/CFS (male 1815, female 4532 and no information: 741, mean age: 37.0 ± 10.1) participated, which were consisted of 54 RCTs for adult patients (n = 6706) and 6 RCTs for minor subjects (n = 382). Twenty-one RCTs evaluated the efficacy of pharmacological interventions, while 39 RCTs were conducted to evaluate non-pharmacological interventions (Table  1 ). The mean treatment period was 37.0 ± 10.1 weeks (data not shown). All studies were published between 2001 and January 2024 and were conducted across 15 countries. Upon a quality assessment, 45 studies (75%) were classified as having a low risk or some concerns (Additional file 2 : Fig. S2).

Flow chart of study selection diagram. n: Number of study

Overall fatigue severity in participants with ME/CFS

Among the 60 RCTs, the overall fatigue severity in the total 7,088 participants with ME/CFS was 77.9 (95% CI 74.7–81.0). The fatigue severity in adult patients (6706 participants from 54 RCTs) was 77.7 (95% CI 74.3–81.0), compared to 79.6 (95% CI 69.8–89.3) in 382 adolescent patients from 6 RCTS, respectively (Fig.  2 A; Table  2 ). The result of forest plot by age was shown in Additional file 3 : Fig. S3A. Unfortunately, no RCT presented fatigue severity-related data separately for each male and female.

Fatigue severity by age and domain of fatigue. Fatigue severity (out of 100) was calculated and analyzed by subgroups of age ( A ) and fatigue domains ( B ). The correlation among domains of fatigue was shown in ( C ) and ( D ). Each dot represents the value of each study included in this article. The mean score was represented by a horizontal line inside the square, while the 95% CI was depicted by the range of square. *Meta-analysis was done together for each subgroup

Fatigue severity in participants with ME/CFS by domain of fatigue

When we recalculated fatigue severity as maximum of 100 points (indicating an unendurable level) according to three domains of fatigue (physical, mental, cognitive fatigue), the ‘mental’ fatigue was the lowest (70.1, 95% CI 64.4–75.8), compared to ‘physical’ fatigue (74.3, 95% CI 68.3–80.3) and ‘cognitive’ fatigue (74.2, 95% CI 65.4–83.0), respectively (Fig.  2 B; Table  2 ). These three domain-related fatigue levels were well correlated, such as R 2  = 0.68 (p < 0.0001) between physical and mental fatigue (Fig.  2 C and D ). The result of forest plot by fatigue domain was represented in Additional file 3 : Fig. S3B.

Fatigue severity in participants with ME/CFS by intervention type

When we analyzed fatigue severity of ME/CFS patients by intervention type, the total fatigue severity in participants for the non-pharmacological intervention (39 RCTs) was slightly higher (79.1, 95% CI 75.2–83.0) than those for the pharmacological intervention (75.5, 95% CI 70.0–81.0 from 21 RCTs). As we expected, the overall feature of the fatigue domain-related scores were similar with data from total the 60 RCTs, showing lower score in ‘mental fatigue’ than ‘physical’ or ‘cognitive fatigue’ in both pharmacological and non-pharmacological intervention RCTs, respectively (Fig.  3 A).

Fatigue severity by intervention type. Fatigue severity (out of 100) was calculated and analyzed by intervention type (A). The results by subgroups of pharmacological and non-pharmacological research are presented in (B) and (C), respectively. Each dot indicates the value of each study included in this article. The mean score was represented by a horizontal line inside the square, while the 95% CI was depicted by the range of square. *Meta-analysis was done together for each subgroup

Regarding fatigue severity in ME/CFS patients according to kinds of pharmacological interventions, patients enrolled in nutrients-derived RCTs had the highest fatigue severity (85.5, 95% CI 79.1–92.0) followed by mitochondria modulators (76.6 95% CI 64.3–89.0), antiviral drugs (77.3, 95% CI 74.1–80.6), and psychiatric drugs (72.1, 95% CI 57.6–86.6) (Fig.  3 B; Table  2 ). Meanwhile, patients enrolled in RCTs of ‘self-care’ (85.7, 95% CI 75.6–95.8) had the highest fatigue severity, followed by cognitive behavior therapy (CBT) (83.8, 95% CI 79.4–88.3), and graded exercise therapy (GET) (77.2, 95% CI 68.5–85.8), among RCTs with non-pharmacological interventions (Fig.  3 C; Table  2 ). The result of forest plot by intervention type was shown in Additional file 3 : Fig. S3C and Fig. S3D. In linear-mixed effect model,

Fatigue severity in participants with ME/CFS by case definition

From the analyses for fatigue severity of ME/CFS patients by case definition, no notable difference was observed between two most adapted tools (Table  1 ), 1994 CDC criteria (77.8, 95% CI 74.5–81.1, 55 RCTs) and Oxford criteria (77.1, 95% CI 71.0–83.1, 8 RCTs). In particular, patients enrolled by Canadian criteria exhibited the highest fatigue severity (83.6, 95% CI 69.7–97.6, 2 RCTs), and conversely, the lowest score was observed in patients by International Consensus Criteria (ICC) (54.2, 1 RCT) (Fig.  4 A; Table  2 ).

Fatigue severity by case definition of ME/CFS, continent, fatigue assessment tool and publication year. Fatigue severity (out of 100) was calculated and analyzed by case definition of ME/CFS ( A ), continent where the patients lived ( B ), fatigue assessment tool ( C ), and publication year ( D ). Each dot represents the value of each study included in this article. The mean score was represented by a horizontal line inside the square, while the 95% CI was depicted by the range of square. *Meta-analysis was done together for each subgroup

Fatigue severity in participants with ME/CFS by continents

Regarding the countries where studies were conducted, the highest fatigue severity was observed in RCTs conducted in Africa (95.5, but only one RCT) and in Europe (80.3, 95% CI 76.9–83.7, 45 RCTs), compared to the relatively lower scores in Asia (66.6, 95% CI 61.1–72.1) and North America (83.2, 95% CI 76.4–90.1) (Fig.  4 B; Table  2 ).

Fatigue severity in participants with ME/CFS by assessment tool

Fatigue severity in ME/CFS patients varied according to 6 fatigue assessment tools. Both CIS and CFQ were most frequently adapted in equally 20 RCTs (Table  1 ), and then fatigue scores were highest in patients assessed by CIS (88.6, 95% CI 85.4–91.8), but 73.2 (95% CI 70.0–76.4) in CFQ. The lowest fatigue sore was observed in patients assessed by MFS (54.2, only one RCT) and MFI (68.8, 95% CI 56.4–81.1), respectively (Fig.  4 C; Table  2 ).

Fatigue severity in participants with ME/CFS by publication year

When we compared the fatigue severity by publication year, patients participating in 11 RCTS before 2010 presented a more severe fatigue score (84.8, 95% CI 79.1–90.5), compared to 49 RCTs thereafter (76.3, 95% CI 72.7–79.8) (Fig.  4 D; Table  2 ).

In general, fatigue is the most common comorbidity of various diseases and disorders, which impairs the quality of life in diseased individuals. Fatigue sometimes plays a risky factor in the progression of diseases, such as cancer [ 20 ], fibromyalgia [ 7 ], and major depressive disorder (MDD) [ 8 ]. However, for the patients suffering from ME/CFS, fatigue itself is the inherent condition, as the most debilitating illness [ 21 ]. Due to this reason, the accurate assessment of fatigue severity is a critical issue in the diagnosis and management of ME/CFS patients in clinical fields and the process of clinical trials [ 11 ]. Nevertheless, there is no comprehensive knowledge about the global features of fatigue severity in ME/CFS patients yet.

In order to systematically investigate the features of fatigue severity, we analyzed fatigue severity-related data from RCTs in which ME/CFS patients participated globally. Due to the subjective nature of fatigue symptoms, severity assessment usually relies on patients-reported questionnaires [ 12 ]. Among the 60 RCTs finally selected, 6 types of assessment tools were adopted, such as CFQ, CIS, and MFI (Table  1 ). Each tool has the unique characteristics in terms of questionaries and scoring scales, likely CFQ consisting of 11 questionnaires giving a maximum score of 33 points [ 13 ] and MFI consisting of 20 questionnaires giving a maximum score of 100 points [ 22 ]. In this study, for easy and intuitive presentation of fatigue severity, we converted the baseline fatigue scores derived from different tools in each RCT to a maximum score of 100 points and conducted meta-analysis. From the data of 60 studies involving 7,088 ME/CFS patients, the overall fatigue level of total patients was 77.9 (95% C I 74.7–81.0) (Fig.  2 A).

Regarding the clinical relevance of the 77.9 point fatigue score, one study presented the impact on daily life performance compared to an MFI-derived average fatigue score of 73.8 ± 13.6 for 150 ME/CFS patients [ 23 ]. These patients exhibited reduced activity by 50% in 92% of them and were unable to maintain full-time work or attend school in 82%. Moreover, almost half of them (48%) were bedridden or unable to participate in any productive tasks during the period of peaked fatigue, respectively. These findings are very comparable to the known features of the impaired life activity in ME/CFS patients, with approximately 27% of individuals with severe ME/CFS being bedridden, and 57% experiencing either housebound or bedridden status for more than six years [ 3 , 24 ]. Also, 21.9% of patients with ME/CFS are working part-time jobs [ 25 ] and 53.4% of them are unemployed [ 26 ]. The medical impact of fatigue severity would vary depending on the types of diseases. For example, a study reported that fatigue scores over 60 points, assessed using the MFI in patients with Parkinson’s disease were considered to have clinically severe fatigue [ 27 ]. Also, in another study, the fatigue severity of Critical Illness Polyneuropathy (CIP) patients who were transferred from acute care Intensive Care Unit (ICU) to post-acute ICU was 55.9, assessed by MFI [ 28 ]. When comparing fatigue severity among patients with other diseases in RCT data, fatigue score was 73.4 in those with fibromyalgia [ 29 ], 50.5 in MDD [ 30 ], by MFI-assessed score. It is well acknowledged that fibromyalgia leads to severe fatigue and even has overlapping characteristics with ME/CFS [ 31 ], while depression, fatigue and/or pain are commonly accompanied within individuals suffering from MDD [ 32 , 33 ].

Fatigue is acknowledged as subjective, variable, and influenced by multiple factors, focusing on the unpleasant, distressing, and persistent feeling of tiredness, weakness, or exhaustion experienced [ 34 ]. Because of the complexity of fatigue, it is necessary to classify fatigue into various dimensions such as physical, mental, and cognitive to understand it comprehensively. When we performed the sub-analyses, the three different domains of fatigue showed the very similar score with total fatigue, likely 74.3 in physical, 70.1 in mental, and 74.2 in cognitive fatigue score, respectively (Fig.  2 B). Also, these three domain-related fatigue levels showed a highly positive correlation (Fig.  2 C, D ). According to previous research, the primary symptom of fatigue of ME/CFS impacts both physical and cognitive activities, often leading to an extended exacerbation following activities [ 35 ]. In fact, PEM, a core symptom of ME/CFS, is raised by any of physical, mental or cognitive activity [ 36 ]. Also, the majority of ME/CFS patients experience not only limitations for doing daily activities but also emotional exhaustion and prolonged cognitive activities simultaneously [ 37 ]. These results indicate that each fatigue domain cannot be interpreted as separate options but as a systemic phenomenon [ 38 ]. There is also research emphasizing that overall impairment of well-being in ME/CFS patients was related to diverse types of fatigue [ 39 ].

Fatigue prevalence and severity could be affected by gender, age, ethnicity, and cultural backgrounds [ 40 , 41 ]. In general, adults tend to exhibit higher levels of fatigue than adolescent patients due to the elderly’s underlying pathogenic conditions and psychological aspects of aging [ 42 , 43 ]. However, our data shows a 1.9-point higher fatigue score in adolescents compared to adults (Fig.  2 A; Table  2 ). This discrepancy might be attributed to the relatively fewer studies for adolescents (6 RCTs) and the enrollment of individuals with particularly significant levels of fatigue, as noted by the authors [ 44 ]. Regarding gender difference, it is well acknowledged that females are predominant and more sensitive to fatigue, with approximately 1.5-fold higher prevalence not only in the general population [ 5 ] but also in patients with ME/CFS [ 45 ], along with higher fatigue levels in females. Only 4 RCTs exclusively targeted female patients (4 RCTs, n = 326), which presented higher scores of fatigue severity 84.4 (95% CI 76.2–96.2) compared to 77.4 (95% CI 74.1–80.6) from the rest 56 RCTs (data not shown). When comparing fatigue severity by ethnicity, patients from European countries showed higher fatigue severity (80.3) than those from Asian countries (66.6), respectively (Fig.  4 B; Table  2 ). Unfortunately, our present study could not provide additional characteristics related to ethnicity or socioeconomic status due to absence of data from RCTs.

Because our study is based on the RCTs, we attempted to compare the fatigue severity of ME/CFS patients according to intervention. Fatigue severity was slightly higher in participants in non-pharmacological studies (39 RCTs, 79.1) than in those of pharmacological studies (21 RCTs, 75.5) (Fig.  3 A; Table  2 ). Due to the absence of proven therapeutics for ME/CFS, various trials have been performed since the first RCT using GET [ 46 ]. Our previous systematic review demonstrated the predominance of pharmacological RCTs in the 1990s and 2000s comparing to non-pharmacological interventions thereafter [ 47 ]. In present results, we could find that fatigue severity in participants undergoing ‘self-care’ (85.7 from 6 RCTs) and ‘CBT’ (83.8 from 19 RCTs) were relatively higher (Fig.  3 C; Table  2 ). Given the ongoing debate about which treatment methods should be used for managing ME/CFS [ 48 ], this finding might stem from that non-pharmacological interventions can be utilized for managing ME/CFS patients, particularly those experiencing severe levels of fatigue, as recommended by NICE [ 49 ]. Unlike age (R 2  = 0.003, p = 0.681), the type of intervention (R 2  = 0.327, p = 0.011) demonstrated significant influence on fatigue severity scores in ME/CFS patients according to the linear mixed-effects model (see Additional file 7 : Table S4).

Although ME/CFS has been defined as a complex neurological disease, concerns about its heterogeneity have led to the use of various case definitions. Out of the 25 currently used case definitions, we observed the application of four different case definitions in our study, including the 1994 CDC criteria (55 RCTs). Among these four case definitions, the Oxford criteria are the most lenient, primarily focusing on fatigue-related symptoms such as sleep disturbance, while the Canadian criteria encompass a broader range of pathological symptoms including anorexia, cardiovascular symptoms, and gastrointestinal symptoms [ 50 ]. The 1994 CDC criteria are generally considered moderately stricter, diagnosed by the presence of 4 or more symptoms encompassing the essential fatigue-related symptoms as well as four regional pains [ 50 ] Interestingly, participants in 2 RCTs using the Canadian criteria showed the highest average fatigue score of 83.6 (Fig.  4 A; Table  2 ). Fatigue severities also notably differed according to each assessment tool; with relatively severe levels of fatigue observed in patients of RCTs using CIS (88.6 from 20 RCTs), while the lowest levels of fatigue were seen in patients of RCTs using MFI (68.8 from 9 RCTs) and one RCT that used MFS (54.2) (Fig.  4 C; Table  2 ). CIS has been shown to effectively distinguish individuals with ME/CFS from those who do not suffer from ME/CFS based on the scores of each questionnaire’s criteria [ 51 , 52 , 53 ]. From our analyses using a linear mixed effect model, we found the notable influence between assessment tool (R 2  = 0.437, p < 0.0001) and fatigue severity, but not by case definition (R 2  = 0.084, p = 0.296) (Additional file 7 : Table S4).

Based on the publication bias and quality assessment, we investigated the robustness of synthesized results. Then an additional meta-analysis after compensation of publication bias showed overall fatigue severity 71.5 (Additional file 5 : Table S2), while fatigue severity was 77.2 after removing studies with high risk of bias (Additional file 6 : Table S3). We herein produced a comprehensive feature of fatigue levels in patients with ME/CFS, but there are some limitations in our study. In order to obtain an objectively assessed fatigue data, we extracted only from RCTs. This means that we may have excluded the patients with extremely high or low levels of fatigue severity, as they may not have been able to easily participate in RCTs or may not have been suitable for assessing interventions. Thus, the data obtained from RCTs may not fully represent the real-world features of fatigue severity in ME/CFS patients. Another limitation is that different questionnaire-based assessment tools could reflect varying levels of fatigue severity due to the varying levels of sensitivity and specificity, even for the same fatigue score when converted into a maximum of 100. This strategy may affect the relatively high level of heterogeneity in our meta-analyzed data. Additionally, there may be a potential language bias as we excluded non-English studies due to concerns about our disability and quality issues. In future studies, it may be necessary to include longitudinal cohort studies to investigate changes in fatigue severity over time.

Despite the limitations above, our results firstly produced the overall features of fatigue severity in patients with ME/CFS. Our data will provide comparative insights not only for clinicians in the processes of diagnosis, therapeutic assessment and decision-making management of patients, but also for researchers involved in fatigue-related investigations.

Availability of data and materials

All data related to this study are available in the public domain.

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This research was supported by the Ministry of Education, Science and Technology (NRF‑2018R1A6A1A03025221).

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Research Center for CFS/ME, Daejeon Oriental Hospital of Daejeon University, 176 Daedeok‑Daero, Seo‑Gu, Daejeon, 35235, Republic of Korea

Jin-Seok Lee & Chang-Gue Son

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J‑WP conducted the literature search, data collection, analysis, and wrote manuscript. B-JP and Y-CA supported data analysis. J-SL and E-JL supported the study design and writing of manuscript. C‑GS supervised all processes of study design, data collection, analysis and manuscript writing. All authors read and approved the final manuscript.

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Park, JW., Park, BJ., Lee, JS. et al. Systematic review of fatigue severity in ME/CFS patients: insights from randomized controlled trials. J Transl Med 22 , 529 (2024). https://doi.org/10.1186/s12967-024-05349-7

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DOI : https://doi.org/10.1186/s12967-024-05349-7

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Long COVID Basics

• Long COVID is a serious illness that can result in chronic conditions requiring comprehensive care.
• Long COVID can include a wide range of ongoing symptoms and conditions that can last weeks, months, or even years after COVID-19 illness.
• Anyone who had a SARS-CoV-2 infection, the virus that causes COVID-19, can experience Long COVID, including children.
• COVID-19 vaccination is the best available tool to prevent Long COVID.
• Living with Long COVID can be difficult and isolating, especially when there are no immediate answers or solutions.

About Long COVID

Long COVID is defined as a chronic condition that occurs after SARS-CoV-2 infection and is present for at least 3 months. Long COVID includes a wide range of symptoms or conditions that may improve, worsen, or be ongoing.

Long COVID occurs more often in people who had severe COVID-19 illness, but anyone who gets COVID-19 can experience it, including children.

Most people with Long COVID experience symptoms days after first learning they had COVID-19, but some people who later develop Long COVID do not know when they were infected. People can be reinfected with SARS-CoV-2 multiple times. Each time a person is infected with SARS-CoV-2, they have a risk of developing Long COVID. Long COVID symptoms and conditions can emerge, persist, resolve, and reemerge over weeks and months. These symptoms and conditions can range from mild to severe, may require comprehensive care, and can even result in a disability .

While rates of new cases of Long COVID have decreased since the beginning of the COVID-19 pandemic, it remains a serious public health concern as millions of U.S. adults and children have been affected by Long COVID.

Signs and symptoms

People with Long COVID can have a wide variety of symptoms that can range from mild to severe and may be similar to symptoms from other illnesses. Symptoms can last weeks, months, or years after COVID-19 illness and can emerge, persist, resolve, and reemerge over different lengths of time. Long COVID may not affect everyone the same way. Some people can experience health problems from different types and combinations of symptoms that may:

• Be difficult to recognize or diagnose
• Require comprehensive care
• Result in disability

Fatigue, brain fog, and post-exertional malaise (PEM) are commonly reported symptoms, but more than 200 Long COVID symptoms have been identified.

General symptoms 

• Tiredness or fatigue that interferes with daily life
• Symptoms that get worse after physical or mental effort

  Respiratory and heart symptoms

• Difficulty breathing or shortness of breath
• Fast-beating or pounding heart (also known as heart palpitations)

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• Difficulty thinking or concentrating (sometimes referred to as “brain fog”)
• Sleep problems
• Dizziness when you stand up (lightheadedness)
• Pins-and-needles feelings
• Change in smell or taste
• Depression or anxiety

  Digestive symptoms

• Stomach pain
• Constipation

  Other symptoms

• Joint or muscle pain
• Changes in menstrual cycles

Symptoms that are hard to explain and manage

Some people with Long COVID have symptoms that are hard to explain or difficult to manage. There is no laboratory test that can determine if your unexplained symptoms are due to Long COVID. People with these unexplained symptoms may sometimes even be misunderstood or experience stigma. This can result in a delay in diagnosis and receiving the appropriate care or treatment. Long COVID treatment is focused on managing symptoms, reducing their impact on daily activities, and improving your quality of life.

Talk to your healthcare provider if you are experiencing symptoms that are hard to explain or that persist, or if you think you or your child has Long COVID.

Complications

Some people, especially those who had severe COVID-19, may experience multi-organ effects or autoimmune conditions lasting weeks, months, or even years after COVID-19 illness. Multi-organ effects can involve many body systems, including the heart, lungs, kidneys, skin, and brain. Symptoms for many of these multi-organ complications are similar to commonly reported Long COVID symptoms. As a result of these effects, people who have had COVID-19 may be more likely to develop new or worsening of health conditions such as:

• Heart conditions
• Blood clots
• Neurological conditions

Who is at risk

While anyone who gets COVID-19 can develop Long COVID, studies have shown that some groups of people are more likely to develop Long COVID than others, including (not a comprehensive list):

• Hispanic and Latino people
• People who have experienced more severe COVID-19 illness, especially those who were hospitalized or needed intensive care
• People with underlying health conditions and adults who are 65 or older
• People who did not get a COVID-19 vaccine

Health inequities affect populations at risk for Long COVID

Health inequities from disability , economic, geographic, and other social factors disproportionately affect some groups of people. These inequities can increase the risk of negative health outcomes and impact from Long COVID.

CDC emphasizes core strategies  to lower health risks from COVID-19, including severe outcomes such as hospitalization and death. Preventing severe outcomes from COVID-19 illness helps prevent Long COVID. Steps you can take to protect yourself and others include:

• Staying up to date on COVID-19 vaccination .
• Practicing good hygiene  (practices like handwashing that improve cleanliness)
• Taking steps for cleaner air
• Use precautions to prevent spread
• Seek healthcare promptly for testing and/or treatment if you have risk factors for severe illness ; treatment  may help lower your risk of severe illness

Research shows COVID-19 vaccination  is the best available tool to prevent Long COVID.

Testing and diagnosis

Long COVID is not one illness. There is no laboratory test that can determine if your symptoms or conditions are due to Long COVID. A positive SARS-CoV-2 test is not required for a Long COVID diagnosis. Your healthcare provider considers a diagnosis of Long COVID based on:

• Your health history
• If you had a diagnosis of COVID-19 by a positive test, symptoms, or exposure
• A health examination

Clinical evaluations and results of routine blood tests, chest X-rays, and electrocardiograms may be normal in someone with Long COVID. People experiencing Long COVID should seek care from a healthcare provider to create a personal medical management plan and improve their symptoms and quality of life. Talk to your healthcare provider if you think you or your child has Long COVID.

Similar conditions

Some people experiencing Long COVID symptoms have symptoms similar to those reported by people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)  and other poorly understood chronic illnesses that may occur after other infections. These unexplained symptoms or conditions may be misunderstood by healthcare providers, which can result in a delay in diagnosis and people receiving the appropriate care or treatment.

What CDC is doing

CDC is working with other federal agencies to better understand and address the long-term impacts of Long COVID , who gets Long COVID, and why. CDC supports these goals by:

• Partnering with state and local jurisdictions
• Supporting healthcare providers
• Promoting and conducting research

Studies are in progress to learn more about Long COVID and identify further measures to help prevent Long COVID. CDC and partners use multiple approaches to support and conduct research that estimates:

• How many people experience Long COVID and why
• Which groups of people are disproportionately impacted by Long COVID
• How new variants may affect Long COVID
• The role that COVID-19 vaccination plays in preventing Long COVID

Each approach helps CDC and its partners better understand Long COVID and how healthcare providers can treat or support patients living with these long-term effects. CDC posts data on Long COVID and provides analyses. The most recent CDC data and analyses on Long COVID can be found on the  U.S. Census Bureau’s Household Pulse Survey . CDC will continue to share information with healthcare providers to help them evaluate and manage these conditions.

• The Office of Long COVID Research and Practice (OLC) (HHS)
• Long COVID (Veterans Affairs)
• Coronavirus Resources (Department of Labor)
• RECOVER COVID Initiative

Long COVID Reports

• A Long COVID Definition: A Chronic, Systemic Disease State with Profound Consequences | The National Academies Press
• Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection | The National Academies Press
• Implementation of the Government-wide Response to Long COVID (HHS)
• National Research Action Plan (covid.gov)
• Services and Supports for Longer-Term Impacts of COVID-19
• Health+ Long Covid Human-Centered Design Report (HHS)
• Whole Health System Approach to Long COVID (Veterans Affairs)

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