Rajesh R. Tampi, MD, MS, DFAPA

The English word apathy originates from the Greek word apathes, which means “without pathos or feeling,”

 but scholars have shared various definitions. For example, Robert S. Martin, MD, defined apathy as a syndrome of primary motivational loss that is not attributable to emotional distress, intellectual impairment, or 

 According to Drs Richard Levy and Bruno Dubois apathy is the quantitative reduction of self-generated voluntary and purposeful behaviors, which are observable and can be quantified.

 In addition, the underlying mechanism(s) responsible for apathy may be seen as dysfunctions occurring at the level of elaboration, execution, and control of goal-directed behaviors. According to an international consensus criterion, apathy is defined as a disorder of motivation in which the symptoms are present for at least 4 weeks.

 In addition, 2 of the following 3 should be present: reduced goal-directed behavior, reduced goal-directed cognitive activity, and reduced emotions. Furthermore, these symptoms cause clinically significant impairments in personal, social, occupational, or other important areas of functioning, with such symptoms not exclusively explained by or due to other causes (ie, physical disabilities [such as blindness or loss of hearing], motor disabilities, diminished level of consciousness, or direct physiological effects of a substance [such as a drug of abuse or a medication]).

 of individuals who have no cognitive deficits.

 It is also seen among individuals with major depressive disorder, schizophrenia, strokes, multiple sclerosis, and traumatic brain injury. Apathy is more prevalent among individuals with neurodegenerative disorders than in those free of such disorders.

Apathy has been noted throughout the spectrum of neurocognitive disorders (

 The prevalence rates for apathy among individuals with mild cognitive impairment ranges from 

 Apathy is also the most frequently reported behavioral symptom among individuals with dementia. The results of one study showed that individuals with frontotemporal dementia (FTD) and vascular dementia (VaD) report more severe apathy than individuals with Alzheimer disease (AD).

Apathy Among Individuals With Neurocognitive Disorders

Apathy usually appears early in dementia and tends to persist throughout; it is associated with longer illness duration and it worsens with the 

 Risk factors for developing apathy include older age and greater severity of cognitive impairment. Akyol et al found that apathy was correlated with the degree of cognitive impairment among individuals with AD and VaD, but not with FTD; but apathy did not correlate with age or gender in individuals with AD, FTD, and VaD. Additionally, the degree of apathy correlated with the level of functional impairment and dementia severity across all 3 types of dementia.

Individuals with dementia who present with apathy often have more rapid cognitive decline and are more impaired in their activities of daily living.

 In addition, apathy increases the risk for earlier institutionalization among individuals with dementia.

 Distress is also significantly higher among caregivers of individuals with dementia who have apathy, when compared with individuals with dementia without it.

Emerging evidence indicates that apathy in individuals with dementia occurs due to a complex interaction among neuroanatomy, neuropathology, neurochemistry, and genetics.

 Among individuals with AD, apathy is associated with an increased neurofibrillary tangle burden in the parahippocampal, frontal, and parietal regions, in addition to the anterior cingulate gyrus. Emerging evidence indicates that the severity of apathy is also associated with amyloid plaque burden, especially in bilateral frontal cortices and the right anterior cingulate gyrus along with 

One study that evaluated the cerebrospinal fluid (CSF) biomarkers among individuals with AD showed that apathy was significantly correlated with tau and p-tau, but not with amyloid β١–٤٢.

 Another study examined regions of cortical thinning and CSF biomarkers (amyloid-β ١-٤٢, total tau, and phosphorylated tau) among 3 groups—clinically normal elderly individuals, individuals with mild cognitive impairment, and individuals with mild AD dementia with apathy—and found that reduced baseline inferior temporal cortical thickness was predictive of increasing apathy over time.

 The investigators of this study did not find any association between CSF biomarkers and the severity of apathy in cross-sectional or longitudinal analyses.

Another study found that individuals with AD and apathy had a loss of white matter integrity in the genu of the corpus callosum when compared with individuals with AD without apathy.

 In addition, the loss of white matter integrity in the genu, body, and splenium of the corpus callosum was negatively correlated with the severity of apathy among individuals with AD. Neuroradiological studies indicate that the dysfunction of the anterior cingulate cortex is the strongest anatomical correlate of apathy in AD, whereas lesions of the basal ganglia are the most common correlates of apathy in cerebrovascular disorders.

Neuroimaging studies indicate that the apathy among individuals with behavioral variant of FTD is associated with prominent atrophy in: the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex, right caudate (including the ventral striatum), right temporoparietal junction, right posterior inferior and middle temporal gyri, and left frontal operculum-anterior insula region.

A recent meta-analysis that analyzed data from 41 studies indicated that apathy is associated with hypometabolism and a decrease in gray matter volume in the left inferior frontal gyrus.

 The investigators also found altered brain perfusion and decreased gray matter volume in the anterior cingulate cortex among individuals with AD, and decreased gray matter volume in the inferior frontal gyrus and parietal cortex among individuals with FTD. These findings indicate that apathy occurs due to a cortical dysfunction of areas involved with executive cognitive processing (action planning) and emotional regulation (autoactivation and reward processing).

Individuals with AD and apathy have been found to have reduced dopaminergic activity in the putamen, reduced acetylcholine in the lateral frontal cortex, and lower levels of plasma gamma-aminobutyric acid.

 In evaluating the association between apolipoprotein E ɛ4 allele and apathy in probable AD, investigators found that the presence of this allele was indeed significantly associated with apathy in these individuals.

Among individuals with dementia, the assessment of apathy is often complicated. It is particularly difficult to distinguish between reduced motivation to do things due to apathy and the loss of ability or motivation secondary to cognitive dysfunction. Additionally, there may be overlap between symptoms of apathy and depression (

 Often, as well, psychotropic medications (ie, antipsychotics, antidepressants) are used to treat neuropsychiatric symptoms (NPS) of dementia, and the adverse effects of these medications include fatigue, lethargy, listlessness, and decreased initiative to respond to external stimuli. These AEs can mimic symptoms of apathy among individuals with dementia.

The scales that have been developed for the assessment of apathy include the Apathy Evaluation Scale (AES), the Structured Clinical Interview for Apathy, the Apathy Scale, the Apathy Inventory, the Dementia Apathy Interview and Rating (DAIR), and the Lille Apathy Rating Scale (LARS).

 Among these scales, only the DAIR was designed for use among individuals with dementia. The Apathy Scale for Dementia Patients in Nursing Homes was designed to measure apathy among individuals with dementia who live in institutional settings.

 The Neuropsychiatric Inventory (NPI) is considered the gold standard for the assessment of NPS among individuals with dementia. However, the use of a single domain from the NPS prevents a comprehensive assessment of all dimensions of apathy among individuals with dementia. A recent systematic review found that the DAIR, the AES–clinical version (AES-C) in AD, and the LARS in Parkinson disease (PD) had psychometrically favorable qualities and the highest quality among the scales used to assess apathy among individuals with neurodegenerative disorders.

Available evidence indicates that both nonpharmacological and pharmacological treatment modalities can benefit individuals with dementia who present with apathy (

Selected Pharmacotherapy and Nonpharmacological Treatments

A systematic review by Brodaty et al found that therapeutic activities—including stimulation, creative activities, cooking, Montessori methods, music, exercise, multisensory stimulation, and pet therapy—as well as placement in special care units may improve apathy among individuals with dementia.

 Another recent systematic review by Cai et al, evaluating the effectiveness of nonpharmacological interventions among individuals with dementia and apathy, also found that multisensory stimulation, music therapy, cognitive stimulation, and pet therapy are useful in improving symptoms of apathy.

 Cai et al found limited evidence as well for the efficacy of art, exercise, reminiscence, and occupational therapies; dementia special care units; comprehensive interventions; nursing staff education; and behavioral management techniques (ie, therapeutic conversations, progressive muscle relaxation). They found that the effects of psychomotor therapy and validation therapy were still unclear; evidence also indicates that receptive music therapy is better than interactive music therapy. Pet therapy that includes the introduction of domestic pets and companion robots tends to reduce loneliness and improve well-being. Tailoring the overall lifestyle of individuals with dementia to increase recreational activities, physical exercise, cognitive stimulation, and social activities also reduces apathy.

Various pharmacological agents have been trialed for the treatment of apathy,

 including acetylcholinesterase inhibitors (ChEIs), memantine, stimulants, calcium antagonists, and antipsychotics.

 In their systematic review and meta-analysis, Sepehry et al found a total of 15 randomized controlled trials that assessed the efficacy of pharmacotherapy.

 For cognitive enhancers (donepezil and galantamine), there was no was significant effect of treatment on apathy (Hedges’ g = –0.055; 

 = .687). The average donepezil dosage was 10 mg/day, while galantamine dosage ranged between 16 mg/day and 32 mg/day. All but 1 study used the NPI-apathy subscale as an outcome measure, and these trials included individuals with mild-to-severe AD.

For memantine, the investigators found a small and nonsignificant benefit for apathy (Hedges g = .092; P = .423). The average dose of memantine was 20 mg/day, and the trials included individuals with moderate-to-severe AD and used the NPI-apathy subscale. The effect of psychostimulants on apathy was small and nonsignificant when compared with placebo (Hedges’ g = –.063; 

 = .903). All stimulant trials included individuals with mild-to-moderate AD, used multiple scales including the NPI-apathy and Frontal Systems Behavior Scale (FrSBe) apathy subscale, and included mixed drugs with noncomparable dosages. The investigators did not find enough individual studies to do a meta-analysis for antipsychotics and drug classes with antidepressant properties, but the data from the individual atypical antipsychotic studies did not support their use for apathy in AD. The investigators indicated that the analysis for cognitive enhancers and memantine were appropriately powered, whereas the psychostimulant studies were underpowered due to limited patient enrollment in each arm of the trials.

In another quantitative meta-analysis, Ruthirakuhan et al included data from 21 studies.

 The investigators found that methylphenidate may improve apathy when compared with placebo; this held true when apathy was assessed using the AES (mean difference [MD] = – 4.99) but not when using the NPI-apathy subscale (MD = –.08).

The investigators further found that methylphenidate may also improve cognition (MD = –.08) and instrumental activities of daily living (MD = 2.30), when compared with placebo. There was no difference between methylphenidate and placebo in the risk of developing an adverse event (risk ratio = 1.28). The investigators indicated that there was insufficient evidence from a small study of modafinil to determine its effect on apathy assessed with the FrSBe-apathy subscale (MD = 0.27). They reported that in all other included studies, apathy was a secondary outcome and participants were not selected on the basis of clinically significant apathy at baseline. The investigators considered the evidence on apathy from these studies to be indirect and associated with publication bias. They reported that there was low or very low quality of evidence on ChEIs, ChEI discontinuation, antipsychotics, antipsychotic discontinuation, antidepressants (2 studies), and valproate for the treatment of apathy in dementia.

A recent systematic review by Theleritis et al evaluated data from 90 unique studies and relevant reviews but noted that in many studies, apathy was not considered the primary outcome measure.

 They concluded that after considering the amount of evidence, ChEIs may be the best available pharmacological treatment choice for the treatment of apathy, while data from 3 studies indicated that gingko biloba may also be effective. The investigators found weaker evidence for memantine’s efficacy. Stimulants like methylphenidate alone or in combination with ChEIs were found to be beneficial in treating apathy. Atypical antipsychotics, however, appear to have limited benefit for this purpose, and their long-term use is not recommended due to their adverse effect profile. Data from one study indicated that the combination of citalopram and memantine reduced apathy among individuals with AD when compared with placebo.

Apathy can be described as the quantitative reduction of self-generated voluntary and purposeful behaviors that are observable and quantifiable. Apathy commonly presents in individuals with many different illnesses, including major depressive disorder, schizophrenia, strokes, multiple sclerosis, and traumatic brain injury. However, apathy is more prevalent among individuals with neurodegenerative disorders, including dementias. Among individuals with dementia, apathy is considered to be the most frequently reported behavioral symptom. Apathy worsens morbidity and mortality in AD and is associated with greater caregiver distress.

The exact neurobiological mechanisms associated with apathy in dementia are unclear, but emerging evidence indicates a complex interaction among neuroanatomy, neuropathology, neurochemistry, and genetics. The assessment of apathy is often complicated, and it is difficult to distinguish between reduced initiative to do things due to the loss of cognitive ability vs the loss of motivation due to apathy. In addition, there may be an overlap between symptoms of apathy and depression. Among the many scales that have been developed to assess apathy, the DAIR, the AES-C in AD, and the LARS in PD have the highest quality. Emerging evidence indicates efficacy for both nonpharmacological and pharmacological treatments for improving apathy. Multisensory stimulation, music therapy, cognitive stimulation, and pet therapy are beneficial nonpharmacological treatments; and among pharmacotherapy options, ChEIs may be the best available treatment choice, followed by gingko biloba, memantine, and stimulants like methylphenidate either alone or in combination with ChEIs.

Future directions in the evaluation of apathy in dementia should include the study of animal models as well as genetic studies that improve the knowledge of the neurobiological mechanisms underlying this condition. In addition, well-designed clinical trials of nonpharmacologic and pharmacological interventions that exclusively target apathy in dementia are needed. These trials should assess not only the symptomatic improvement of apathy but also evaluate its effect on the individual’s functioning and on caregiver burden. These studies should use advances in both neuroimaging techniques and biomarkers to provide surrogate metrics for treatment response.

is chairman of the Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, Akron, Ohio; chief, Section for Geriatric Psychiatry, Cleveland Clinic, Ohio; and professor of medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio; The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

1. Cipriani G, Lucetti C, Danti S, Nuti A. Apathy and dementia. nosology, assessment and management. 

2. Marin RS. Apathy: a neuropsychiatric syndrome. 

3. Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortex–basal ganglia circuits. 

4. Robert P, Onyike CU, Leentjens AFG, et al. Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. 

5. Harrison F, Aerts L, Brodaty H. Apathy in dementia: systematic review of recent evidence on pharmacological treatments. 

6. Theleritis C, Politis A, Siarkos K, Lyketsos CG. A review of neuroimaging findings of apathy in Alzheimer’s disease. 

7. Lanctôt KL, Agüera-Ortiz L, Brodaty H, et al. Apathy associated with neurocognitive disorders: recent progress and future directions. 

8. Sherman C, Liu CS, Herrmann N, Lanctôt KL. Prevalence, neurobiology, and treatments for apathy in prodromal dementia. 

9. Berman K, Brodaty H, Withall A, Seeher K. Pharmacologic treatment of apathy in dementia. 

10. van Dyck CH, Arnsten AFT, Padala PR, et al. Neurobiologic rationale for treatment of apathy in Alzheimer’s disease with methylphenidate. 

11. Mele B, Van S, Holroyd-Leduc J, et al. Diagnosis, treatment and management of apathy in Parkinson’s disease: a scoping review. 

12. Akyol MA, Küçükgüçlü Ö, Yener G. Investigation of factors affecting apathy in three major types of dementia. 

13. Sepehry AA, Sarai M, Hsiung G-YR. Pharmacological therapy for apathy in Alzheimer’s disease: a systematic review and meta-analysis. 

14. Mori T, Shimada H, Shinotoh H, et al. Apathy correlates with prefrontal amyloid β deposition in Alzheimer’s disease. 

15. Marshall GA, Donovan NJ, Lorius N, et al. Apathy is associated with increased amyloid burden in mild cognitive impairment. 

16. Skogseth R, Mulugeta E, Jones E, et al. Neuropsychiatric correlates of cerebrospinal fluid biomarkers in Alzheimer’s disease. 

17. Donovan NJ, Wadsworth LP, Lorius N, et al; Alzheimer Disease Neuroimaging Initiative. Regional cortical thinning predicts worsening apathy and hallucinations across the Alzheimer disease spectrum. 

18. Hahn C, Lim H-K, Won WY, et al. Apathy and white matter integrity in Alzheimer’s disease: a whole brain analysis with tract-based spatial statistics. 

19. Starkstein SE, Brockman S. The neuroimaging basis of apathy: empirical findings and conceptual challenges. 

20. Massimo L, Powers C, Moore P, et al. Neuroanatomy of apathy and disinhibition in frontotemporal lobar degeneration. 

21. Eslinger PJ, Moore P, Antani S, et al. Apathy in frontotemporal dementia: behavioral and neuroimaging correlates. 

22. Raimo S, Santangelo G, D’Iorio A, et al. Neural correlates of apathy in patients with neurodegenerative disorders: an activation likelihood estimation (ALE) meta-analysis. 

23. Agüera-Ortiz L, Gil-Ruiz N, Cruz-Orduña I, et al. A novel rating scale for the measurement of apathy in institutionalized persons with dementia: the APADEM-NH. 

24. Radakovic R, Harley C, Abrahams S, Starr JM. A systematic review of the validity and reliability of apathy scales in neurodegenerative conditions. 

25. Brodaty H, Burns K. Nonpharmacological management of apathy in dementia: a systematic review. 

26. Cai Y, Li L, Xu C, Wang Z. The effectiveness of non-pharmacological interventions on apathy in patients with dementia: a systematic review of systematic reviews. 

27. Ruthirakuhan MT, Herrmann N, Abraham EH, et al. Pharmacological interventions for apathy in Alzheimer’s disease. 

28. Theleritis CG, Siarkos KT, Politis AM. Unmet needs in pharmacological treatment of apathy in Alzheimer’s disease: a systematic review. 

29. Zhou T, Wang J, Xin C, et al. Effect of memantine combined with citalopram on cognition of BPSD and moderate Alzheimer’s disease: a clinical trial. 

Articles

Apathy occurs throughout the spectrum of neurocognitive disorders, but it is easy to mistake for other conditions, like depression. How can clinicians identify apathy, and treat it?

Addressing Apathy in Dementia

The goals for this activity are to understand the epidemiology and neurobiology of poststroke depression, to learn how to complete an appropriate assessment, and to be able to provide comprehensive treatment for these individuals.

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It is estimated that in the United States alone, approximately 795,000 individuals have a stroke annually. The prevalence of stroke is greater among men than women, but the stroke incidence doubles among postmenopausal women. Furthermore, 

 was rated as the third most common cause of disability adjusted life-years worldwide in 2010.

 In the United States, stroke has been established as the most burdensome of all neurological disorders.

 found that among the long-term (15 year) survivors of stroke, 33.8% have mild disability, 14.3% have moderate disability, and 15.0% have severe disability (

). The prevalence of disability increased with time, but 10% of these individuals had lived with moderate-severe disability since their stroke.

Available evidence indicates that there are a multitude of neuropsychiatric syndromes that occur after a stroke (

 Poststroke bipolar disorder, mania, and psychotic symptoms are rare sequelae to stroke. Cognitive impairment occurs in approximately one-third of individuals post stroke.

 often impede the recovery of motor functioning, reduce social functioning, and decrease the overall quality of life.

A recent meta-analysis found that the prevalence of any depressive disorder post stroke is approximately 33.5%.6 In this study, the point prevalence of major depression was 17.7% with the prevalence for minor depression being 

.1%. Prevalence of dysthymia and adjustment disorder was 3.1% and 6.9%, respectively. An earlier meta-analysis found that the frequency of poststroke depression was approximately 31%.7 The proportion of those with depression between 1 and 5 years after stroke was 25%, and the proportion of those with depression at 5 years after stroke was 23%.

Figure 1. Disability Among Long-Term Survivors of Stroke

Figure 2. Neuropsychiatric Symptoms Occurring After a Stroke

In the DSM-5, poststroke depression (PSD) is classified under the criteria for “

Depressive Disorder Due to Another Medical Condition

). To meet the DSM-5 criteria, individuals should present with a prominent and persistent period of depressed mood or markedly diminished interest or pleasure in all or almost all activities. The history, physical examination, or laboratory findings should show that the depressive symptoms are due to the direct pathophysiological consequence of a stroke. Furthermore, the presence of depressive symptoms should not be better explained by another mental disorder, including an adjustment disorder, nor should the depressive symptoms occur exclusively during the course of a 

. In addition, these symptoms should cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

Figure 3. Prevalence of Depressive Disorders After a Stroke

PSD symptoms can be further subclassified as presenting with (1) depressive features when all criteria for a major depressive episode are not met, (2) a major depressive-like episode when the criteria for a major depressive episode are met, and (3) mixed features when symptoms of mania or hypomania are also present but do not predominate in the clinical presentation.

PSD phenomenology is similar to, but not the same as, that described by other individuals with depression.

 For example, individuals with PSD are less likely to report “inability to feel” or “disturbed sleep.” In addition, individuals with PSD may be less likely to report anhedonia and apathy when compared with other individuals who have 

. In one study, researchers compared symptoms in (1) poststroke patients with and without depression, (2) individuals who were being seen in general practice, and (3) patients with symptomatic atherosclerotic diseases.

 They found that although the 3 cohorts demonstrated broadly similar symptom profiles, as well as comparable levels of individual symptom prevalence, the individuals with PSD had more severe symptoms than individuals in the other 2 groups.

A recent meta-analysis by Shi et al indicated that a history of mental illness (depression/anxiety) was the highest-ranking risk factor for PSD (odds ratio [OR] 2.93).

 Other risk factors for PSD were family history of mental illness (OR = 1.95), age (< 70 years, OR = 1.94), female sex (OR = 1.77), level of handicap (OR = 1.52), severity of stroke (OR = 1.12), and neuroticism (OR = 1.08). The investigators also found that education (> 8 years) and social support (OR = 0.93) were protective factors for PSD. Brain damage in the left frontal lobe and left basal ganglia was associated with PSD, and specified levels (< 10.2 ng/ml) of brain-derived neurotrophic factor and leptin (> 20.7 ng/ml) were risk factors for PSD. Biochemical factors, including interleukin-1b (IL-1b) and intercellular cell adhesion molecule-1 (ICAM-1), hypertension, 

 mellitus, hyperlipidemia, atrial fibrillation, and myocardial infarction were not found to be associated with PSD.

In a prospective observational study of individuals who were post stroke and in the emergency department or admitted to acute care in designated stroke centers, individuals with PSD had more severe strokes, greater functional handicap, and longer hospital stays and were less likely to be discharged home following acute hospitalization (all P < .001) than patients without PSD.

 One systematic review indicated that individuals with PSD tend to experience a moderate increase in the risk of poor functional outcome (OR = 2.16) when compared with stroke patients without depression.13 This association did not seem to be caused by poor rehabilitation and functional improvement among individuals with PSD.

 is also a consequence of PSD. A meta-analysis by Bartoli et al found the pooled proportion of suicidal ideation among stroke survivors was 11.8%.

 Current (OR = 11.50; P < .001) and past (OR = 6.96; P < .001) depression, recurrent stroke (OR = 1.77; P < .001), disability (P = .01), and cognitive impairment (P = .03) were all associated with

. Suicidal ideation was less likely to occur in stroke survivors who were married (OR = 0.63; P < .001), employed (OR = 0.57; P = .02), and had higher education levels (OR = 0.55; P = .002). A meta-analysis by Cai et al found that PSD was associated with significantly increased risk for mortality among stroke survivors (HR = 1.59).

The pathogenesis of PSD involves complex interactions between neuroanatomical and neurochemical factors.

 It is thought that the processes involved in development of PSD include reduced levels of monoamines, abnormal neurotrophic response to the occurrence of stroke, increased 

 in the brain, dysregulation of hypothalamic-pituitary-adrenal (HPA) axis, and glutamate-mediated excitotoxicity.

 Available studies indicate that large lesions in critical areas of the brain, including the left frontal lobe and basal ganglia or the accumulation of silent cerebral lesions beyond a critical threshold, may interrupt the pathways of monoamine neurotransmitters or pathways that control mood regulation.

 Cytokines that are produced post stroke increase glutamate-induced excitotoxicity, resulting in neuronal death in critical areas of the brain. This may also lead to the enlargement of cerebral infarctions. This process, coupled with hypercortisolism induced by stress or inflammation after the stroke, may reduce intracellular serotonin transporters, resulting in depression. Additionally, hippocampal neurogenesis may be inhibited by the interaction among cytokines, glucocorticoid, and neurotrophin. Available evidence indicates that these neurobiological processes, seen among individuals who develop PSD, may differ from individuals who do not develop depression after a stroke, but the details regarding these complex mechanisms are only emerging.

Although fairly common, PSD is often underdiagnosed.

 Differential diagnosis is difficult, as many of these individuals who are post stroke may present with cognitive impairment and may not be able to report their symptoms accurately (

). In addition, some symptoms of stroke and depression (eg, loss of appetite, difficulty concentrating, and 

) may be indistinguishable from one another. In these situations, the presence of nonsomatic symptoms including guilt, depressed mood, hopelessness, or worthlessness is more suggestive of PSD.

In one study, PSD was diagnosed in only 4.8% of the patients, and only 6.7% of these individuals were treated with a new antidepressant.

 However, compared with patients admitted to standard units, individuals admitted to specialized stroke units were more likely to be diagnosed with depression (5.2% vs 4.0%, P < .014) and were more likely to receive a new prescription for an antidepressant (7.8% vs 4.5%, P < .001). These results indicate that there should be routine screening post stroke for PSD. Additionally, specialized stroke unit care may improve the detection and treatment of PSD.

A number of tools may be helpful in identifying PSD. One meta-analysis found that the Center of Epidemiological Studies-Depression Scale (CES-D) (sensitivity, 0.75 and specificity, 0.88), the Hamilton Depression Rating Scale (HDRS) (sensitivity, 0.84 and specificity, 0.83), and the Patient Health Questionnaire (PHQ)-9 (sensitivity, 0.86 and specificity, 0.79) were optimal screening tools.21 The PHQ-2 performed less well than other measures. However, the investigators found that the clinical utility of these tools was modest for case-finding. They cautioned that these screening tools should not be used in 

; a more detailed clinical assessment to detect PSD should also be used.

A meta-analysis by Hackett et al evaluated interventions for preventing PSD. The investigators included data from 10 pharmaceutical trials (12 comparisons) and 4 psychotherapy trials. 

 Most of the participants were recruited within 1 month of acute stroke, and the duration of treatment ranged from 2 weeks to 1 year. The proportion of participants meeting the study criteria for depression was lower in the antidepressant‐treated group; however, meta‐analysis was not performed, as the study methods and end point measured varied among studies. There was no evidence of benefit of 

 on the mean depression scores at the end of treatment or change in mean scores from baseline. Additionally, there was no evidence of 

 improving cognitive function or activities of daily living (ADL) or reducing disability. There was no clear evidence of harm demonstrated in the analysis of adverse events. The investigators noted benefit of psychotherapy in the pooled proportion of participants who met the study criteria for depression at the end of treatment (OR = 0.64) and a reduction in psychological distress scores from baseline on the 28-item General Health Questionnaire (mean difference [MD] = ‐1.37). There was no evidence of benefit or harm either in ADL or social activities. There were also fewer adverse events noted in the intervention group (OR = 3.73).

In a meta-analysis that included data from 10 randomized placebo-controlled trials (RCTs) that evaluated the prophylactic effects of antidepressants in nondepressed individuals with stroke to prevent PSD, Chen et al found the pooled occurrence rates of newly developed PSD cases in the intervention and control groups were 12.54% (41 of 327 participants) and 29.17% (91 of 312 participants), respectively.

 (SSRIs) and tricyclic antidepressants (TCAs) were associated with reductions in the incidence of PSD. The reductions in the incidence of PSD were not related to the interval between stroke onset and the administration of an antidepressant (P = .47), and the prophylactic effects of antidepressants were not related to duration of their use (P = .11).

In a recent meta-analysis, Gu et al included data from 12 studies that evaluated the use of prophylactic antidepressants to prevent the occurrence of PSD.

 The investigators found antidepressants following acute stroke reduced PSD incidence (relative risk [RR] = 0.33, P < .001). There were no differences detected in efficacy noted between the SSRIs, TCAs, and serotonin norepinephrine reuptake inhibitors (SNRIs) in the subgroup analysis. When compared with the control group, the RR of PSD recurrence during the follow-up period in the treatment group was 0.51 (P < .001). The pooled mean difference in reduction of depression severity on the HDRS between the antidepressant and control groups was 5.73 (P < .001). Additionally, there were improvements in the motor function (weighted mean difference [WMD] = 12.56, P < .001) and neurological function (WMD = 1.13, P < .001) between the antidepressant and the control groups. There were no differences between the 2 groups with regard to mortality rates (RR = 1.63, P = .377) or incidence of adverse events (RR = 0.93, P = .806).

In a cross-sectional study of data from the National Ambulatory Medical Care Survey and its outpatient department, Bhattacharjee and colleagues found that only 47.32% of the participants with PSD received treatment, which was mainly driven by the use of antidepressant alone. In this study, men were approximately 3 times more likely to receive depression treatment compared with women.

 Additionally, individuals who were Caucasian were almost 4 times more likely to receive depression treatment compared with other races or ethnicities. This study also found that an increase in number of chronic diseases was associated with a lower likelihood of receiving any 

In a meta-analysis of 28 RCTs that evaluated cognitive behavioral therapy (CBT) for PSD, the investigators found that CBT had positive effects on PSD when compared with control groups (P < .001).

 Both CBT alone (P = .001) and CBT in combination with antidepressants (P < .00001) improved depressive symptoms in PSD. CBT resulted in significantly higher remission rates (P < .00001) and response rates (P < .00001), improving anxiety, neurological functional deficits, and ADL. Data from 8 studies showed no significant relationship between CBT effects and the mean duration after stroke (P > .05).

In a network meta-analysis of 23 RCTs that evaluated 

 PSD treatment interventions, the investigators found that SNRIs were associated with the highest reduction in the depression scores, followed by TCAs, psychotherapy plus antidepressant, and SSRI antidepressants.

 In a second network meta-analysis, the investigators included data from 15 RCTs in which 13 antidepressant drugs were considered.

 The investigators found that for efficacy, paroxetine was ranked the best antidepressant for reduction in depression scores at the end of treatment, followed by imipramine, reboxetine, nortriptyline, citalopram, and fluoxetine. They also found that duloxetine ranked the best for the reduction in depression scores at durations of 4 weeks and 8 weeks. For tolerability, paroxetine was ranked the best, but there was no significant difference noted between any of the comparisons. In a third network meta-analysis of 14 RCTs with 9 different antidepressant treatments, the investigators found that doxepin, paroxetine, and nortriptyline were significantly more effective than placebo (standardized mean differences: -1.93, -1.39, and -1.25, respectively) in the treatment of PSD.

In a study that evaluated transcranial direct current stimulation (tDCS) for PSD, the investigators randomized 48 antidepressant-free individuals with PSD into 2 groups: active and sham tDCS.30 Participants received twelve 30-minute sessions of left/cathodal right dorsolateral prefrontal tDCS over a 6-week period: once daily on weekdays for 2 weeks, then 1 session every other week. The primary outcome was a change in the 17-item HDRS at 6 weeks. The investigators found that active tDCS was superior to sham at the end point (P < .001). The response and remission rates were also significantly higher in the active treatment group (37.5% and 20.8%, respectively) when compared with the sham treatment group (4.1% and 0%, respectively). The number-needed-to-treat for response and remission were 3 and 5, respectively. There were no changes in cognitive performance due to tDCS, and the frequency of adverse events was not significantly different between the active and sham groups at all time points. Additionally, no serious adverse events were reported.

 The investigators did not identify any potential predictors of response including depression onset after stroke, duration of the 

A systematic review and meta-analysis of 22 RCTs evaluated the effect of 

repetitive transcranial magnetic stimulation

 (rTMS) on PSD.31 The primary outcome was severity of depression as measured by the HDRS. The secondary outcomes were response rates, remission rates, stroke severity, and ability to perform daily activities. The investigators found that rTMS was beneficial for PSD on all of the following: HDRS (P < .001); response rates (OR = 3.46, P < .00001); remission rates (OR = 0.99, P < .00001); National Institutes of Health Stroke Scale (P < .001); ADL (P < .001); and Montgomery-Asberg Depression Scale (P = .0001). A total of 15 (1.7%) participants in the active treatment group and 6 (0.7%) participants in the control group experienced headache; 2 (0.2%) participants in the active treatment group and 9 (1.0%) participants in the control group developed gastrointestinal reactions; 3 (0.3%) participants in the active treatment group and 7 (0.8%) participants in the control group had dry mouth; 1 (0.1%) participant in the active treatment group suffered from tinnitus; 1 (0.1%) participant in the active treatment group felt weak; and 6 (0.7%) participants in the control group experienced other adverse events. The investigators did not find any statistically significant differences in withdrawals due to adverse events between the 2 groups; 0.2% (2 of 881) of patients in the control group withdrew due to gastrointestinal effects. Because of the significant heterogeneity between the different studies, the effect of frequency of treatment, site, duration of illness, type of basic treatment, type of control intervention, and total session on outcomes could not be evaluated.

PSD is a common sequela of stroke. The pathogenesis of PSD involves complex interactions between both neuroanatomical and neurochemical factors. PSD is associated with more severe strokes, greater functional handicap, longer hospital stays, lower likelihood of discharge to home following acute hospitalization, and a greater risk for mortality. Common risk factors for PSD include a history of mental illness (depression/anxiety), a family history of mental illness, age (< 70 years), female sex, level of handicap, severity of stroke, and neuroticism.

Although fairly common, PSD often remains underrecognized and poorly treated. Available evidence indicates efficacy of both nonpharmacological and pharmacological treatment strategies for the prevention of PSD. Early identification and appropriate management of PSD will reduce the morbidity and mortality due to this condition. Future research should investigate the pathophysiological underpinnings of PSD, so that more effective preventative and treatment strategies can be developed.

is professor and chairman, Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General and Chief, Section for Geriatric Psychiatry, Department of Psychiatry and Psychology, Cleveland Clinic. 

 is a research coordinator, Department of Research at Cleveland Clinic Akron General and clinical assistant professor of Obstetrics and Gynecology, Northeast Ohio Medical University.

1. Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. 

2. Feigin VL, Vos T, Alahdab F, et al; GBD 2017 US Neurological Disorders Collaborators. Burden of neurological disorders across the US from 1990-2017: a global burden of disease study. 

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https://dsm.psychiatryonline.org/doi/full/10.1176/appi.books.9780890425596.dsm04

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Available evidence indicates that there are a multitude of neuropsychiatric syndromes that occur after a stroke. Cognitive impairment occurs in approximately one-third of patients. These neuropsychiatric manifestations often impede the recovery of motor functioning, reduce social functioning, and decrease the overall quality of life.

Rajesh R. Tampi, MD, MS, DFAPA

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