Post-Stroke Psychiatric Syndromes: Diagnosis and Pharmacologic Intervention

The post-stroke patient is at significant risk for various psychiatric syndromes. The most commonly reported of these in the literature are post-stroke depression (PSD) and post-stroke dementia (PSDem), which may present simultaneously with overlapping mood and cognitive symptoms. In this article, we offer a review of current literature on post-stroke psychiatric syndromes and an integrated clinical approach to screening, diagnosis, and pharmacologic intervention.

The post-stroke patient is at significant risk for various psychiatric syndromes. The most commonly reported of these in the literature are post-stroke depression (PSD) and post-stroke dementia (PSDem), which may present simultaneously with overlapping mood and cognitive symptoms. In this article, we offer a review of current literature on post-stroke psychiatric syndromes and an integrated clinical approach to screening, diagnosis, and pharmacologic intervention.The importance of psychiatric illness complicating the post-stroke period is well established.1 Integrating assessment for psychiatric symptoms into the care of post-stroke patients is especially critical in the first 6 months following a stroke, a period of high risk for psychiatric complications. Psychiatric and substance abuse history, past treatment with psychopharmacologic agents, family psychiatric history, and personal and family history of suicidal behavior are important items to assess.Evaluation of the patient's living situation, level of social support, and cultural variables is also critical. Careful attention to caregivers' and family members' behavioral observations is necessary, especially in patients with cognitive impairment or other neurologic barriers to communication, such as residual aphasia. Social support for caregivers and patients may decrease the risk of PSD.1,2 Considering psychiatric referral at a low threshold is advisable in these patients, particularly those with more than 1 post-stroke psychiatric disorder.Post-Stroke DepressionDepression that is attributable to a medical disorder, such as stroke, is referred to as "secondary" depression in the psychiatric literature, as opposed to "primary" or "endogenous" depression.1 PSD is thus classified as "mood disorder due to a general medical condition" (code 293.83) in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR).3 It is advisable to apply DSM-IV-TR criteria inclusively in cases of apparent PSD, rather than to attribute mood symptoms to other, less specific causes, such as "stress" or the challenges of coping with neurologic impairment.4 Attribution of mood symptoms to nonspecific stressors can lead to delayed or deficient clinical intervention for PSD.A higher risk of PSD has been linked to left-sided cortical and basal ganglia lesions and to lesions closer to the frontal lobe than to left posterior or right frontal lesions.5-9 This hemispheric localization of PSD risk may be most robust in the first month following stroke.2,4,9 Large reviews have found the risk of PSD to be between 20% and 79%.10-13 For up to 18 months post-stroke, the risk of major depression is nearly twice that in persons who have not suffered stroke.2,14,15 Although patients with PSD may recover spontaneously within 12 months, untreated patients are at risk for chronic illness (even beyond 2 years).12,16Risk factors for PSD include female sex, age less than 60 years, being divorced, alcoholism, nonfluent aphasia, major motor deficit, cognitive deficits, and nursing home residence.17,18 PSD is associated with delayed functional recovery, decreased social function, and greater mortality.12,16,19-24 Suicidal ideation in PSD has been reported up to 24 months after stroke.25PSD may involve a spectrum of mood disorders, including major and minor depression, "vascular depression," and dementia-related depression. Vascular depression (predating stroke) is associated with anhedonia and psychomotor retardation as well as with older age at onset, fewer feelings of guilt, and higher degrees of cognitive impairment than that seen in "primary" major depression.16,26,27 Vascular depression may predict subsequent stroke, myocardial infarction, and greater mortality, although this relationship is complex.21,26,28,29 In addition, primary major depression may present with prominent cognitive symptoms, a condition referred to as depressive pseudodementia, which may itself be a prodromal state for later Alzheimer disease (AD).30 Because these relationships between depression and dementia are imprecise at present, the physician is advised to offer treatment of PSD early in the post-stroke period to maximize mood and cognitive function.24,31-35A helpful screening mnemonic for depression is SIGECAPS: Sleep, Interest level, Guilt, Energy level, Concentration, Appetite, Psychomotor activity level, and Suicidal thoughts can be quickly examined with use of this mnemonic device. The presence of 5 or more of these symptoms (one of which must be depressed mood or decreased interest level) for 2 weeks is the threshold for a diagnosis of major depression. Sub-threshold cases involving clinically significant impairment may also be considered for psychopharmacologic therapy. Other depressive symptoms include tearfulness, pessimism, hopelessness, and nihilism.Depression inventories such as the self-administered Beck Depression Inventory (BDI) and clinician-administered Hamilton Rating Scale for Depression (HDS) can be used to quantify depressive symptoms.36,37 The clinician-administered Post-Stroke Depression Rating Scale (PSDRS) addresses the "major" and "minor" forms of PSD.38 Alternative self-administered scales for PSD and post-stroke anxiety disorders include the Geriatric Depression Scale (GDS) and General Health Questionnaire (GHQ).39 Generally, patients can complete either the BDI, GDS, or GHQ; however, if a patient has significant cognitive deficits, he or she may not be able to report mood symptoms reliably, and clinician evaluation by the HDS or PSDRS may be more helpful.Evaluation for PSD must include an assessment of suicidality, with an urgent psychiatry referral to assess need for psychiatric hospitalization in actively suicid-al patients. As part of the systemic workup for PSD, one should check thyroid-stimulating hormone (TSH) levels, since mild hypothyroidism may mimic depression.40-43 Other systemic factors in PSD include various medications, such as opioids and corticosteroids, and electrolyte abnormalities, which can alter mood and/or cognition.Evidence-based psychopharmacologic treatments for PSD include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and psychostimulants (eg, methylphenidate). No controlled trials have been conducted on other classes of antidepressants (eg, bupropion, venlafaxine, and mirtazapine) for post-stroke treatment, although they are commonly used in clinical practice. Dosing information for antidepressants and augmenting agents in PSD is included in the Table.In the acute phase of PSD, it is advised that SSRIs be used as first-line treatments, since they cause fewer serious side effects, such as delirium and sedation, than do TCAs.44 Case reports of SSRI-related stroke suggest that these medications may increase bleeding risk in some patients because of their effects on platelet function, although a recent major review found no causal relationship between SSRIs and bleeding in post-stroke patients.45 Dosing should follow the aphorism of "start low and go slow," with cautious initial dosing and slower pace of dose increases to avoid significant side effects, but the usual full dose of antidepressant ultimately may be needed. Consider starting antidepressants at half the typical adult starting dose. In an extremely regressed patient, concurrent therapy with a psychostimulant and antidepressant may allow for an earlier response. In general, allow 1 to 2 weeks between dose increases for most antidepressants. It is best to conduct an adequate trial (dose and duration) of the antidepressant: minimally, a trial of 6 weeks' duration at the usual adult therapeutic dose. If the patient achieves clinical remission, continue treatment for up to 12 months at the full effective dose.If no clinical response is seen despite demonstrated adherence, or if the initial antidepressant is poorly tolerated, switch to a different antidepressant class and/or augment the therapy with a psychostimulant (eg, methylphenidate, dextroamphetamine). Consider psychiatric consultation after 2 failed monotherapy trials with different antidepressants or 1 failure with augmentation using a psychostimulant.Psychostimulants may be effective as monotherapy in the short term (1 to 14 days), are generally well tolerated, and may be combined with antidepressants. However, no information is available on long-term effectiveness, tolerability, or other risks. Follow up at least monthly until clinical remission is achieved, repeating the cognitive examination and depression inventory at each visit to monitor treatment response. Post-stroke patients at high risk for PSD-for example, those with prior episodes of depression, left-sided lesions, history of other psychiatric illness, or strong family history of psychiatric illness-may be considered for prophylactic treatment with an antidepressant.The use of psychostimulants for PSD and/or apathy states may be associated with a risk of seizure and/or cardiac side effects. There is little prospective research on the side effects of psychostimulants for PSD, but some studies have shown either no difference from placebo with regard to side effects46 or low incidence of treatment-emergent side effects.47 Concern for these risks must be balanced against undertreatment of PSD. In cases of premorbid cardiac disease, consultation with a cardiologist and careful dosing of psychostimulantsappear warranted. In a patient with post-cerebral vascular accident depression and a history of seizures, consideration of antiseizure medication, along with psychostimulants, appears reasonable.48,49In treatment-refractory cases leading to psychiatric referral, the psychiatrist will consider electroconvulsive therapy for depression-related emergencies, such as repeated suicide attempts and severe melancholic PSD; cases refractory to maximal medication management; or cases in which complex psychopharmacologic regimens cause intolerable side effects. Psychotherapeutic and psychosocial treatments may also be helpful in treatment-refractory cases.Post-Stroke DementiaPSDem, a type of vascular dementia (VaD), is another common psychiatric complication of stroke.50 VaD is coded in the DSM-IV-TR as 290.4X, the fifth digit of the code being "0" for uncomplicated, "1" with concurrent delirium, "2" with concurrent delusions, or "3" with concurrent depressed mood.3 PSDem is the subject of some semantic imprecision because of its overlap with multi-infarct dementia (MID), which results from a series of deep white matter infarcts.51 Some patients may have a mixed model of VaD: preexisting MID with subsequent further decline in cognitive status following a larger stroke.50Some cases of dementia diagnosed in the post-stroke period may represent previously unrecognized cases of AD. In addition, many patients have PSDem because of combined neuropathology, the most important "mixed dementia" being concurrent AD and VaD. Mixed dementia, coded as 290.1X, has multiple causes. The fifth digit of the code is "0" to signify lack of behavioral disturbances; "1" signifies presence of behavioral disturbances.3Dementia symptoms include amnesia, cognitive disorganization, paranoia, visual-spatial dysfunction, language deficits, apraxia, disinhibited and/or unsafe behavior, and poor social judgment. Clinical cognitive examinations such as the Folstein Mini-Mental State Examination or the cognitive portion of the Cambridge Examination for Mental Disorders of the Elderly should be used even in cognitively asymptomatic patients post-stroke and can be repeated serially to monitor progression and/or treatment response.52,53Any precipitous deterioration in cognition in a patient post-stroke should raise the index of suspicion that an additional stroke may be responsible. Structural abnormalities, such as hemorrhagic conversion of stroke or subdural hematoma, also should be considered and usually can be readily excluded with noncontrast CT.54Treatment for post-stroke dementia begins with a low threshold for psychiatry referral for agitated behavior, persistent confusion, or cognitive inability to participate in treatment. An additional workup (vitamin B12, folate, and TSH analysis; toxicology screening; and rapid plasma reagent and HIV testing) for reversible causes of dementia should also be accomplished.55,56The clinical similarities and overlap of VaD and AD should lead the physician to treat PSDem with antidementia pharmacotherapy, even though cholinesterase inhibitors and memantine have been FDA-approved only for AD. PSDem patients may benefit from pharmacotherapy for AD (cholinesterase inhibitors and memantine) and consideration of possibly neuroprotective agents such as antioxidants (vitamin E) and NSAIDs.55,56 Therapy with cholinesterase inhibitors has been shown to benefit AD patients with multiple vascular risk factors, many of whom may represent the mixed dementia described above.57 Some preliminary work with cholinesterase inhibitors for VaD has shown promising results.58,59Patients with PSDem should be followed up monthly, with reassessment of cognitive examination, repeated depression inventory, and screening for psychotic symptoms.-The dose of cholinesterase inhibitor can be increased at monthly intervals if needed to titrate dose to response.-Initiate atypical antipsychotics and/or antidepressants for agitated behavior in PSDem, with a low threshold for psychiatry referral for these symptoms.-Seek caregiver support through psychoeducation, the Alzheimer's Association (, and other community resources-and screen for caregiver distress and depression.-Assess safety of driving and other potentially hazardous activities, which need to be curtailed in patients with significant cognitive and/or psychotic symptoms.-Be sure that PSDem patients have matters of consent, legal competency, and durable power of attorney addressed early in the course of illness.-Facilitate respite care for caregivers through adult day-care centers, in-home caregivers, and outreach nursing intervention.-If the patient cannot safely live independently because of cognitive impairment, agitated behavior, or inability to care for self, assist in getting the patient placed in an appropriate facility (eg, skilled nursing facility expert in caring for patients with dementia).Post-Stroke Psychotic DisorderPost-stroke psychotic disorder, coded as 293.81 with delusions and 293.82 with hallucinations, may be difficult to clearly distinguish from PSD and PSDem.3 Psychotic symptoms include delusions, hallucinations (which may affect various sensory modalities; auditory and visual hallucinations are the most common), ideas of reference, thought disorganization, and regressed motor behavior. Psychotic symptoms may represent PSDem with associated psychosis. Post-stroke psychotic disorder has been reported to correlate with right-sided lesions and cortical/subcortical atrophy.4 Any history of premorbid psychotic illness should be explored. Because of the complexity of these overlapping diagnostic possibilities, and because of the risk of dangerous and disorganized behavior, persons with post-stroke psychosis should be referred for psychiatric care, with subsequent comanagement from the psychiatrist.Treatment includes an atypical antipsychotic, such as risperidone, 0.5 to 1 mg PO bid (use liquid risperidone as needed to facilitate administration), or olanzapine, 2.5 mg PO (tablet), or SL (orally disintegrating Zydis) qhs. Very rare minor strokes have been reported after the use of these medications, but the clinical significance of these events appears to be small.60 Close follow-up every 2 weeks and titration of antipsychotic dose to effect is recommended. Reassessment for reemergence of psychosis, repeated cognitive examination, and depression inventory at each visit are recommended.A patient with preestablished psychotic illness, such as schizophrenia, may decompensate into psychotic symptoms following a major stressor such as a stroke. The "cleanest" case of post-stroke psychosis would be a patient with no previous history of psychotic symptoms in whom psychosis develops only following stroke. It is not clear how previous psychiatric illness affects risk of post-stroke syndromes. Treatments would not differ because they are based on manifest symptoms.Post-Stroke ManiaPost-stroke mania is rare, although it may be associated with right-sided stroke.5,61,62 Manic symptoms include expansive and/or irritable mood, decreased need for sleep, increased goal-directed activity, recklessness, disregard for social constraints, talkativeness, racing thoughts, excessive laughter or giggling, and poor judgment. The clinician should carefully explore any history of premorbid bipolar disorder, personality disorder characterized by mood instability, and family history of bipolar disorder. In addition, cognitive disorders increase the risk of irritable and aggressive behavior.Because management of bipolar-spectrum disorders often requires complex psychopharmacologic regimens, persons with post-stroke mania should routinely be referred for psychiatric care. Thereafter, ongoing comanagement with a psychiatrist (as with post-stroke psychosis) can be facilitated. The typical psychopharmacologic regimen includes a mood stabilizer (lithium is problematic in patients with renal disease and other medically ill patients) and/or an atypical antipsychotic. Observation for downward cycling of mood into an episode of PSD, using mood screening questions and/or depression inventories and clinical observation, is necessary. Antidepressants may induce an elevated mood episode in patients at risk for mania, and treatment of depressed episodes in bipolar-spectrum patients may require an antidepressant and 1 or more mood stabilizers.Post-Stroke Anxiety DisordersPost-stroke anxiety disorders, coded as 293.84, may be comorbid with PSD and may be more common in cortical than subcortical stroke.3,4,8 Anxiety symptoms include discrete episodes of panic, tonic levels of increased anxiety, excessive sweating, worrying, and decreased sleep. Risks of 26% and 39% have been found for post-stroke anxiety disorders in men and women, respectively.17 A combination of anxiety and depression may be more common in left cortical stroke, while depression without anxiety may be more common in left subcortical stroke.4,63Treatment of post-stroke anxiety disorder includes assessment for comorbid PSD. Many anxiety syndromes respond well to antidepressants but may be exacerbated by psychostimulants.64 A trial of 1 or more antidepressants, as described above in the discussion of PSD treatment, is usually best as first treatment. Avoidance of benzodiazepines is important; these agents may cause cognitive decline, verging on PSDem.65 Follow-up should be done in 1 month to assess response. If symptoms are incompletely responsive to antidepressant(s), consider buspirone, either with an antidepressant or as monotherapy.66Other Post-Stroke Psychiatric SyndromesLess frequently seen post-stroke psychiatric symptoms include pathologic crying, pathologic laughter, apathy, and isolated fatigue. These are coded as 293.9: mental disorder due to a general medical condition not otherwise specified.3 Pathologic laughter and crying are sometimes grouped as pathologic emotions (PE) with sudden paroxysms of either laughter or crying, irrespective of the ambient mood state.4 PE can be triggered by nonspecific stimuli or by a low-threshold emotive stimulus. Curiously, the PE do not themselves induce a mood change other than during the affective display, and they are not under voluntary control.12,67 Some literature recommends the use of antidepressants for PE; lithium and anticonvulsants are alternatives.5,67-69Apathy in the absence of depression may be difficult to appreciate, but it presents with profound lack of initiative without tearfulness, sleep/appetite disturbance, hopelessness, or suicidality.5 Some literature supports the use of antidepressants and/or psychostimulants for post-stroke apathy.5 Post-stroke fatigue may be difficult to separate from apathy.70 Antidepressants and psychostimulants may be indicated, particularly those with effects on noradrenergic and/or dopaminergic activity (eg, bupropion, venlafaxine, and mirtazapine). Follow-up within 1 month is needed.ConclusionsPatients post-stroke are at risk for a range of specific psychiatric syndromes. Because these may impair function and/or safety, close follow-up, surveillance, and management should be integrated into the care of these patients. Appropriate use of pharmacotherapy and psychiatric referral may facilitate clinical management and optimize treatment and rehabilitative outcomes.James A. Bourgeois, OD, MD, is associate professor, Department of Psychiatry and Behavioral Sciences, and director, Psychiatry Consultation/Liaison Service, University of California, Davis Medical Center.Donald M. Hilty, MD, is associate professor, Department of Psychiatry and Behavioral Sciences, University of California, Davis Medical Center.Celia H. Chang, MD, is assistant professor, Department of Neurology, University of California, Davis Medical Center.Mark E. Servis, MD, is associate professor, Department of Psychiatry and Behavioral Sciences, University of California, Davis Medical Center.REFERENCES1. Bourgeois JA, Hilty DM, Chang CH, et al. 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