Neuropsychiatric Sequelae of Stroke: Issues and Implications for Clinicians

Table 1: Prevalence of post-stroke neuropsychiatric disorders

Table 2: Distinguishing post-stroke apathy from post-stroke depression

Many patients who have had a stroke experience neuropsychiatric sequelae, such as apathy, depression, anxiety, PTSD, irritability, pseudobulbar affect, impulsivity, mania, and psychosis (Table 1). Every year in the United States, almost 800,000 people have a stroke, which creates a large population at risk for post-stroke neuropsychiatric disorders. The prevalence of stroke in younger individuals is increasing, and it is likely that psychiatrists might encounter these disorders.¹ Post-stroke neuropsychiatric disorders can follow either ischemic or hemorrhagic stroke; attempts to link specific psychiatric disorders with the type, mechanism, or location of stroke have not produced clear associations.²

This review focuses on post-stroke depression (PSD), apathy, anxiety, and PTSD, because these disorders occur and have been studied most frequently. Of these disorders, PSD remains the best-understood condition.

Post-stroke neuropsychiatric disorders do not occur solely as an adjustment reaction to disability or increased awareness of one’s mortality-rather, the direct neurophysiological effects of stroke can cause depression and other disorders. For example, older adults with “asymptomatic” ischemic white matter disease and no history of clinical stroke show higher rates of depression.³ Stroke and psychiatric disorders have a bidirectional relationship and may share common risk factors-not only does stroke increase the risk of depression, anxiety, and mania, but individuals with premorbid idiopathic forms of these conditions also have an increased risk of stroke, even after controlling for conventional vascular risk factors. While the definitive explanation remains unknown, shared etiologic factors may include inflammation, hypothalamic-pituitary-adrenal axis deregulation, serotonin-mediated effects on platelet and endothelial function, and excessive sympathetic tone.

Some general treatment principles apply across different post-stroke neuropsychiatric disorders. Up to 25% of stroke patients will experience a second stroke in the next 5 years; a recurrent stroke may well negate any benefits received from interim psychiatric treatment.¹ Thus, patients need appropriate secondary stroke prophylaxis, such as antiplatelet agents or anticoagulation for ischemic stroke; control of hypertension, hyperlipidemia, and diabetes mellitus; assistance with smoking cessation; and regular exercise.

While psychiatrists need not personally provide treatment for comorbid medical conditions, they should make sure a primary care physician (PCP) or an appropriate specialist does, and they should make referrals as necessary. If possible, psychiatrists should avoid prescribing medications with adverse metabolic effects (eg, atypical antipsychotics) or that can cause hypertension (eg, stimulants, SNRIs). Review with patients and families the warning signs of stroke and the importance of immediately calling 911 if such symptoms occur, so that thrombolytics can be administered if appropriate.

Patients with post-stroke neuropsychiatric disorders require ongoing evaluation of suicide risk. Up to 7% of patients with stroke subsequently die by suicide, a much higher rate than the general population, and elevated suicide risk may persist for 5 years after a stroke.⁴ Depression represents the most significant risk factor for post-stroke suicide, although patients with less severe strokes and younger patients also show increased risk. Post-stroke fatigue may constitute an independent risk factor for suicidal ideation, but this has not been clearly established.

Post-stroke depression

PSD may take the form of a major depressive episode or may resemble minor depression; however, both have significant clinical implications. Clinicians need to be able to differentiate symptoms of PSD from those of post-stroke apathy because they are similar; however, many patients experience both. Post-stroke irritability may also occur in the context of depression.²

PSD may persist for more than 1 year in up to half of patients. If depression does not manifest in the initial post-stroke period, it may develop anytime over the next year. A history of previous depression significantly increases the risk of PSD, but de novo depression can also develop following a stroke in persons without any prior psychiatric history.

In addition to causing personal suffering, PSD is associated with other adverse outcomes. Among individuals who have experienced a stroke, those with PSD have increased mortality; however, antidepressant treatment may ameliorate this excess mortality. Patients with PSD also recover more slowly from neurological deficits and have more disability and worse quality of life.

PSD responds to treatment, and treatment can improve both mood and overall health outcomes, such as degree of disability, independent functioning, and mortality. Multiple randomized placebo-controlled trials have established the efficacy of SSRIs and TCAs for treatment of PSD.³ Moreover, SSRIs given to patients following stroke may actually prevent the development of depression, improve motor and cognitive outcomes, and reduce mortality.

SNRIs, mirtazapine, stimulants, repetitive transcranial magnetic stimulation, and electroconvulsive therapy may also improve PSD, but the evidence base for SSRIs and TCAs remains far more robust.^3,5 Patients who receive antidepressants for PSD may benefit from continuing these medications for at least 2 years, since earlier discontinuation can worsen depression symptoms. One randomized controlled trial (RCT) of patients with stroke and transient ischemic attack (TIA) who underwent intensive vascular risk factor modification demonstrated less depression 1 year after the event-yet another reason for psychiatrists to promote secondary stroke prophylaxis.⁶

SSRIs probably represent the best first-line choice for pharmacotherapy for PSD because persons with stroke experience more vulnerability to adverse cognitive effects from anticholinergic medications such as TCAs. SSRIs may also be beneficial for post-stroke motor deficits. An increased risk of hemorrhagic stroke was seen in persons in the general population who were taking SSRIs. The risks and benefits of SSRIs for depression following hemorrhagic stroke should be carefully considered, particularly when patients take other medications known to increase intracerebral hemorrhage.

Psychotherapeutic interventions aimed at optimizing patient and family function, and behavioral activation and problem-solving strategies may improve PSD. Behavior therapy may be effective for depression in patients with aphasia. Regular vigorous exercise may also decrease stroke-related depression symptoms.

CASE VIGNETTE

Linda, a 54-year-old right-handed woman, experienced a small left frontal ischemic stroke that resulted in mild right arm weakness but no other apparent disability. On follow-up with her PCP, Linda reported that ever since the stroke, she has felt sad and down, and she finds it difficult to enjoy socializing with her family and friends, playing with her pets, and pursuing any of her previous hobbies: “I don’t know what’s wrong; I’ve never had anything like this happen before. I’ve always been a happy person.” She cries frequently and has had more of a temper since the stroke, but she denies any thoughts of harming herself. Her PCP initiates treatment with fluoxetine and refers her to a psychiatrist.

Linda is given a diagnosis of depressive disorder due to stroke. The psychiatrist continues the treatment with fluoxetine, provides behavioral activation interventions, and counsels her on the importance of taking her daily aspirin and blood pressure medication. The psychiatrist continues to monitor her symptoms and titrates the fluoxetine until her depression symptoms fully remit. She begins long-term maintenance at this dose. At a follow-up visit, Linda’s mood has returned to normal, and she feels her right hand function improved as well.

Post-stroke apathy

Post-stroke apathy can manifest as lack of motivation, impairment of goal-directed activity, loss of spontaneity and initiative, decreased interest, and/or emotional blunting. Apathy may begin in the acute post-stroke period or develop in the chronic phase. Patients with post-stroke apathy show more disability and impairment of cognition than patients without apathy and have worse health-related quality of life.^7,8

Distinguishing apathy from depression, particularly in the context of neurological illness, poses challenges. However, because prognosis and treatment may differ, making a correct diagnosis remains essential. Table 2 outlines features that help differentiate post-stroke apathy from PSD. Apathy frequently causes more distress to patients’ families than to the patients themselves. Although the family often reports that the patient is “depressed,” the patient denies low mood or true anhedonia, precluding the diagnosis. However, apathy and depression frequently coexist, and apathy constitutes a risk factor for depression.

One study found that prophylactic post-stroke treatment with an SSRI or problem-solving therapy reduced the incidence of apathy.⁹ However, apathy-regardless of cause-generally responds less robustly to treatment than does depression. Thus far, there are no RCTs of treatment for post-stroke apathy with drugs readily available in the US. Case reports and small series describe improvement in apathy with dopamine agonists and stimulants, and these medications have some evidence for treating apathy due to other disorders.^8,10,11 There has been concern that SSRIs could worsen apathy in nonstroke patients, but one small open-label study of older adults with idiopathic MDD found that SSRIs improved comorbid apathy, although less so than they improved symptoms of depression.¹²

While no studies have examined psychotherapeutic or psychosocial treatments for existing post-stroke apathy, interventions such as animal therapy, music therapy, and participation in activities may improve dementia-related apathy.

CASE VIGNETTE

Dennis, a 62-year-old right-handed man, is brought to a psychiatrist by his wife. She is concerned that he has been depressed since his right anterior cerebral artery stroke 6 months previously. He does not cry or complain of sadness but sits in his recliner all day doing nothing, even though he does not have significant sensorimotor deficits that would prevent more activity. When the psychiatrist asks Dennis about his mood, he says he feels “fine” but acknowledges that he no longer gardens-previously his favorite hobby-and never makes plans to socialize. However, he enjoys visits from his grandchildren. His PCP has initiated treatment with sertraline, but this medication does not seem to help.

The psychiatrist diagnoses post-stroke apathy and starts Dennis on a regimen of low-dose methylphenidate. The psychiatrist also encourages Dennis’s wife to maintain a regular routine and to continue to initiate activities. The psychiatrist and PCP carefully monitor Dennis’s blood pressure and pulse to make sure the methylphenidate does not produce or aggravate hypertension or a cardiac arrhythmia. At his follow-up 1 month later, Dennis shows more spontaneity in his interactions with others, and he is generally more active.

Post-stroke anxiety

Most studies of anxiety disorders following stroke have focused on symptoms of generalized anxiety disorder (GAD) and panic. Post-stroke anxiety is frequently comorbid with depression and is associated with worse health-related quality of life.

Findings indicate that SSRIs, buspirone, and an SSRI plus supportive psychotherapy are beneficial for post-stroke anxiety.¹³ Moreover, the rates of subsequent GAD were lower in patients prophylactically treated with an SSRI or problem-solving therapy following stroke than in untreated patients.¹⁴

Post-stroke PTSD

In one-quarter of patients who experience the potentially life-threatening event of stroke or TIA, PTSD may develop.¹⁵ These patients demonstrated worse adherence to secondary stroke prophylaxis interventions, placing them at higher risk for subsequent stroke.

Thus far, no studies have examined treatment strategies for post-stroke PTSD. Currently, standard treatments for idiopathic PTSD, such as SSRIs and psychotherapy, may represent the best interventions.

Conclusions

Neuropsychiatric disorders occur frequently following stroke and lead to poorer health outcomes and worse quality of life. Psychiatrists should know how to diagnose and treat these disorders, because timely intervention can improve prognosis. SSRIs have the most evidence for treatment of PSD; however, the most effective treatments for other common post-stroke neuropsychiatric disorders remain to be elucidated. Aggressive secondary post-stroke prophylaxis should be seriously considered.

Disclosures:

Dr Byars is a Courtesy Assistant Professor of Neurology at the University of Florida College of Medicine in Gainesville. Dr Jorge is Professor in the department of psychiatry and behavioral sciences at the Baylor College of Medicine in Houston and Staff Psychiatrist in the department of psychiatry at the Michael E. DeBakey Veterans Affairs Medical Center in Houston. The authors report no conflicts of interest concerning the subject matter of this article.

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