Article Archive
September/October 2015

Poststroke Depression
By Mark D. Coggins, PharmD, CGP, FASCP
Today's Geriatric Medicine
Vol. 8 No. 5 P. 6

With a prevalence estimated to range from 30% to 50%,1 poststroke depression (PSD) is common. While the incidence of depression increases with age and disability and in individuals with chronic conditions, the risk of depression in stroke survivors is double that seen in the general population. PSD is a common consequence of ischemic stroke and peaks within the first three to six months; however, depression can occur at any point following a stroke. Persistent depression occurs in approximately 30% of poststroke patients, with as many as 59% of poststroke survivors experiencing PSD within five years of stroke.2 About one-half of individuals with PSD suffer from major depression while the other one-half experience minor depression.3 For up to 18 months following a stroke, the risk of major depression is nearly twice that of patients who have not suffered stroke.4 In studies, recovery from PSD ranged from 15% to 57% one year after stroke. Although patients with PSD may recover spontaneously within 12 months, untreated patients are at risk for chronic depression beyond two years.2

Risk Factors
The pathophysiology of PSD is complex, but it is believed to be influenced by the location and extent of brain injury, vascular comorbidities, and reaction to new functional disability. Depressive symptoms may be caused by the ischemic brain injury as well as a psychological reaction to the illness.5

Risk factors for PSD include female gender, history of depression, degree of functional limitations, and cognitive impairment. A history of depression and the need for assistance with activities of daily living appear to correlate most closely to depression risk.2

While stroke leads to a higher risk of depression, individuals with significant depressive symptoms prior to a stroke appear to be about twice as likely as persons with few depressive symptoms to have a stroke within 10 years.6

Having a stroke has been described as a "small death," which may initiate both normal grieving processes and/or progression to depressive symptoms. Stroke survivors experience varying degrees of anger, frustration, anxiety, sadness, fear, and hopelessness.7 Patients often experience decreased appetite and weight loss, disturbed sleep patterns, loss of energy, sense of worthlessness, anhedonia, psychomotor retardation, and/or agitation.8 Furthermore, depression increases mortality, worsens preexisting medical conditions including cardiovascular disease and diabetes, and ultimately may lead to suicidal ideation, which has been reported up to 24 months after stroke.8-10

Approximately 20% of stroke patients require institutional care at three months after stroke, further contributing to social isolation commonly seen in PSD patients and leading to reduced quality of life, longer stroke recovery, and increased health care burden.11 PSD may reduce the capacity and desire to participate in rehabilitation, making rehabilitation much more difficult than for nondepressed stroke patients. PSD patients' hospital recovery time is slower and less successful with patients who are less likely to regain normal lifestyles after discharge and poorer survival rates long term. In fact, PSD patients are 3.4 times more likely to have died during the 10 years poststroke when compared with patients who are not depressed following stroke.3

Screening and Assessment
PSD is often underrecognized and undertreated in stroke patients due to a number of challenges, including difficulty in differentiating between depression and normal poststroke grief, lack of consistency of screening tools, language and cognition disturbances, change in emotional and behavioral cues related to stroke location, social stigma, and general lack of awareness of care providers.12

The Patient Health Questionnaire (PHQ-9) is a nine-item question scale based directly on the nine diagnostic criteria for major depressive disorder in the Diagnostic and Statistical Manual of Mental Disorder, 4th Edition and can help overcome challenges associated with assessing for PSD. Some clinicians recommend using the first two items (PHQ-2) as an initial depression screening. If a patient responds affirmatively to either of these two items, the remaining seven items are asked. The PHQ-9 is shorter than other depression scales and can be administered in person or by telephone or can be self-administered. It assesses symptom severity, has been proven effective in a geriatric population, and is well validated and documented in a variety of populations. The biggest flaw of the PHQ-9 with regard to stroke patients is its reliance on good verbal communication.13 Other screening tools include the Becks Depression Inventory, Global Depression Scale, and the Clinical Global Impression assessment.14 The Cornell Scale for Depression in Dementia incorporates both observer- and informant-based information and is helpful in evaluating cognitively impaired patients for depression.

The PHQ-9 is available in multiple languages and can be accessed for free at

PSD is widely undertreated with nearly 70% of people experiencing persistent depression untreated with antidepressants at both three or 12 months poststroke.5

Pharmacotherapy Treatment Options15
Treatment options include pharmacotherapy, psychological and behavioral interventions, or a combination of the two. However, the goal of treatment during the acute phase is remission, which is defined as the absence of depressive symptoms or the presence of minimal depressive symptoms.

It is widely accepted that all antidepressants have similar efficacy, so the choice of agent is based primarily on the antidepressant's expected tolerability and side-effect profile. Starting with low doses (eg, one-half of the usual effective dose) and then slowly titrating the dose upward after one to two weeks until the usual therapeutic dose is achieved can result in improved tolerability with fewer side effects. Patients without at least a partial response by week four to six at the usual adult therapeutic dose are unlikely to respond to that treatment and should be switched to a different antidepressant medication. For patients experiencing clinically significant improvement at four weeks of therapeutic dose, it is reasonable to extend the initial treatment if the current antidepressant is tolerated.

The conclusion of the acute phase of treatment is remission, which ideally occurs within the first six to 12 weeks of therapy. The primary goal of the second phase (continuation phase) is to sustain remission and prevent relapse with treatment continued at the same dose for an additional six to 12 months to decrease the risk of relapse. Because recurrence of depression after a first episode is common, clinicians should educate patients and their families to self-assess for symptoms and risk for recurrent episodes.

Maintenance therapy may be required for patients at high risk for recurrent depressive episodes. The maintenance phase begins at the time the physician considers the patient to be recovered yet at a risk for recurrence, which may last many years, and perhaps even indefinitely.

General Recommendations
• The choice of antidepressant is based on side-effect profiles, history of prior response, concurrent medical illnesses, concurrently prescribed medications, and antidepressant cost.

• Lower initial doses should be considered and then slowly titrated upward to the full antidepressant dose in elderly who are at an increased risk of side effects.

• Prior to discontinuing an antidepressant as a failure, providers should ensure that an appropriate dose titration and target dose range has been achieved and an adequate response period allowed (a minimum of four to six weeks).

• Discontinuation of antidepressant maintenance therapy should be done with a slow taper, as it may result in adverse withdrawal symptoms or return of original depressive symptoms. Tapering should be guided by the elimination half-life of the parent compound and metabolites and by close monitoring of depressive symptoms.

Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs (eg, citalopram, escitalopram, fluoxetine, paroxetine, sertraline) work at the level of the synapse by blocking serotonin reuptake. SSRIs are generally considered first-line agents for PSD due to their greatest levels of tolerability in the general population. SSRIs are most often associated with nausea and mild headache. Decreased libido and difficulty achieving orgasm have also been noted to be persistent problems and are most widely observed in paroxetine, which also has the greatest potential for anticholinergic side effects among SSRI agents. Most importantly, SSRIs may increase the risk of bleeding in the elderly population and may cause hyponatremia, requiring monitoring of sodium levels. Bleeding risk results from their inhibiting platelet function, and disorders may range from bruising to gastrointestinal bleeding. Therefore, caution should be used with regard to hemorrhagic strokes. Other potential side effects include anorexia early in treatment; gastrointestinal disturbances such as nausea, vomiting, and diarrhea; sedation or insomnia; and serotonin syndrome. Sertraline appears to exhibit the most significant gastrointestinal side effects.

Patients who fail or are intolerant of one SSRI can be switched to another SSRI or to another first-line antidepressant. Following a second failure with a different SSRI, the patient should be switched to another class of antidepressant.

Tricyclic Antidepressants (TCAs)
While they are as effective as other antidepressant agents, TCAs have many potentially dangerous side effects and should generally be avoided in elderly patients. If the use of TCAs is necessary, nortriptyline and desipramine should be considered first. The most common side effects of the TCAs include anticholinergic effects such as dry mouth, blurred vision, increased intraocular pressure, constipation, and urinary retention; cardiovascular effects such as orthostatic hypotension, syncope, tachycardia, and arrhythmias; central nervous system effects such as sedation and confusion; weight gain, especially with amitriptyline and doxepin; and sexual dysfunction. TCAs can also lower seizure threshold.

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)
SNRIs (eg, venlafaxine and duloxetine) are potent inhibitors of serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. SNRIs may also be considered first-line agents for PSD; however, they appear to have higher discontinuance rates compared with SSRIs.

Mirtazapine increases the release of norepinephrine and serotonin via its action as a central presynaptic alpha2-adrenergic agonist. Mirtazapine also antagonizes 5-HT3 serotonin, H1 histamine, and peripheral alpha1-adrenergic and muscarinic receptors. Because of its unique mechanism of action and pharmacologic profile, mirtazapine's adverse event profile differs from other antidepressants, most notably in its sedative properties at lower doses. Mirtazapine, along with SSRIs, SNRIs, and bupropion, is considered a first-line treatment option for major depressive disorder. Mirtazapine can also be used in combination with other antidepressants.

Augmentation with medication may be considered for patients who have had a partial response to antidepressant monotherapy at a therapeutic dose after at least six weeks. The augmenting medication selected should be based on the patient's current medications, including antidepressants, comorbid conditions, and adverse effect profile. Mirtazapine may be a good option for patients where weight gain is desired.

Bupropion is an augmentation option for patients who have partially responded to a different antidepressant but have not achieved remission. Bupropion may be considered for patients for whom weight gain would be problematic or for patients who experienced intolerable weight gain with another antidepressant. Bupropion should not be prescribed to patients with a history of seizure disorder or anorexia nervosa or bulimia and may not be the best choice for patients with significant anxiety.

Bupropion SR and the antianxiety agent buspirone are equally effective at achieving remission when used to augment first-line antidepressant treatment (eg, SSRIs). Bupropion SR and buspirone are recommended as initial choices for augmentation since their efficacy has been demonstrated in at least one randomized clinical trial and their safety and tolerability profiles are more favorable than lithium.

The psychostimulants may have a role as augmentation agents. There is limited research regarding use of psychostimulants in PSD although there is clinical use reported, especially in patients with marked vegetative symptoms, apathy, and lethargy. Primary stimulants used are methylphenidate (Ritalin) and dextroamphetamine with 82% of patients improved and 47% showing marked improvement.16 Psychostimulants work quickly although effectiveness as monotherapy may be limited due to development of tolerance. Anorexia does not appear to be a concern as appetite often improves with mood. Caution should be exercised with psychostimulants as they are controlled substances and have abuse potential.

— Mark D. Coggins, PharmD, CGP, FASCP, is senior director of pharmacy services for skilled nursing centers operated by Diversicare in eight states, and is a director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

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5. El Husseini N, Goldstein LB, Peterson ED, et al. Depression and antidepressant use after stroke and transient ischemic attack. Stroke. 2012;43(6):1609-1616.

6. Jonas BS, Mussolino ME. Symptoms of depression as a prospective risk factor for stroke. Psychosom Med. 2000;62(4):463-471.

7. Koewenhoven SE, Kirkevold M, Engedal K, Kim HS. 'Living a life in shades of grey': experiencing depressive symptoms in the acute phase after stroke. J Adv Nurs. 2012;68(8):1726-1737.

8. Graven C, Brock K, Hill K, Ames D, Cotton S, Joubert L. From rehabilitation to recovery: protocol for a randomized controlled trial evaluating a goal-based intervention to reduce depression and facilitate participation post-stroke. BMC Neurol. 2011;11:73.

9. Gelenberg AJ, Hopkins HS. Assessing and treating depression in primary care medicine. Am J Med. 2007;120(2):105-108.

10. Kishi Y, Robinson RG, Kosier JT. Suicidal ideation among patients with acute life-threatening physical illness: patients with stroke, traumatic brain injury, myocardial infarction, and spinal cord injury. Psychosomatics. 2001;42(5):382-390.

11. Creutzfeldt CJ, Holloway RG, Walker M. Symptomatic and palliative care for stroke survivors. J Gen Intern Med. 2012;27(7):853-860.

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15. Department of Veteran Affairs, Department of Defense. VA/DoD clinical practice guideline for management of substance use disorders (SUD). Published August 2009.

16. Masand P, Murray GB, Pickett P. Psychostimulants in post-stroke depression. J Neuropsychiatry Clin Neurosci. 1991;3(1):23-27.


Consequences of Poststroke Depression
• Worse long-term functional outcomes

• Reduced rehabilitation treatment efficacy

• Limitations in activities of daily living

• Cognitive impairment

• Higher risk of recurrent stroke

• Increased mortality risk