Table 1B: Overview of Antidepressant Therapy for Post-Stroke Depression This table provides a summary of the pharmacotherapeutic properties, side effects, drug interactions and other important information on select medications identified through the evidence reviews as the most frequently used medications for the management of post-stroke depression. This table should be used as a reference guide by health care professionals when selecting an appropriate agent for individual patients. Patient compliance, side effects, drug interactions and comorbidities should all be taken into consideration during decision-making, in addition to other information provided in this table and available elsewhere regarding these medications. Selective Serotonin Serotonin–norepinephrine Other Reuptake Inhibitors (SSRI) reuptake inhibitors (SNRI) Medication citalopram – Celexa duloxetine - Cymbalta methylphenidate – Ritalin Generic and escitalopram – Cipralex milnacipran – not available in Canada (amphetamine) Trade Names fluoxetine – Prozac reboxetine – special access program nortriptyline – Aventyl (tricyclic fluvoxamine - Luvox only antidepressant) paroxetine – Paxil venlafaxine – Effexor trazodone – Desyrel, PMS-, Apo-, sertraline - Zoloft Dom-, Mylan-, Nu-, Phl-, ratio-, Teva- trazodone (tetracylic antidepressant) Contra- Fluoxetine – intracranial hemorrhage Hypersensitivity, patients with a Nortriptyline – cardiac abnormalities indications seizure disorder, or taking MAOIs Hypersensitivity, patients with All- Hypersensitivity to SSRIs, or uncontrolled narrow angle glaucoma, taking Monoamine oxidase inhibitors or patients taking: MAOIs, certain (MAOIs) antibiotics , CYP1A2 inhibitors (eg. fluvoxamine and quinolones) Side Effects SSRI: Serotonin syndrome, sedation, Venlafaxine - Increases in heart rate nortriptyline – may increase risk of increased risk for seizures (0.2% can occur by 3-4bpm, QTc delirium in stroke patients; serotonin incidence), bleeding, and arrhythmia at 75-225mg/day. syndrome, ventricular arrhythmias hyponatremia and orthostatic hypotension Duloxetine - been associated with fluoxetine: interacts with certain an increase in blood pressure and Generally reported: dry mouth, loss cardiac medication e.g. clopidogrel clinically significant hypertension in of appetite and weight-loss, loss of most severely, nimodipline, and some patients libido, constipation, nausea, beta-blockers dizziness, anxiety, somnolence, Generally reported: dry mouth, loss sweating Generally reported: dry mouth, loss of appetite and weight-loss, loss of of appetite and weight-loss, nausea, libido, constipation, nausea, dizziness, loss of libido, constipation insomnia, dizziness or diarrhea, insomnia or somnolence, anxiety, sweating CSBPR Fifth Edition June 2015 Page 1 of 9 Heart and Stroke Foundation Mood, Cognition and Fatigue Following Stroke Canadian Stroke Best Practice Recommendations Pharmacotherapy for Post-Stroke Depression Selective Serotonin Serotonin–norepinephrine Other Reuptake Inhibitors (SSRI) reuptake inhibitors (SNRI) sweating Landmark citalopram6,14, fluvoxamine8 , reboxetine10 , milnacipran11, trazodone15,16 , nortriptyline17,18 Trials fluoxetine 1-5,14 sertraline7,14 venlafaxine12 , duloxetine14 methylphenidate19 paroxetine9 Inclusion / First ever and recurrent strokes SNRI: PSD following from first ever First ever and recurrent strokes Exclusion stroke. Criteria & Mild depression5, 7, 8 trazodone: mild15 and moderate16 Depression Moderate depression1,2,4,5,6 Reboxetine: only severe “retarded depression severity Severe depression 3, 9, 14 depression” in first ever stroke. nortriptyline: mild17 and moderate18 Milnacipran: mild depression, prior depression depression or antidepressant use was excluded. methylphenidate: moderate Venlafaxine: moderate depression depression Duloxetine: severe depression Dose ranges fluoxetine: 10 - 40mg /day (including venlafaxine: 75 – 150 mg/day trazodone: 200 – 300mg/day tested variable dose study)citalopram: 20 – reboxetine: 4mg/ 2x day mirtazepine: 30mg/day 60mg/ day milnacipran: 50 – 100mg/day nortriptyline: 20 – 100mg/day escitalopram: 10 – 20mg/day duloxetine: 60 – 120mg/day sertraline: 50 - 100mg/day Summary of mild: 1 negative, 1 positive studies mild: 2 positive studies mild: 2 positive studies Findings moderate: 2 negative, 3 positive moderate: 1 positive studies moderate: 3 positive studies studies severe: 1 positive studies severe: no studies severe: 1 negative, 3 positive studies Studies were open-label or uncontrolled; no level 1 RCT Level 1 RCT evidence available to Level 1 RCT evidence supports the evidence available to support efficacy support nortriptyline and efficacy of SSRIs fluoxetine and of SNRI for treatment of post-stroke methylphenidate for treatment of citalopram for treatment of moderate depression. post-stroke depression. to severe post-stroke depression. Other Prevention of PSD: fluoxetine, Anxiety in PSD: duloxetine more Mortality & PSD: increased survival Outcomes escitalopram and sertraline studied effective than citalopram in treating of depressed and non-depressed CSBPR Fifth Edition June 2015 Page 2 of 9 Heart and Stroke Foundation Mood, Cognition and Fatigue Following Stroke Canadian Stroke Best Practice Recommendations Pharmacotherapy for Post-Stroke Depression Selective Serotonin Serotonin–norepinephrine Other Reuptake Inhibitors (SSRI) reuptake inhibitors (SNRI) as prophylaxis anxiety symptoms treated with fluoxetine or nortriptyline over placebo in 9-year follow-up3 Mortality & PSD: increased survival Alexithymia: venlafaxine results in of depressed and non-depressed greater improvement of emotional Functional status (ADLs): trazodone treated with fluoxetine or nortriptyline awareness than fluoxetine treatment resulted in trending over placebo in 9-year follow-up1 improvement Executive function: maintenance of executive function compared to placebo over 21 months follow-up2; no improvement of executive function Sleep: fluvoxamine improved sleep disturbances as measured by peripheral melatonin blood levels. Safety Discontinuation: Discontinuation of Duloxetine: should be used with Trazodone: serious warning for escitalopram may increase caution in patients with uncontrolled priapism, associated with increased poststroke depressive symptoms hypertension as it may expose them risk of syncope and falls, particularly over 6 months4 to hypertensive crisis in older patients Cerebrovascular AE: rare (<1/1000) Nortriptyline: special consideration in fluoxetine, infrequent to rare (1/100 for geriatric population with to 1/1000) for other SSRIs but orthostatic hypotension and vigilance required for use in high-risk anticholinergic effects; caution is bleeding & vasoconstrictive stroke.5 advised if used in patients with a personal or family history of Geriatric: anticholinergic effects and cardiovascular disease, arrhythmias orthostatic hypotension can be or conduction disturbances particularly problematic in older patients, resulting in increased risk of i Jorge, Am J Psychiatry 2003 Oct;160(10):1823-9 2 Narushima, B J Psych 2007, 190:260-265 3 Jorge, Am J Psychiatry 2003 Oct;160(10):1823-9 4 Mikami, Stroke 2011; Aug 42:3281-3283 5 Ramasubbu, J Clin Psychiatry 2004; 64:1642-1653 CSBPR Fifth Edition June 2015 Page 3 of 9 Heart and Stroke Foundation Mood, Cognition and Fatigue Following Stroke Canadian Stroke Best Practice Recommendations Pharmacotherapy for Post-Stroke Depression Selective Serotonin Serotonin–norepinephrine Other Reuptake Inhibitors (SSRI) reuptake inhibitors (SNRI) cognitive impairment, confusion, urinary retention and falls. Delirium : anticholinergic effects may play role in delirium in acute stroke patients6 $ per month/ citalopram $0.33/day (regular benefit) duloxetine – Cymbalta (30mg) $1.89 methylphenidate – $0.28-$4.18 (10- coverage in escitalopram $1.84 (regular benefit) and (60mg) $3.79 80mg) Canada fluoxetine (20mg) $0.46 (regular milnacipran – not available trazodone ~$0.10/day (regular benefit) reboxetine - not readily available, not benefit) paroxetine – (20mg) $0.45 and covered by provincial drug coverage (30mg) $0.4796 plans sertraline - (25mg) $0.20 and venlafaxine $0.3469/day (regular ~(100mg) $0.40 benefit) fluvoxamine - (50mg) $0.21 and (100mg) $0.38 6 Caeiro, Eur J. of Neurology 2004; 11: 699–704 CSBPR Fifth Edition June 2015 Page 4 of 9 Appendix One: Pharmacotherapy Trials Ref Class Drug Reference Patients Depression Severity Treatment Dose Drop- +/- Finding AEs of No. (Treated/ (Treated/Control) (wks) (mg/day) out treated Control) group Fluoxetine improvement in Cravello moderate; baseline 1 SSRI (randomized, 25 8 20-40 + depressive symptoms (2009) ‡ HAM-D: 19; uncontrolled) similar to venlafaxine not significant on PSD, 10 AE, 1 Choi-Kwon moderate; baseline but improvements 2 SSRI Fluoxetine 76/76 12 20 15/76 - hospitalizatio (2006) BDI: 19 observed in emotional n disturbances non-significant over placebo in 3 months, Freuhwald severe; baseline significant lowered none 3 SSRI Fluoxetine 28/ 26 12 20-40 4/50 - (2003) HAM-D: 33/30 depression at 18 detected months open-label follow-up no significant Weight loss, Robinson moderate; baseline differences between Anxiety, 4 SSRI Fluoxetine 23 / 17 12 10-40 13/23 - (2000) HAM-D: 20/18 fluoxetine and placebo Insomnia in depression GI symptoms significant 1 AE of moderate; MDD by improvement in transient increase of Wiart ICD-10 and MADRS depression 5 SSRI Fluoxetine 16/15 6.5 20 2/31 + transaminase (2000) ≥ 19; baseline s; MADRS: 29/27 well- tolerated significant reduction of depression,