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Table 1B: Overview of Therapy for Post-Stroke Depression

This table provides a summary of the pharmacotherapeutic properties, side effects, drug interactions and other important information on select 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– Other Inhibitors (SSRI) reuptake inhibitors (SNRI) – Celexa - Cymbalta – Ritalin Generic and – Cipralex – not available in () Trade Names – Prozac – special access program – Aventyl ( - Luvox only antidepressant) – Paxil – Effexor – Desyrel, PMS-, Apo-, - 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 , taking Monoamine oxidase inhibitors or patients taking: MAOIs, certain (MAOIs) antibiotics , CYP1A2 inhibitors (eg. fluvoxamine and quinolones)

Side Effects SSRI: , sedation, Venlafaxine - Increases in heart rate nortriptyline – may increase risk of increased risk for seizures (0.2% can occur by 3-4bpm, QTc 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 pressure and Generally reported: dry mouth, loss cardiac medication e.g. clopidogrel clinically significant in of appetite and weight-loss, loss of most severely, nimodipline, and some patients libido, constipation, , 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

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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

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Selective Serotonin Serotonin–norepinephrine Other Reuptake Inhibitors (SSRI) reuptake inhibitors (SNRI) as prophylaxis anxiety symptoms treated with fluoxetine or nortriptyline over 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 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 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

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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

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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, fewer Anderson moderate; baseline 10 – 20 1 death, 6 AE, 6 SSRI Citalopram 33/33 6 + meet HAM-D (1994) HAM-D: 19/19 up to 60 3 strokes depression criteria at endpoint mild; mean no significant Murray 7 SSRI Sertraline 62/61 baseline MADRS: 26 50 – 100 54/123 - improvement on 8 AE (2002) 19/20 depression; sertraline

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Heart and Stroke Foundation Mood, Cognition and Fatigue Following Stroke Canadian Stroke Best Practice Recommendations Pharmacotherapy for Post-Stroke Depression

Ref Class Drug Reference Patients Depression Severity Treatment Dose Drop- +/- Finding AEs of No. (Treated/ (Treated/Control) (wks) (mg/day) out treated Control) group found superior only in emotional distress, and QoL improved sleep mild; ZDS ≥ 40; Sunami disturbance & 8 SSRI Fluvoxamine 19 / 10 baseline ZDS: 4 25-75 3/9 T + not reported (2012) † depressive scores; no 47/47 change in cognition mean HAM-D decreased from 25 to 8.2% AE: 12 by 3rd week, 9 by 8th nausea/vomit Paroxetine Horvath severe; baseline ing, dizziness, 9 SSRI 788 8 20-40 10% + week of treatment. (uncontrolled) (2006) †‡ HAM-D: 25 Depressive scores and diarrhea decreased further by 1.9% of SAE follow-up at 26 weeks. significant dryness of severe; baseline faeces, Rampello improvement of 10 SNRI Reboxetine 16/15 HAMD: 24/24; 16 8 0 + constipation, (2005)† retarded depressed baseline BDI: 21/20 patients hyper perspiration significant Milnacipran improvement in self- mild; DSM-IV MDD (open label, varied on reported depression Yamakawa or MinD; no AE’s 11 SNRI unblended, 11 length of 30-60 0 + compared to the (2005)†‡ baseline ZDS: reported historical stay historical control 52/53; control) group; no change in ADLS. improvement in depressive symptoms Venlafaxine on venlafaxine similar Cravello moderate; baseline 12 SNRI (randomized, 25 8 75-150 0? + to fluoxetine, (2009) ‡ HAM-D: 17; uncontrolled) venlafaxine results in greater improvement on alexithymia severity Duloxetine, Karaiskos D20 /C20 severe; DSM-IV 60-120/ duloxetine more not 14 SNRI 12 + Citalopram, (2012)†‡ /S20 , 20-40/ effective than significantly

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Ref Class Drug Reference Patients Depression Severity Treatment Dose Drop- +/- Finding AEs of No. (Treated/ (Treated/Control) (wks) (mg/day) out treated Control) group Sertraline depressive 50-200 citalopram and different episode; baseline sertraline for anxiety from HAM-D: 25/24/24 symptoms in PSD; all 3 citalopram or AD were effective at sertraline. 15% for treating depressive somnolence symptoms and nausea trazodone significantly Raffaele mild; baseline ZDS: improved self-reported 15 Other Trazodone 11/11 5 300 + 6 AE (1996) 59/62; depression; not significant in placebo. trazodone trends moderate; DSM-3 towards better MDD or dysthymic functional status Reding 16 Other Trazodone 27 disorder or 4-5 200 + (ADLS) for depressed (1986) “abnormal” ZDS patients (depressive baseline: 62/66 severity was NOT primary outcome) nortriptyline higher Robinson moderate; baseline sedation, 17 Other Nortriptyline 14/17 12 25- 100 5/14 + response rate than (2000) HAM-D: 23/18 rash fluoxetine or placebo improvement of MDD, reduction of Lipsey mild; baseline 18 Other Nortriptyline 14/20 4 20 – 100 8/34 + depression with (1984) HAM-D: 14/17; nortriptyline over placebo significant lower Methylpheni- Grade moderate; baseline 19 Other 10/11 3 5-60 + depressive scores date (1998) HAM-D: 20/25; compared to placebo † The outcome assessor was not blinded ‡Open-label study

ADL = Activities of Daily Living; AE = adverse event; BDI = Beck Depression Inventory; DSM = Diagnostic and Statistical Manual of Mental Disorders; HAM-D = Hamilton Depression Rating Scale; ICD-10 = International Classification of Diseases, 10th Revision; MADRS = Montgomery-Asberg Depression Rating Scale; MDD = Major Depressive Disorder; MinD = Minor Depressive Disorder; QoL = Quality of Life; SNRI = Selective Noradrenaline ; SSRI = Selective Serotonin Reuptake Inhibitor; ZDS = Zung Depression Scale

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Appendix Two: PSD Prophylaxis Trials of Non-depressed patients

Patients Dosing Ref Treatme Drop AEs of treated Class Drug Reference (Treated/Contr schedule +/- Finding No. nt weeks -out group ol) (mg/day) hypoatronemia, Chollet significant lower frequency of transient digestive 5 SSRI Fluoxetine (FLAME) 57/56 12 20 + depression at endpoint than placebo disorders, partial (2011) seizure Fluoxetine, no significant treatment effect on SSRI, Narushim F: 10 – 40 3 Nortriptylin 17/15/16 12 2 - intention to treat; significant effect Other a (2002) N: 25-100 e observed in completed patients Nortriptyli SSRI, Robinson N: 25-100 6 ne 13/13/15 12 - no significant treatment effect TCA (2000) F: 10-40 Fluoxetine Almeida 29/5 no improvement of depression over 2 SSRI Sertraline 55/56 24 50 - (2006) 6 placebo significantly fewer treated treated had Rasmusse developed MDD (HAM-D > 18) 1 SSRI Sertraline 70/67 52 50-150 49% + significantly fewer n (2003) compared to placebo ; superiority AE starts at 6 - 21 weeks significantly fewer on escitalopram Escitalopra or problem-solving therapy decreased libido, m Robinson 15/1 4 SSRI 59/58 52 10 + developed MDD or minor episodes fatigue, GI (unblinded (2008) 49 compared to placebo symptoms )

no significant Milnacipra Tsai 21/4 significant for preventing PSD in the 7 SNRI 46/46 52 50 - 100 + difference from n (2001)7 6 first year following a stroke placebo significantly lower incidence of mind Duloxetine Zhang 12/4 and MDD with duloxetine. 8 SNRI (single- 47/48 12 30-90 + nausea, vomiting (2013)†8 8 Significant higher ADL and QoL blinded) scores than placebo at endpoint

7 Int Clin Psychopharmacol. 2011 Sep;26(5):263-7 8 Eur Neurol. 2013;69(6):336-43. doi: 10.1159/000345374.

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Mirtazepin Niedermai significantly fewer developed PSD e 9 Other er 66/64 52 52 30 + when treated mirtazepine (2) over (open- (2005)‡ no treatment (14) label) † The outcome assessor was not blinded ‡Open-label study

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