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(Stroke. 1999;30:691-692.)
© 1999 American Heart Association, Inc.
Letters to the Editor |
Therapy of Early Poststroke Depression With Venlafaxine: Safety, Tolerability, and Efficacy as Determined in an Open, Uncontrolled Clinical Trial
Department of Psychiatry
Department of Neurology, University of Mainz, Manz, Germany
Neurological Rehabilitation Hospital, Bad Camberg, Germany
Key Words: antidepressive agents • depression • stroke
To the Editor:
The development of persistent depressive symptoms is a severe and frequent complication of ischemic or hemorrhagic stroke.1 The etiology of poststroke depression is not well understood. Only few placebo-controlled, double-blind studies have been carried out, all reporting various degrees of superiority of standard antidepressants over placebos.1 2 On the other hand, serious side effects have been reported.3 4
In most of these studies, patients were examined whose stroke had occurred several weeks to several months before the antidepressive therapy was started. Antidepressive therapy in the first weeks after stroke has not yet been attempted in studies. Drug-induced improvement of neurotransmission, in particular adrenergic transmission, facilitates recovery in animal brain trauma and stroke models.5 Antidepressants enhance neurotransmission by blockade of serotonergic and/or adrenergic reuptake transporters, by blocking the enzymatic degradation of monoamines or by other mechanisms, such as the blockade of presynaptic adrenergic receptors. Therefore, the treatment with antidepressants might in some cases exert a favorable effect on functional recovery independent of the psychopathological state.6
We report data on the safety, tolerability, and efficacy of venlafaxine in patients suffering from acute poststroke depression. Venlafaxine was chosen because of its relatively good tolerability compared with tricyclic antidepressants and because it exerts effects on both adrenergic and serotonergic reuptake transporters.7 Because venlafaxine may increase blood pressure at higher doses,8 particular attention was given to the cardiovascular parameters of blood pressure and heart rate. Patients fulfilled the diagnostic criteria for a major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, on 4 consecutive days, with the exception of the time criterion. We examined 12 patients during a 5-week treatment. Patients had experienced ischemic stroke no longer than 2 weeks before the beginning of the antidepressant therapy. Exclusion criteria were progressive or fluctuating stroke symptomatology, all malignancies, neurological system degeneration, or a history of psychiatric disorders. Patients were administered 75 mg venlafaxine on the first 2 days and 150 mg for the rest of the study period. On the day of the initiation of treatment (day 0) and after 2 weeks and 5 weeks, the depressive symptomatology was measured with the Hamilton Depression Rating Scale (HAM-D; 17 items) and the Montgomery Asberg Depression Rating Scale (MADRS). The European Stroke Scale (ESS) was used to measure the neurological deficit, and the Rankin Scale (RS) and Modified Barthel Rehabilitation Index (MBRI) were used to evaluate the course of rehabilitation. Blood pressure, pulse, and routine laboratory parameters, including liver enzymes, were monitored regularly. ECG was recorded at least 3 times in the course of the treatment.
The mean age of the 6 female and 6 male patients was 66±12 years. Risk factors included diabetes mellitus (n=2), adiposity (n=6), hypertonia (n=10), and smoking (n=5). These and additional ailments were treated as clinically indicated. Eleven patients received thrombocyte aggregation inhibitors, mostly in combination with low-dose heparin (n=10). One patient was anticoagulated with coumarin.
Venlafaxine was generally well tolerated. One patient with additional chronic hepatitis developed elevated liver enzymes. Dosage had to be reduced to 75 mg/d in 1 case because of agitation. Cardiovascular or hepatic parameters were not systematically affected by the treatment. Three patients suffered from nausea at the beginning of treatment. No other side effects were observed. Drug therapy did not have to be discontinued in any case.
Positive treatment response, defined as a reduction in HAM-D scores of
>50%, was observed in 10 of 12 patients after 2 weeks of treatment.
Mean±SD HAM-D scores were 24.3±3.2 in the beginning and 7.25±2.3
after 5 weeks of treatment (Figure 1
A). Similarly, MADRS scores showed a reduction from 26.7±5.0 to
7.6±2.2 after 5 weeks. Reduction in depression scores were accompanied
by significant improvements in scores measuring neurological deficits
and rehabilitation: the ESS was 68.3±13.9 on day 0 and 81.4±12.4
after 5 weeks. The RS was 4.25±0.7 on day 0 and 3.0±0.6 after 5
weeks. The MBRI was 35.5±26.6 on day 0 and improved markedly to
82.0±14.3 after 5 weeks (Figure 1B).
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This is the first study specifically aimed at the therapy of early depression after stroke. The main finding of this pilot study is that venlafaxine was well tolerated in all 12 patients although patients were elderly, suffered from a recent stroke (<14 days), and had significant other comorbidity. However, the study is limited by its small size, and it cannot be concluded that venlafaxine is an entirely safe drug in stroke patients. Nevertheless, this result differentiates the treatment of poststroke depression with venlafaxine from treatment with tricyclic and other antidepressants, in which side effects often were therapy-limiting.3 4 9 Moreover, the clinical impression was favorable, although our data do not allow us to give a conclusive statement on the antidepressive efficacy. Without a placebo group there was no adequate control for spontaneous recovery.10
In preclinical models and in patient trials, antidepressant medication has been reported to promote functional recovery after stroke. Because venlafaxine has an effect on serotonin and noradrenaline uptake, one would expect that its positive effect on rehabilitation could be more pronounced than that of selective serotonergic agents, which in animal models under certain circumstances may actually slow recovery.5 6 Again, our data do not allow a definitive clinical statement.
In summary, the most important finding was that no patient had to be withdrawn because of side effects. Double-blind, placebo-controlled, randomized studies comparing the efficacy and side effects of various treatments for the reduction of poststroke depression and the improvement of poststroke recovery, including therapy with antidepressants and psychostimulatory drugs as well as various forms of psychotherapy, are needed. In the meantime, we consider venlafaxine a therapeutic option in selected patients for whom antidepressant medication is needed.
References
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9. Lauritzen L, Bjerg Bendsen B, Vilmar T, Bjerg Bendson E, Lunde M, Bech P. Post-stroke depression: combined treatment with nimipramine or desipramine and mianserine: a controlled clinical study. Psychopharmacology. 1994;114:119–122.[Medline] [Order article via Infotrieve]
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