Галантамин в лечении депрессии
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Galantamine as an Adjunctive Treatment in Major Depression
Journal of Clinical Psychopharmacology • Volume 28, Number 3, June 2008
This studywas supported byRx&D Research Grant (Canada). Galantamine and placebo samples were supplied by Janssen-Ortho, Inc, Toronto, Ontario, Canada.
Safa Elgamal, MD, PhD Glenda MacQueen, MD, PhD
* McMaster University and Mood Disorder Program St Joseph’s Health Care Hamilton Hamilton, Ontario, Canada
Galantamine hydrobromide is a long-acting acetylcholinesterase inhibitor (AChEI) that modulates nicotinic receptor sites.1 Galantamine improves cognition and delays behavioral disturbances when giventopatientswithmildtomoderate Alzheimer disease.2 Several reports suggested that AChEIs may improve mood symptoms in patients with mild cognitive impairment3; given the reported mechanisms of action of galantamine, improved mood is plausible consequence of treatment with this medication.
The association between smoking and mental illness highlights the possible involvement of nicotine in the neuro-pathology of several disorders including depression.4 Evidence supports the role of nicotinic acetylcholine receptors in the clinical symptomatology of depression.5 Nicotine patches administered to depressed patients improved mood symp-toms,6 and nicotine administration in rats had an antidepressant-like effects.7 Given the involvement of nicotine in mood and cognition and reports that galantamine could have benefit in patients with a range of psychiatric disorders, we initiated this pilot study to examine the tolerability of galantamine and its effects on symptoms of depression including mood and cognition.
The study was a randomized, double-blinded, placebo-controlled trial conducted at the Mood Disorder Clinic, St Joseph’s Health Care, Hamilton, Ontario. The study was approved by the local ethics board and was conducted in accordance with the ethical principals stated in the Revised Declaration of Helsinki and consistent with the Good Clinical Practice Guidelines. Patients with major depressive disorder (MDD) as diagnosed by the Diagnostic and Statistical Manual ofMental Disorders Fourth Edition, not in an acute episode, aged 40 to 80 years were recruited for the study.
Twenty patients who signed an informed consent were randomly allocated to either placebo or galantamine. Neuropsychologic and mood assessment was completed at baseline and included the Hamilton Depression Rating Scale8 (H9DRS), California Verb1a0l
Learning Test,9 Trail Making A and B,10 Ruff 2 and 7 Selective Attention Test,11 Digit Span Forward and Backward Test,12 Digit Symbol Substitution Test,12 and Controlled Oral Word Association Test.13 After baseline assessment, patients received either placebo for 8 weeks or galantamine (8 mg for 4 weeks, then 16 mg for another 4 weeks). Repeated assessment was done after 8 weeks.
Baseline characteristics for patients (n = 10) and controls (n = 10) showed no significant baseline differences on mean age (52.8 and 52.1), sex, education, estimated intelligence quotient as measured by the National Adult Rating Test,14 and mood state as measured by HDRS (6.5 and 9.2). Patients in the galanta-mine group were maintained on a stable dose of the following medications: venlafaxine, venlafaxin, nefazodone, desipramine, desipramine + bupropion, citalopram + bupropion, citalopram, sertraline, sertraline + trazodone, and mirtazapine. Patients in the placebo group were maintained on a stable dose of the following medications: venla-faxin, venlafaxin, venlafaxin, bupropion+ citalopram, bupriopion, fluoxetine, cita-lopram + clonazepam, venlafaxin + mitrazapine + lithium + gabapentine, citalopram, and venlafaxin + paroxetine.
Nineteen patients completed the study, and one dropped out from the galantamine arm before the final assessment. Analyses were conducted according to an intention-to-treat. Missing data were managed by carrying forward the last observation (baseline scores) to the end point. All analyses were done using SPSS statistical software program, version 10. Performance on neuropsychologic tasks was examined using mixed Analysis of Variance. The galantamine group had larger reduction in depressive symptoms on HDRS (2.3 points) compared with the placebo group (0.3 points), however, the change in scores was not significant. The galantamine group had a greater numerical improvement on several California Verbal Learning Test variables, Trail Making A Test, Digit Span Backwards Test, Controlled Oral Word Association Test, and the speed variables of the Ruff 2 and 7 Test than the placebo-treated patients, although there were no statistically significant differences for the interaction because of the small sample.
However, during the study, 4 of the enrolled patients, although blinded, reported improvement in mood after starting the treatment. When the study was terminated and unmasked, all of the 4 patients were found to be in the galantamine arm, whereas no one in the placebo group reported improvement. Follow-up analysis showed that greater reduction in HDRS for these 4 patients (6.5 points) compared with the rest of the galantamine patients (—0.6 points) and to the placebo patients (0.3 points) (Fig. 1). Comparing the HDRS reduction from preassess-ment to postassessment for these 4 patients to the patients in the placebo group (n = 10) showed a significant improvement in mood scores (P = 0.037) on repeated-measures Analysis of Variance. Galantamine was well tolerated by the patients with few side effects reported (mainly gastrointestinal) except for 1 patient who dropped out because of fatigue and hypersomnia; no deterioration in mood symptoms or sleep were reported by any of the patients.
DISCUSSION
This pilot study examined the effect of galantamine on mood, cognition, and its tolerability in patients with MDD. Galantamine did not impact mood symptoms negatively despite being an AChEI. Nevertheless, galantamine improved mood symptoms for patients which were significant for those who had a higher HDRS scores at baseline. We recruited stable patients avoiding patients in depressive state intentionally as a safety precaution for the patients; we did not know the effect of the study drug on mood symptoms and whether it may precipitate an acute episode if given to unstable patients. Those patients who had lower HDRS had no chance for improvement. Our results support the presence of an antidepressant effect for nicotine. It is possible that the nicotinic effect of galantamine in depressed patients may have prevailed over the cholinergic effect resulting in improved mood. Despite the small sample size, however, and that patients were chosen to have subthreshold levels of depression only, improvement in mood was noted for some galantamine patients, but not for placebo-treated patients. Although the galantamine-treated group had greater numeric improvement on cognitive measures, the results were insignificant because of the small sample size, and inferences could not be made from our study. To our knowledge, this is the first randomized, blinded, controlled trial of AChEIs in patients with MDD, and although providing only pilot data, the data suggest that further investigation of galantamine as an adjunctive treatment of mood symptoms in depression is warranted. We acknowledge the limitation of the study because of the small sample size and the inclusion of patients with low HDRS that did not allow the change from pretest to posttest to show. We recommend initiation of a larger study including patients in a more depressed state.
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