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12, 163±165 (1997)
New Developments in Antidepressant Therapy
MICHAEL SHAW 1
14 Rivercourt, Trinity Street, Oxford, OX1 1TN, UK
Hum. Psychopharmacol Clin. Exp. 12; 163±165 (1997). No. of Figures: 0. No. of Tables: 0. No. of Refs: 0.
KEY WORDS Ð antidepressant therapy; onset of antidepressant action; mechanism of antidepressant action; milnacipran; venlafaxine; mirtazapine; nefazodone
Can we achieve a faster onset of antidepressant action than is possible with tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), and do agents that act on both the serotonergic and noradrenergic systems oer any therapeutic advantages? These questions were addressed at symposia during the 9th European College of Neuropsychopharmacology Congress, which took place in Amsterdam in September 1996. IS A RAPID ONSET OF ACTION POSSIBLE? Evidence that venlafaxine, an inhibitor of noradrenaline and serotonin reuptake, has an early È ller onset of action was presented by H.-J. Mo (Ludwig-Maximilian University, Munich, Germany). In a placebo-controlled study, venlafaxine produced a signi®cant reduction in symptom scores at day 4, but a meta-analysis of placebo-controlled trials with venlafaxine in doses of up to 375 mg/day found that the speed of onset of response was largely dependent on the dose. A comparative study with venlafaxine and ¯uoxetine showed a tendency towards earlier improvement with venlafaxine, but this did not become signi®cant until week 4. There is, therefore, some evidence to support an early onset of action with venlafaxine. However, studies of onset of action are subject to methodological diculties and new study designs are needed to establish whether new agents do oer signi®cantly faster action. This was emphasized by S. A. Montgomery (St Mary's Hospital Medical School, London), who showed that the eect of antidepressant drugs can be detected within a few days of starting
CCC 0885±6222/97/020163±03$17.50 # 1997 by John Wiley & Sons, Ltd.
treatment. In an overview of trials with moclobemide or imipramine, the proportion of patients showing at least a 20 per cent reduction in symptom scores was signi®cantly greater than with placebo after 5 days, and the maximum eect occurred after 14 days. This suggests that the onset of action may be quick, but the subsequent progression of the therapeutic eect delayed. Support for this comes from survival analysis, which shows that the speed of response is comparable with placebo, moclobemide and imipramine. In view of these ®ndings, new study designs, using better assessment criteria and survival analysis, should be developed to focus on the ®rst 14 days of treatment. P. Blier (McGill University, Montreal, Canada) described how combination therapy with the 5-HT1A receptor antagonist pindolol and an SSRI may result in improved ecacy and a faster onset of action, by preventing the initial decrease in serotonergic activity during SSRI treatment. Promising results have been obtained in preliminary studies with this combination. Pharmacological studies with BIMT 17, a 5-HT1A agonist and 5-HT2 antagonist, were described by F. Borsini (Boehringer Ingelheim Italia, Milan, Italy). Such agents are believed to mimic the down regulation of 5-HT2 receptors that occurs during chronic antidepressant treatment, with a fast onset of action due to their direct eects on postsynaptic receptors. In electrophysiological experiments, single doses of BIMT 17 decreased the number of spontaneously active cells in the rat frontal cortex, and the compound was also eective in animal models of depression after acute administration. Further studies are needed to determine
such as headache.d. therefore.and heteroreceptors and postsynaptic 5-HT2 and 5-HT3 receptors. the mean decrease in symptom # 1997 by John Wiley & Sons. the incidence of nausea was higher during SSRI treatment. however. whereas that of dry mouth and headache was higher in milnacipran-treated patients. was signi®cantly higher for milnacipran than for TCAs. nefazodone produced signi®cant HUMAN PSYCHOPHARMACOLOGY. an animal model of long-term depression. mean changes in symptom scores and response rates (the proportion of patients showing a decrease in symptom score of at least 50 per cent from baseline) during milnacipran treatment tended to be higher among hospitalized patients than in the overall population. In microciones Biome dialysis studies. M. consistent with the known potentiation of antidepressant eects by lithium in clinical practice. a serotonin± noradrenaline reuptake inhibitor (SNRI). sweating and constipation. In comparative trials with imipramine and clomipramine. The Netherlands) reviewed clinical experience with mirtazapine. 163±165 (1997) . was reviewed by M. In general the incidence of these eects is comparable to that in placebotreated patients. and was more eective than trazodone. milnacipran treatment was associated with greater mean changes in symptom scores. are lower than with SSRIs. as were the proportions of patients with scores of 7 or below. 4 and 6 weeks. however. The incidence of serotonergic adverse eects believed to be mediated by 5-HT2 and 5-HT3 receptors. tremor. In comparative studies. muscarinic or histaminergic H1 receptors. Lader (Institute of Psychiatry. R. Oss. Hence. optimal antidepressant ecacy might require an eect on both the serotonergic and noradrenergic systems. Response rates were also similar with both treatments. UK). The adverse event pro®les of the two treatments were similar.164 M. Milnacipran inhibits the in vitro and in vivo reuptake of noradrenaline and 5-HT with equal potency for both neurotransmitters. This suggests that blockade of noradrenaline and serotonin reuptake may be more eective in increasing extracellular 5-HT concentrations than inhibiting 5-HT reuptake alone. Laboratory studies of the interactions between the noradrenergic and serotonergic systems were described by F. have a high anity for histamine H1 receptors. was lower than in placebo-treated patients. Pinder (NV Organon. It has little anity for 5-HT1A receptors. London.. Spain). The Clinical Global Impression score. M. Ltd. clomipramine and doxepin. SHAW whether BIMT 17 has an early onset of action in clinical use. In placebocontrolled trials. It has no activity on a1 -adrenergic. Milnacipran. an antidepressant that combines weak inhibition of serotonin reuptake with powerful antagonism at 5-HT2 receptors. ARE TWO ACTIONS BETTER THAN ONE? There is some evidence that the speci®city of SSRIs may result in limited ecacy. the incidence of headache. Â dicament. Mirtazapine acts by antagonism of a2 auto. appears to be comparable in ecacy and better tolerated than TCAs. In a meta-analysis of placebo-controlled trials with milnacipran. TCAs were associated with a higher incidence of adverse events. It does. In comparisons with ¯uoxetine and ¯uvoxamine. which takes into account both ecacy and tolerability. 12. cholinergic or dopaminergic receptors. Poland) presented results obtained with the chronic mild stress test. 50 mg b. M. agitation and insomnia. A recent comparison with ¯uoxetine showed greater improvements in symptom scores among mirtazapine-treated patients at 3. than milnacipran. Considerable eort. scores was similar with milnacipran and TCAs. The clinical pharmacology of nefazodone. Such ®ndings suggest that this technique provides a useful means of studying the ecacy and timecourse of action of novel antidepressant agents. In this model. whereas desipramine had no eect when given alone. and to be more eective and equally well tolerated compared with SSRIs. a noradrenergic and speci®c serotonergic antidepressant (NaSSA). therefore. the speci®c noradrenaline reuptake inhibitor desipramine potentiated the eects of ¯uoxetine on 5-HT release in the frontal cortex. Castres. compared with TCAs. which may be responsible for the sedation seen in some patients. Mirtazapine is associated with a lower incidence of anticholinergic adverse eects than TCAs. and higher response and remission rates. has been devoted to the development of antidepressants with a double mechanism of action. Briley (Pierre Fabre Me France) described the pharmacological and clinical properties of milnacipran. Artigas (Instituto de InvestigaÂ dicas de Barcelona. mirtazapine showed comparable ecacy to amitriptyline. Papp (Polish Academy of Sciences. particularly in patients with severe depression. nausea. Krakow. particularly dry mouth. concomitant administration of antidepressants and lithium led to complete reversal of the animals' response to stress. VOL.
SSRIs appear to be less eective in severe depression. however. In a comparative study with paroxetine. By contrast. such as sexual dysfunction and sleep disturbances. Venlafaxine is also eective in patients with mild depression. This is comparable to the changes seen with standard doses of SSRIs. Paris. J. This may represent a clinical advantage. compared with placebo. Puech (Pitie Ã trie Hospital. are less common with nefazodone than with SSRIs. venlafaxine appears to be more eective than SSRIs.3 points in the MADRS score. milnacipran and mirtazapine. nefazodone had no signi®cant eect on sleep patterns. The incidence of sexual disorders such as reduced libido. 163±165 (1997) . A meta-analysis of clinical trials with venlafaxine showed a clear dose±response relationship. nefazodone has been found to be comparable in ecacy with TCAs and SSRIs. which is apparent after 1 week of treatment. which suggests that combined inhibition of noradrenaline and serotonin reuptake may oer advantages in such patients. # 1997 by John Wiley & Sons. This ecacy pro®le is similar to that of TCAs. by contrast. The incidence of adverse events such as somnolence. increases in blood pressure were seen with high doses. Adverse events attributable to 5-HT2 receptor activation. is comparable to that seen in placebo-treated patients. Compared with SSRIs and imipramine. especially in patients with severe depression. impotence or ejaculation diculties. particularly in severely depressed patients. as anxiety is a common ®nding in depressed patients. Doses of 75 mg produce a decrease of about 3. The clinical signi®cance of venlafaxine's inhibition of serotonin and noradrenaline reuptake Â -Salpe Á re was discussed by A. paroxetine was associated with a reduction in rapid eye movement (REM) sleep time and an increase in REM sleep latency. therefore. VOL. venlafaxine produced signi®cantly greater reductions in symptom scores than SSRIs after 4 weeks of treatment. The principal adverse events were dose-related gastrointestinal disturbances. Ltd. but the drug is generally well tolerated.MEETING REPORT 165 improvements in symptom scores and response rates in patients with major depression. nefazodone produces a signi®cant improvement in anxiety symptoms. France). 12. The clinical experience with venlafaxine. In comparative studies. High doses (350 mg/day) are signi®cantly more eective than low doses. suggests that inhibition of noradrenaline reuptake may be bene®cial. In hospitalized patients with melancholia and baseline Montgomery± Ê sberg Depression Rating Scale (MADRS) scores A of about 35. the eect becoming apparent after 2 weeks. At higher doses (150 mg/day and above). supporting the hypothesis that agents with a double mechanism of action may oer therapeutic advantages in the treatment of depression. HUMAN PSYCHOPHARMACOLOGY. dry mouth and nausea associated with nefazodone is higher than with placebo.
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