HUMAN PSYCHOPHARMACOLOGY, VOL.

12, 163165 (1997)

MEETING REPORT

New Developments in Antidepressant Therapy

MICHAEL SHAW 1
1

14 Rivercourt, Trinity Street, Oxford, OX1 1TN, UK

Hum. Psychopharmacol Clin. Exp. 12; 163165 (1997). No. of Figures: 0. No. of Tables: 0. No. of Refs: 0.
KEY WORDS 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 ller onset of action was presented by H.-J. Mo (Ludwig-Maximilian University, Munich, Germany). In a placebo-controlled study, venlafaxine produced a signicant 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 signicant 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 signicantly 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 08856222/97/02016303$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 signicantly 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

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whether BIMT 17 has an early onset of action in clinical use. M. Papp (Polish Academy of Sciences, Krakow, Poland) presented results obtained with the chronic mild stress test, an animal model of long-term depression. In this model, concomitant administration of antidepressants and lithium led to complete reversal of the animals' response to stress, consistent with the known potentiation of antidepressant eects by lithium in clinical practice. Such ndings suggest that this technique provides a useful means of studying the ecacy and timecourse of action of novel antidepressant agents. ARE TWO ACTIONS BETTER THAN ONE? There is some evidence that the specicity of SSRIs may result in limited ecacy, compared with TCAs, particularly in patients with severe depression. Hence, optimal antidepressant ecacy might require an eect on both the serotonergic and noradrenergic systems. Considerable eort, therefore, has been devoted to the development of antidepressants with a double mechanism of action. Laboratory studies of the interactions between the noradrenergic and serotonergic systems were described by F. Artigas (Instituto de Investiga dicas de Barcelona, Spain). In microciones Biome dialysis studies, the specic noradrenaline reuptake inhibitor desipramine potentiated the eects of uoxetine on 5-HT release in the frontal cortex, whereas desipramine had no eect when given alone. 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. dicament, Castres, M. Briley (Pierre Fabre Me France) described the pharmacological and clinical properties of milnacipran, a serotonin noradrenaline reuptake inhibitor (SNRI). Milnacipran inhibits the in vitro and in vivo reuptake of noradrenaline and 5-HT with equal potency for both neurotransmitters. It has no activity on a1 -adrenergic, muscarinic or histaminergic H1 receptors. In a meta-analysis of placebo-controlled trials with milnacipran, 50 mg b.d., 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 comparative trials with imipramine and clomipramine, the mean decrease in symptom
# 1997 by John Wiley & Sons, Ltd.

scores was similar with milnacipran and TCAs. Response rates were also similar with both treatments, as were the proportions of patients with scores of 7 or below. TCAs were associated with a higher incidence of adverse events, particularly dry mouth, tremor, sweating and constipation, than milnacipran. The Clinical Global Impression score, which takes into account both ecacy and tolerability, was signicantly higher for milnacipran than for TCAs. In comparisons with uoxetine and uvoxamine, milnacipran treatment was associated with greater mean changes in symptom scores, and higher response and remission rates. The adverse event proles of the two treatments were similar; the incidence of nausea was higher during SSRI treatment, whereas that of dry mouth and headache was higher in milnacipran-treated patients. Milnacipran, therefore, appears to be comparable in ecacy and better tolerated than TCAs, and to be more eective and equally well tolerated compared with SSRIs. R. M. Pinder (NV Organon, Oss, The Netherlands) reviewed clinical experience with mirtazapine, a noradrenergic and specic serotonergic antidepressant (NaSSA). Mirtazapine acts by antagonism of a2 auto- and heteroreceptors and postsynaptic 5-HT2 and 5-HT3 receptors. It has little anity for 5-HT1A receptors, cholinergic or dopaminergic receptors. It does, however, have a high anity for histamine H1 receptors, which may be responsible for the sedation seen in some patients. In comparative studies, mirtazapine showed comparable ecacy to amitriptyline, clomipramine and doxepin, and was more eective than trazodone. A recent comparison with uoxetine showed greater improvements in symptom scores among mirtazapine-treated patients at 3, 4 and 6 weeks. Mirtazapine is associated with a lower incidence of anticholinergic adverse eects than TCAs. The incidence of serotonergic adverse eects believed to be mediated by 5-HT2 and 5-HT3 receptors, such as headache, nausea, agitation and insomnia, are lower than with SSRIs. In general the incidence of these eects is comparable to that in placebotreated patients; the incidence of headache, however, was lower than in placebo-treated patients. The clinical pharmacology of nefazodone, an antidepressant that combines weak inhibition of serotonin reuptake with powerful antagonism at 5-HT2 receptors, was reviewed by M. Lader (Institute of Psychiatry, London, UK). In placebocontrolled trials, nefazodone produced signicant
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improvements in symptom scores and response rates in patients with major depression, the eect becoming apparent after 2 weeks. In comparative studies, nefazodone has been found to be comparable in ecacy with TCAs and SSRIs. Compared with SSRIs and imipramine, however, nefazodone produces a signicant improvement in anxiety symptoms, which is apparent after 1 week of treatment. This may represent a clinical advantage, as anxiety is a common nding in depressed patients. The incidence of adverse events such as somnolence, dry mouth and nausea associated with nefazodone is higher than with placebo, but the drug is generally well tolerated. Adverse events attributable to 5-HT2 receptor activation, such as sexual dysfunction and sleep disturbances, are less common with nefazodone than with SSRIs. The incidence of sexual disorders such as reduced libido, impotence or ejaculation diculties, is comparable to that seen in placebo-treated patients. In a comparative study with paroxetine, nefazodone had no signicant eect on sleep patterns. By contrast, paroxetine was associated with a reduction in rapid eye movement (REM) sleep time and an increase in REM sleep latency. The clinical signicance of venlafaxine's inhibition of serotonin and noradrenaline reuptake -Salpe re was discussed by A. J. Puech (Pitie trie Hospital, Paris, France). In hospitalized patients with melancholia and baseline Montgomery

sberg Depression Rating Scale (MADRS) scores A of about 35, venlafaxine produced signicantly greater reductions in symptom scores than SSRIs after 4 weeks of treatment. Venlafaxine is also eective in patients with mild depression. This ecacy prole is similar to that of TCAs; by contrast, SSRIs appear to be less eective in severe depression, which suggests that combined inhibition of noradrenaline and serotonin reuptake may oer advantages in such patients. A meta-analysis of clinical trials with venlafaxine showed a clear doseresponse relationship. Doses of 75 mg produce a decrease of about 3.3 points in the MADRS score, compared with placebo. This is comparable to the changes seen with standard doses of SSRIs. At higher doses (150 mg/day and above), venlafaxine appears to be more eective than SSRIs, particularly in severely depressed patients. High doses (350 mg/day) are signicantly more eective than low doses. The principal adverse events were dose-related gastrointestinal disturbances; increases in blood pressure were seen with high doses. The clinical experience with venlafaxine, milnacipran and mirtazapine, therefore, suggests that inhibition of noradrenaline reuptake may be benecial, especially in patients with severe depression, supporting the hypothesis that agents with a double mechanism of action may oer therapeutic advantages in the treatment of depression.

# 1997 by John Wiley & Sons, Ltd.

HUMAN PSYCHOPHARMACOLOGY, VOL.

12, 163165 (1997)

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