RESEARCH & DEVELOPMENT

-Kate Palmer-

Two of the main problems with currently available antidepressants are their slow onset of action and their lack of effect in some patients. However, if data presented at the 20th Collegium Internationale Neuro-psychopharmaco-logicum (CINP) [Melbourne, Australia; June 1996] are conf'mned, a new approach to overcoming these issues could be on the way. Researchers have taken advantage of the drug interactions of selective serotonin reuptake inhibitors (SSRIs) to develop a method of augmenting antidepressant activity.

Like all other antidepressants, the SSRIs generally take several weeks to exert their effect. This can create problems, as there is an initial period during which patients are receiving no benefit from their medication. Furthermore, after this initial period, some patients fail to respond or to maintain a response to these drugs.

Making the most of drug interactions One of the approaches that has been investigated to

enhance the antidepressant effects of SSRIs is to take advantage of pharmacodynamic interactions between SSRIs and other drugs.

The serotonin hypothesis of depression suggests that this disorder is associated with dysfunctional serotonergic neurotransmission. All antidepressants. including SSRIs, cause a selective increase in extracellular serotonin levels in the midbrain raphe nuclei (RN; an area containing the cell bodies of serotonin neurons).

This would. at first glance. appear to be consistent with an antidepressant effect (i.e. given that depression results from a lack of serotonin, the solution is to increase serotonin levels). However. the firing of serotonergic neurons is controlled, in part, by a negative feedback loop involving sero-toninlA autoreceptors located on cell bodies in the RN. As serotonin levels are increased by SSRIs in the RN, the autoreceptors located here are stimulated, causing a decrease in neuronal firing.

The consequence of this is a reduction in the release of serotonin at nerve terminals in the forebrain - an opposite effect to that required for relieving depression. Tolerance to this effect develops with repeated administration of SSRIs, as a result of desensitisation of the serotoninlA receptors.

These findings have led investigators to hypothesise that the addition of an agent that blocks serotoninlA autoreceptors might prevent this negative feedback loop and so enhance the effect of SSRIs.

Preclinical and early clinical results Preclinical data support this hypothesis. In animal

studies. microdialysis techniques have demonstrated that local application of SSRIs to the dorsal RN reduces serotonin release in the dorsal striatum, an area that receives neuronal projections from the dorsal RN. This is prevented by administration of the /3-blocker and serotoninlA receptor antagonist pindolol.

Furthermore, open-label pilot clinical studies have shown that pindolol reduces the latency of response to paroxetine, and improves the response to other SSRIs and other types of antidepressants. 1.2

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Controlled trial confums pindolol's effect •.. Dr F Artigas from the Consejo Superior de

Investigaciones Cientificas, Barcelona, Spain, who was one of the principal investigators in the open-label studies. presented data from a recently completed double-blind. placebo-controlled trial investigating the ability of pindolol to augment fluoxetine's antidepressant effect.

Patients with depression were recruited from primary-care settings. After a placebo run-in for 7 days, all patients who did not show a ~ 25% decrease in Hamilton Depression Rating (HAM-D) scale score were randomised to receive fluoxetine 20 mg/day in combination with either pindolol 7.5 mg/day (n = 55) or placebo (56) for 6 weeks. The effects of the 2 treat-ments were assessed using several criteria [see table].

The addition of pindolol to fluoxetine resulted in a more pronounced overall improvement in depressive symptoms, compared with the addition of placebo. This included a greater reduction in HAM-D and Montgomery-Asberg Depression Rating Scale (MADRS) scores. Furthermore, there was a significantly greater number of patients who responded to treatment in the fluoxetine/pindolol group, compared with patients in the fluoxetinel placebo group.

Similarly, a significant result in favour of fluoxetine/pindolol was seen for the endpoint of remission [see graph on next page]. The effects of pindolol were not due to anxiolytic activity, as the anxiety items on the HAM-D scale were not significantly different between the 2 treatment groups.

The median time to achieve a sustained response was only 19 days in the fluoxetinelpindolol group, compared with 29 days in those given the SSRI + placebo. In fact, after just 9 days of treatment, a significant difference had already emerged between treatment groups regarding the number of patients who eventually had a sustained response. This significant difference was maintained to the end of the study.

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10 RESEARCH & DEVELOPMENT

The combination of fluoxetine and pindolol was well tolerated. There was no difference between the 2 treatment groups in terms of adverse events, with the exception of postural hypotension and anxiety (which occurred more frequently in those patients who had placebo added to the SSRI), and reduced heart rate (a greater decrease in this parameter was seen in patients receiving fluoxetine/pindolol). The number of patients who completed the study was similar in the 2 treatment groups (83.6% of fluoxetine/pindolol and 75.0% of fluoxetine/placebo recipients).

The beneficial effects of pindolol did not appear to be due to a pharmacokinetic effect, as the concen-trations of fluoxetine were similar in both groups.

... but no such effect seen in US study In contrast to the encouraging results from Dr

Artigas' group, other investigators have found that pindolol has no effect on the antidepressant response to SSRIs. Dr Dennis Charney from Yale University, US, presented the results of another double-blind, placebo-controlled trial of a fluoxetine/pindolol combination.

The patients involved were outpatients with moderate-to-severe major depression. After a placebo run-in period, they were randomised to receive fluoxetine 20 mg/day in combination with either pindolol 2.5mg 3-times daily (n = 23) or placebo (20) for 6 weeks. This was followed by a 3-week single-blind phase.

Partial remission rates (defined as a ~ 50% de-crease in HAM-D score) after 2 weeks of therapy were 17 and 15% in fluoxetine/pindolol and fluoxetine/placebo recipients, respectively. At the end of the study, there was still no significant difference in partial remission rates between groups. This indicates that the addition of pindolol did not hasten or enhance the response to fluoxetine.

It was suggested that the reason for the contrasting results of the 2 studies was that the patients in the Spanish study had less severe depression. In addition, since the majority of these patients were recruited from primary-care settings, they were more likely to have been drug-naive than those in the US study sample.

Future approaches Pindolol is a ~-blocker. As such, it has a number

of effects on the cardiovascular system that could be Results of a study investigating the antidepressant-

aUQmenting effects of pindolol 100%~----~~------------.------------,

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detrimental in patients with depression. For example, in the studies mentioned previously, pindolol was associated with reduced heart rate in the Spanish study and reduced blood pressure in the US study, compared with baseline levels.

Ideally, an agent is required that is selective for the serotonin lA receptor SUbtype and that does not affect the cardiovascular system. WAY-100635 [preclinical] is a new agent from Wyeth-Ayerst that may fulfil these criteria.

Regarding the therapeutic effects of WAY-l 00635, Colin Dourish and colleagues from Cerebus, UK, have shown that the drug enhances the acute behavioural effects of SSRIs in animal models. This was demonstrated in a mouse marble-burying model, which is thought to be a model of compulsive behaviour.

In these mice, SSRIs caused a dose-dependent decrease in the number of marbles buried (an activity that is not accompanied by a decrease in locomotor activity). Subcutaneous WAY-100635 0.1 mg/kg potentiated this response when given in combination with fluvoxamine, whereas it had no effect on either the burying response or locomotor activity when administered alone. These results suggest that a combination of selective serotonin lA antagonists, such as WAY-l 00635, and SSRIs deserve investigation in clinical trials involving patients with obsessive-compulsive disorders. 1. Blier P, et aI. Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depreSSion. Journal of Oinical Psycbophannacology IS: 217-222, Jun 1995 2. Artigas F, et aI. Pindolol induces a rapid improvement of depressed patients treaIed with serotonin reuptake inhibitors. Archives of General Psychiatry 51: 248-251, Mar 1994 .,..,.. ..

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