In a double-blind study carried out on elderly patients (older than 65 years) the efficacy and tolerability of the new antidepressant moclobemide was compared. Moclobemide belongs to a new class of substances called RIMA (Reversible inhibitor of the monoamine oxidase type A). Fluvoxamine, a selective reuptake-inhibitor of 5-HT, belongs to a class of antidepressants known for their better tolerability compared to tricyclic especially with elderly patients. Forty elderly patients (mean age 75 years) with major depression (according to DSM III) were randomized to receive either moclobemide (300 mg) or fluvoxamine (100 mg) twice daily. Dosages were increased when necessary on day 8, to a maximum of 450 mg moclobemide or 200 mg fluvoxamine and in most cases were maintained at these levels for the remainder of the study period (four weeks). Moclobemide was more effective than fluvoxamine showing a marked antidepressant effect and an earlier effect on psychomotor retardation. The two drugs were well tolerated showing a low incidence of side effects.

Among HIV patients treated for AIDS-related adjustment, major depressive disorders and other affective disorders, we assessed in an open study the feasibility of using a serotonergic antidepressant (fluvoxamine). Thirty-five seropositive patients with the above conditions (22 men and 13 women) were followed over a minimum period of four weeks. At the end of the treatment, a large number of patients (77%) showed marked improvement. “Nuclear” depressive and anxiety symptoms remitted, while the “somatic” ones seemed less sensitive to treatment. Treatment had to be terminated prematurely due to side effects in only two patients (6%).

The last two decades have witnessed an upsurge in the interest in anxiety disorders. Much research effort has been dedicated to panic disorder and obsessive compulsive disorder. However, it is only very recently that we have begun to understand some of the basic principles about the psychopharmacology of social phobia. Drug classes so far studied include beta-blockers, non-selective and irreversible MAO-inhibitors (MAOI's) and benzodiazepinen. Beta-blockers appear to be of use in specific social phobias, like public speaking. There is considerable evidence suggesting that MAOI's are effective in reducing both social anxiety as well as social avoidance. A disadvantage of the conventional irreversible MAOI's is their risk for hypertensive crises when combined with dietary tyramine.

So far only a small number of studies with selective MAOI-A inhibitors such as moclobemide and brofaromine have been conducted in social phobia, and the results indicate that both compounds are effective.

Drugs exerting selective and specific actions on certain components of e.g. the serotonergic system can now be studied and it is hoped that the role of serotonin and other neuronal systems in social phobia can be elucidated.

In order to gain more information about selective serotonergic drugs the first double blind placebo-controlled study with fluvoxamine in social phobia is here reported. Preliminary results indicate a reduction of social anxiety.

Finally the role of peptides in the treatment of social phobia is critically reviewed. The MSH/ACTH analog Org 2766 was investigated in patients suffering from social phobia. No anxiolytic effects of this peptide could be observed.

In this review the results are discussed on the prediction of response to pharmacotherapy in panic disorder (PD) and social phobia (SP). From the literature it appears that in PD variables indicative of illness severity are predictors of non-response. In our own studies we found that non-responders to pharmacotherapy in PD are characterised by a higher score on the Blood-Injury subscale of the Fear Questionnaire, a higher plasma MHPG and a higher heart rate. In SP non-responders to pharmacotherapy were also characterised by a higher heart rate. They also appeared to have a higher blood pressure. Furthermore non-responders to pharmacotherapy in SP had higher scores on several psychometric scales, indicative of illness severity.

Serotonin (5-HT) plays an important role in depression and specific 5-HT reuptake blockers appear to be clinically important antidepressants. It is unclear however, which serotonergic mechanism is involved in the antidepressant effect, certainly when regarding the existence of at least seven 5-HT receptor subtypes. By testing different 5-HT ligands in two animal models of depression (forced swimming and DRL72-S test) and comparison with data from literature, evidence is provided for potential antidepressant qualities of 5-HT1A receptor-agonists and 5-HT1C receptor-antagonists. Compounds binding to 5-HT1B, 5-HT2 and 5-HT3 receptors do not have an antidepressant profile. Results of clinical research support the predicted antidepressive effects of 5-HT1A receptor-agonists.

Visualization of neurotransmission components in living small animals using positron emission tomography (PET) has the potential of contributing to the preclinical development of neuroactive drugs, although it is yet to be examined whether quantitative animal PET data on candidate compounds can be extrapolated to humans. Here, we investigated the comparability of the occupancies of serotonin transporter (5-HTT) by therapeutic agents in rat PET studies with our predetermined data from ex- vivo animal experiments and clinical PET scans. Rats were treated with varying doses of fluvoxamine and a newly developed compound, (2S)-1-[4-(3,4-dichlorophenyl) piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride (Wf-516), and underwent PET scans with [11C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([11C]DASB), a selective radioligand for in-vivo quantification of 5-HTT. PET images indicated a reduction of [11C]DASB binding to 5-HTT as a function of the doses and/or plasma concentrations of fluvoxamine and Wf-516. The doses of these drugs at half-maximal effect (15.2 mg/kg and 3.1 mg/kg, respectively), determined that using binding potentials for [11C]DASB, were comparable to those estimated by our previous ex-vivo measurements in rats (4.5 mg/kg and 1.1 mg/kg, respectively), as there was only a 3-fold difference between these results. Moreover, the plasma concentration of fluvoxamine needed for 50% occupancy of central 5-HTT (6.1 ng/ml) was almost equivalent to the value determined in human PET studies (4.6 ng/ml). These findings support the view that the conjunctive use of small-animal PET and [11C]DASB facilitates a quantitative comparison of in-development drugs targeting 5-HTT with established inhibitors and a predictive estimation of their plasma concentrations exerting therapeutic effects in humans.

Therapeutic doses of lofepramine and fluvoxamine were associated with the development of first degree and second degree heart block, respectively, in an 83 year old man with a normal ECG prior to treatment and with no history of cardiovascular disease. Caution is recommended in treating patients with newer generation antidepressants, even in cases where cardiac status appears normal prior to treatment.