Limitations of current medical treatments for depression: Disturbed circadian rhythms as a possible therapeutic target

The proportion of diagnosed depressives prescribed antidepressants has increased markedly over the last 20 years, mainly following the introduction of the selective serotonin reuptake inhibitors. However, currently available antidepressants have notable limitations, relating to their only moderate efficacy relative to placebo, relatively slow onset of action, possible withdrawal symptoms, and problems of compliance. Sleep disturbances are often used to identify newly presenting depressive patients, and may be part of a more general alteration of bodily rhythms. There are links between pharmacological treatments and circadian rhythms in depression, which might represent another, new option for the development of a therapeutic approach to depression treatment. Many antidepressants affect sleep, some are sedative, and others have been used specifically in severely insomniac depressives. Disturbances in circadian rhythms may be an integral part of depressive mechanisms, and normalising them via an innovative mechanism of antidepressant action may be a fruitful avenue in the search for improved antidepressant agents.     

Effects of scopolamine,trimipramine and diazepam on explicit memory and repetition priming in healthy volunteers

The effects of scopolamine, an anticholinergic drug, of trimipramine, a tricyclic antidepressant with both anticholinergic and sedative properties, of diazepam and a placebo, on explicit memory and repetition priming were assessed using a free-recall task and a word-stem completion task. Forty-eight healthy volunteers took part in this double-blind study. Diazepam provoked a dissociation between free recall, which was profoundly impaired, and word completion, which was spared. No significant changes in memory performances were observed in the scopolamine group; however, a significant correlation between explicit and implicit memory performances was observed in this group. At the low dose used, the effects of trimipramine on memory were mild. The results suggest that the cholinergic system is involved in the priming effect.     

An alternative mechanism of actions for neuroleptic and antidepressant drugs

It has earlier been proposed by the author that the aetiology of schizophrenic symptomatology may be due to the presence of abnormally connected interhemispheric fibres which link specialised functions in the brains of schizophrenics that are not connected in normal subjects, and that the neuroleptic drugs may produce their action through a local anaesthetic-like effect in suppression of conduction in these fibres. This line of thought has been extended here to consider the possible mechanism of action of the neuroleptic drugs in more detail, as well as that of the tricyclic antidepressant drugs which are derivatives of the phenothiazine group. Pharmacological similarities with the local anaesthetics both structurally and functionally have been considered, as well as the effects that these drug groups may have in common with the lithium salts. It has been suggested that these drugs all produce their primary effect on cell membranes, though not necessarily at the synapse, that the time course of their clinical effect may correlate with their incorporation into various cell membranes within the CNS, and that they may thus bring about a fundamental alteration in cell membrane microstructure. The possible role of electroconvulsive therapy has also been considered. The corollary of this argument is that the affective disorders may be genetically determined diseases of cell membrane microstructure.     

A neurotrophic model for stress-related mood disorders.

There is a growing body of evidence demonstrating that stress decreases the expression of brain-derived neurotrophic factor (BDNF) in limbic structures that control mood and that antidepressant treatment reverses or blocks the effects of stress. Decreased levels of BDNF, as well as other neurotrophic factors, could contribute to the atrophy of certain limbic structures, including the hippocampus and prefrontal cortex that has been observed in depressed subjects. Conversely, the neurotrophic actions of antidepressants could reverse neuronal atrophy and cell loss and thereby contribute to the therapeutic actions of these treatments. This review provides a critical examination of the neurotrophic hypothesis of depression that has evolved from this work, including analysis of preclinical cellular (adult neurogenesis) and behavioral models of depression and antidepressant actions, as well as clinical neuroimaging and postmortem studies. Although there are some limitations, the results of these studies are consistent with the hypothesis that decreased expression of BDNF and possibly other growth factors contributes to depression and that upregulation of BDNF plays a role in the actions of antidepressant treatment.     

Reliability and validity of a health-related quality of life battery for evaluating outpatient antidepressant treatment

This study was designed to evaluate the reproducibility, validity and responsiveness of a health-related quality of life (HRQOL) battery that was assembled for the evaluation of antidepressant therapy. The Montgomery-Asberg Depression Rating Scale was used to measure severity of depression. The HRQOL battery contained measures of energy and fatigue, social behaviour, cognitive function, home and work role function, and general well-being (i.e., health perceptions, life satisfaction) selected from previously developed and validated instruments. The clinical investigators and research nurses reported on difficulty in using the HRQOL battery. Most patients were able to complete the questionnaire without problems within 10 min. Reproducibility was very good with intraclass correlation coefficients ranging from 0.74 to 0.97. The HRQOL scales showed evidence of good concurrent validity. The scales were moderately correlated with MADRS scores (r=0.30–0.62). The magnitude of these correlations indicate that HRQOL scales are related to depression measures, but they are not alternative measures of depression. Changes in MADRS scores were associated with changes in all scales, except for work behaviour, indicating that improvements in depression ratings also resulted in improvements in health status and well-being. The HRQOL scales included in this study were found to be reliable, reproducible, and valid and no appreciable burden was placed on patients or investigators participating in the study. With the exception of the Work Behaviour scale, the HRQOL scales were very responsive to changes in depression severity. This brief HRQOL instrument can provide a comprehensive assessment of the outcomes of antidepressant treatment.This research was supported by a grant from Pfizer International.     

An open pilot study of nefazodone in depression with anger attacks: relationship between clinical response and receptor binding

Nefazodone has been widely used as an antidepressant, but it has not been tested for depression with anger attacks. In an open study, we administered nefazodone (maximum 600 mg/day) for 12 weeks to 16 outpatients who had major depression with anger attacks. Assessment instruments comprised the Structured Clinical Interview for DSM-IV (SCID), Anger Attacks Questionnaire (AAQ), 17-item Hamilton Rating Scale for Depression (HAM-D-17), Clinician Global Impression Scale (CGI), Symptom Questionnaire (SQ), Modified Overt Aggression Scale (MOAS), and MOAS-Self-Rated. Three subjects underwent positron emission tomography (PET) with [¹⁸F]-setoperone for 5-HT2 binding potential (BP) and [¹¹C]-SCH-23,390 for D1 BP, both at baseline and after 6 weeks of treatment. Eight subjects underwent PET with [¹⁸F]-setoperone and with [¹¹C]-SCH-23,390 at baseline only. In an examination of whether D1 and 5HT2 (data available in six subjects) receptor BP predicted treatment response, we found significant decreases in the HAM-D-17, CGI-S, weighted MOAS, MOAS verbal scale, OAS Self-Rated verbal, SQ Depression and Anger/Hostility scales after nefazodone; 50% responded to nefazodone (defined as ≥50% decrease in HAM-D-17 score), and 44% reported disappearance of anger attacks. A statistically significant percentage decrease in 5HT2 BP was observed for the right mesial frontal and left parietal regions after 6 weeks of treatment. No significant change was observed in D1 BP in any region. Although CGI-I scores correlated significantly with D1 BP in the left thalamic region, the correlation was not significant after Bonferroni correction. The effectiveness of nefazodone for depression with anger attacks may be related to widespread changes in 5HT2 receptor BP.     

Depressive symptoms during buprenorphine vs. methadone maintenance: findings from a randomised, controlled trial in opioid dependence

Research suggests that buprenorphine may possess antidepressant activity. The Beck Depression Inventory was completed at baseline and 3 months by heroin dependent subjects receiving either buprenorphine or methadone maintenance as part of a larger, pre-existing, double blind trial conducted by NDARC (Australia). Depressive symptoms improved in all subjects, with no difference between methadone and buprenorphine groups, suggesting no differential benefit on depressive symptoms for buprenorphine compared to methadone.     

Moclobemide versus fluoxetine for a major depressive episode

The efficacy and tolerability of moclobemide (300–600 mg daily) and fluoxetine (20–40 mg daily) were compared in a 6-week, double-blind study of 65 inpatients and 34 outpatients suffering from major depressive episodes (DSM III-R). No statistically significant differences between the two treatment groups were noted regarding efficacy (HDRS, CGI) or safety (adverse events, laboratory examination, vital signs). Moclobemide (300–600 mg daily) and fluoxetine (20–40 mg daily) would thus appear to be comparable both in antidepressant efficacy and tolerability. Doubling the low dosage in non-responders after 3 weeks resulted in a statistically significant improvement of CGI in the moclobemide group by comparison with the fluoxetine group at study end, suggesting that 600 mg moclobemide/day can still improve the patient's condition, while 40 mg fluoxetine/day does not. Sexual dysfunction was reported in two patients taking fluoxetine.