Yves Chaput

Long-term 5-HT reuptake blockade, but not monoamine oxidase inhibition, decreases the function of terminal 5-HT autoreceptors: an electrophysiological study in the rat brain

Summary5-HT-containing terminals possess autoreceptors which modulate the release of 5-HT into the synaptic cleft. Tritiated imipramine ([3H]IMI), and more specifically [3H]citalopram and [3H]paroxetine, bind to a site associated with the 5-HT reuptake carrier on the 5-HT terminals. The function of terminal 5-HT autoreceptors is decreased following long-term treatment with the 5-HT reuptake blocker citalopram. The present study was undertaken to determine whether an increased synaptic availability of 5-HT or, the occupation of the [3H]IMI site, were responsible for this modification. Unitary extracellular recordings were obtained from CA3 dorsal hippocampus pyramidal neurons under chloral hydrate anesthesia in rats treated daily with fluoxetine (10 mg/kg/day × 14 days), a selective 5-HT reuptake blocker, or clorgyline (1 mg/kg/day × 21 days), an inhibitor of type A monoamine oxidase. The function of the terminal 5-HT autoreceptors was assessed by comparing the effectiveness of the electrical stimulation of the ascending 5-HT pathway on the firing activity of hippocampus pyramidal neurons prior to, and following, the administration of methiothepin, an antagonist of the terminal 5-HT autoreceptor, and, by determining the ratio of effectiveness of 0.8 Hz (S1) and 5 Hz (S2) stimulations. Long-term administration of fluoxetine or clorgyline both increased the efficacy of the stimulation of the 5-HT pathway. However, the enhancing effect of methiothepin on the efficacy of the stimulation was attenuated by the fluoxetine, but not by the clorgyline, treatment. The reduction of the function of the terminal 5-HT autoreceptor by the long-term fluoxetine treatment was further indicated by the decreased ratio of effectiveness of the 0.8 and 5 Hz stimulations as compared to that of control rats. To verify that the reuptake blockade per se could not account for the increased synaptic efficacy of 5-HT projections following long-term fluoxetine, the drug was administered acutely to naive rats. It did not increase the efficacy of the stimulation of the 5-HT pathway. Two conclusions are drawn from these results: 1) the increased efficacy of 5-HT synaptic transmission by long-term treatment with antidepressant 5-HT reuptake blockers is not directly due to 5-HT reuptake blockade, but rather, to a reduced function of the terminal 5-HT autoreceptor; 2) the latter phenomenon cannot be ascribed to an increased availability of 5-HT in the synaptic cleft as it was not produced by long-term clorgyline treatment. Hence, these results suggest that long-term occupation of the [3H]IMI site might result in a decreased function of terminal 5-HT autoreceptors.

Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine—I. Effects of acute and long-term administration of tandospirone on serotonin neurotransmission

The acute and long-term effects of the antidepressant/anxiolytic selective 5-HT1A receptor ligand, tandospirone (SM-3997) on 5-HT neurotransmission were assessed using single-cell extracellular recording in chloral hydrate-anaesthetized rats. The acute intravenous administration of tandospirone decreased the firing rate of 5-HT neurones of the dorsal raphe (ED50 = 9.1 +/- 1.1 micrograms/kg). A treatment with tandospirone for 2 days (10 mg/kg/day, s.c.), markedly reduced the firing activity of 5-HT neurones of the dorsal raphe; this was followed by a partial recovery after 7 days and by complete recovery after 14 days of administration of tandospirone. After treatment with tandospirone for 14 days (10 mg/kg/day, s.c.), the responsiveness of 5-HT neurones to the intravenous administration of LSD was reduced, suggesting that somatodendritic 5-HT autoreceptors had desensitized. The depressant effects of microiontophoretically-applied tandospirone and 5-HT, on the firing activity of CA3 pyramidal neurones in the hippocampus were blocked by the intravenous injection of the 5-HT1A receptor antagonist, BMY-7378. The depressant effect of microiontophoretically-applied 5-HT onto these same neurones was markedly reduced during concurrent background application of tandospirone, suggesting that the latter acted as a partial agonist at postsynaptic 5-HT1A receptors. The sustained administration of tandospirone for 14 days (10 mg/kg/day, s.c.) altered neither the effectiveness of microiontophoretically-applied 5-HT and tandospirone nor that of endogenous 5-HT, released by the electrical simulation of the afferent 5-HT pathway, in suppressing the firing activity of pyramidal neurones in the hippocampus, suggesting that postsynaptic 5-HT1A receptors had not desensitized. Furthermore, long-term treatment with tandospirone did not alter the sensitivity of the terminal 5-HT autoreceptor. It is thus concluded that desensitization of somatodendritic 5-HT autoreceptors permits 5-HT neurones to regain their physiological rate of firing during long-term treatment with tandospirone and, consequently, to release a normal amount of 5-HT into the synaptic cleft. This, combined with the sustained activation of normosensitive postsynaptic 5-HT1A receptors by tandospirone, during such a treatment, should result in an enhanced tonic activation of postsynaptic 5-HT1A receptors.

Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine—II. Effects of acute administration of 1-PP and long-term adminstration of tandospirone on noradrenergic neurotransmission

1-(2-Pyrimidinyl)-piperazine (1-PP) is a common metabolite of the antidepressant/anxiolytic 5-HT1A agonists, tandospirone (SM-3997), gepirone, buspirone and ipsapirone. The present electrophysiological studies were undertaken to characterize in vivo the effect of 1-PP on noradrenergic (NE) neurotransmission in rat brain. At small doses, 1-PP (ED50 = 80 micrograms/kg, i.v.) reversed the depressant effect of the alpha 2-adrenoceptor agonist, clonidine (20 micrograms/kg, i.v.) on the firing activity of NE neurones of the locus coeruleus. After long-term treatment with tandospirone (10 mg/kg/day, s.c. x 14 days), the responsiveness of these NE neurones to intravenous administration of clonidine was decreased but their mean firing frequency remained within the control range. The effect of 1-PP on the postsynaptic alpha 2-adrenoceptor of pyramidal neurones in the hippocampus was investigated: intravenous administration of 1-PP (2-8 mg/kg, i.v.) reduced the effect of microiontophoretically-applied NE on CA3 pyramidal neurones of the dorsal hippocampus, without affecting their responsiveness to GABA and 5-HT. The effect of the electrical stimulation of NE neurones of the locus coeruleus in reducing firing activity of pyramidal neurones, which is mediated by postsynaptic alpha 1-adrenoceptors, was increased by 47% after acute administration of 1-PP (4 mg/kg, i.v.), presumably as a result of blockade of terminal alpha 2-autoreceptors. The effectiveness of these stimulations remained unchanged after long-term treatment with tandospirone. Furthermore, the decrease in the effectiveness of stimulation of the locus coeruleus, obtained by increasing the frequency from 1 to 5 Hz, a phenomenon due to an increased activation of terminal alpha 2-adrenergic autoreceptors by endogenous NE, remained unaltered after long-term treatment with tandospirone. In addition to the initial depressant effect, stimulation of the locus coeruleus induces a late activation of these neurones which is mediated by a beta-adrenoceptor. The degree of activation induced by stimulation of the locus coeruleus was similar in controls and in long-term tandospirone-treated rats. It is concluded that 1-PP acts as an antagonist at somatodendritic and terminal alpha 2-adrenergic autoreceptors, as well as at postsynaptic alpha 2-adrenoceptors, in the central nervous system of the rat. However, the levels of 1-PP attained after long-term administration of tandospirone were not sufficient to modify NE neurotransmission.

The co-administration of quetiapine or placebo to cognitive-behavior therapy in treatment refractory depression: A preliminary trial

BackgroundPatients with major depression refractory to repeated pharmacological trials (TRD) may remain symptomatic for many years after their index episode. Augmentation strategies (with lithium or an atypical antipsychotic) or combining an antidepressant with short-term psychotherapy have been used with relative success in these patients. The aim of this study was to assess the effectiveness of the concomitant administration of quetiapine, an atypical antipsychotic, or placebo, to cognitive-behavior therapy (CBT) in TRD.MethodsThirty-one patients who met entrance criteria for unipolar major depression (TRD stage II or greater) underwent 3 weeks of lithium augmentation after which non-responders (N = 22) were randomized to receive either quetiapine or placebo as an adjunct to their 12 weekly CBT sessions (quetiapine/CBT or placebo/CBT groups). Primary efficacy measures were the Hamilton and the Montgomery-Asberg rating scales for depression.ResultsOverall, there was a significant reduction in both primary efficacy measure scores at LOCF for the 11 patients in the quetiapine/CBT group but not in the placebo/CBT treated patients. Patients in the quetiapine/CBT group, compared to those receiving placebo/CBT, showed a significantly greater degree of improvement on one primary and one secondary efficacy measure, were more likely to complete the trial and, completed a greater number of CBT sessions.ConclusionAlthough preliminary, our results suggest that the adjunctive administration of quetiapine to CBT may prove useful in the treatment of stage II TRD.Trial RegistrationCurrent Controlled Trials ISRCTN12638696.

An examination of the temporal and geographical patterns of psychiatric emergency service use by multiple visit patients as a means for their early detection

Background:Frequent users of the psychiatric emergency service (PES) place a heavy burden upon the mental health care delivery system. The aim of this study was to identify distinct temporal or geographical patterns of PES use by these patients as potential markers for their early detection.Methods:Diagnostic profiles were obtained for patients making an intermediate (4 to 10) or a high (11 or more) number of visits to a general hospital PES in Montreal (Canada) between 1985 and 2004. Between-group comparisons were made with regards to several parameters. These included the time intervals between consecutive visits, visit clustering (single, repeating, and the time interval to the first cluster) and visits made to three other services where data was similarly acquired from 2002 to 2004.Results:The two multiple visit groups differed with regards to diagnostic profiles and actual time between consecutive visits (significantly shorter in patients with 11 or more visits). Patients with 11 or more visits were more likely to have a single cluster (3 or more visits/3 months) or repeating clusters (4 visits/3 months) in their patterns of use. Personality disorders were more prevalent in patients with single clusters as they were, along with schizophrenia, in those with repeating clusters. In addition, clusters were found to occur sufficiently early so as to be potentially useful as markers for early detection. Ten percent of those with 11 or more visits and 16% of those with an intermediate number of visits frequented at least one other PES. A small number of patients, primarily those with substance abuse, made over 50% of their visits to other services.Conclusion:Temporal and geographical patterns of use differed significantly between the multiple visit groups. These patterns, combined with distinct diagnostic profiles, could potentially lead to the more rapid identification and treatment of specific sub-groups of multiple visit patients.

Is psychiatric emergency service (PES) use increasing over time

BackgroundSeveral recent studies have reported a significant increase in medical emergency department (ED) use for reasons of mental health. The diagnostic profile of these patients however differs from that usually described for patients visiting the psychiatric emergency service (PES). Few studies have specifically focused upon long-term PES utilization rates. Those that do typically present data from the early 80s, suggesting that deinstitutionalization may be an important contributing factor to the increases found. The aim of this study was to assess PES use using a more recent time frame and, the effects of non-specific factors, such as population growth, on this use.MethodsVisits per year at several different types of PESs were obtained; (a) for an 11-year period at a general hospital PES while the surrounding population remained stable, (b) at that same PES while the catchment area population doubled over a period of a few years, (c) for an 11-year period at two PESs without catchment areas while the surrounding population increased and (d-) for a 12-year period at a PES in a mental health facility while the surrounding population increased. Moderately conservative criteria were used to define either a trend or, a significant increase in utilization rates.ResultsEach site had an inherent, 7 to 15% yearly variability in the number of PES visits. Over time however, only those where the surrounding population increased (either by an increase in the catchment area size or a regional increase in the population census) showed a trend or, a significant increase in utilization rates. These increases however were modest and of the order of 12 to 19%.ConclusionLong observation periods are required in order to detect stable changes in PES utilization rates over time. As such, population growth may be but one of several factors underlying these increases. Organizational changes in mental health care delivery in the vicinity of the services that showed an increase could also have contributed. These latter would simply have redistributed (to the PES) the pre existing pool of mental health care patients, resulting in an increase that is more apparent than real.

A qualitative study of a psychiatric emergency

BackgroundThe psychiatric emergency service (PES) is a major hub in the mental health care delivery system. The aim of this study was to more precisely define what psychiatrists consider to be a psychiatric emergency and to examine the underlying basis of this assessment.MethodsOver twenty-two thousand PES visits were assessed prospectively for pertinence and urgency by psychiatrists in four functionally and structurally different services in the province of Quebec, Canada. This study took place between July 15 1996 and August 31, 2004.ResultsOverall, 57% of visits were judged pertinent and urgent (P/U), 30% pertinent but not urgent (P/NU) and 13% neither pertinent nor urgent (NP/NU). Between 50 and 60% of P/U tagged visits were diagnosed with an affective or a psychotic disorder, often with a suicidal content. They also more frequently resulted in a short-term observation in the PES or a hospitalization. Variables suggesting the presence of a behaviorally disturbed state (aggressive behaviors, involuntary or police referrals) were equally likely to be found in P/U or NP/NU visits. Legal confinement following the consultation was almost exclusively seen in visits judged P/U. The percent of visits tagged P/U at the four individual sites varied substantially above and below the 57% value for the combined data. Interestingly, no major inter-site differences in diagnostic profiles for the three pertinence and urgency anchor points were found that might account for this variability. Finally, visits from high frequency users were less likely to be judged P/U than visits from patients attending less frequently.ConclusionPrimary consideration for a P/U tag was a visit characterized by a behaviorally disturbed state and/or, suicidal ideation (or attempts) within the context of either an underlying psychotic or affective disorder, especially if poor judgment was an issue. Some specific diagnoses appeared to qualify the above core clinical considerations, increasing or decreasing the probability of a P/U tag. Finally, non-clinical site-specific factors related to the individual services themselves, such as the number of readily available specialized resources, also appeared to qualify this assessment. These data may prove useful for the future development of this service.

Lithium Augmentation of Antidepressant Treatments: Evidence for the Involvement of the 5-HT System?

The use of lithium carbonate addition in treatment-resistant depression is now current practice world-wide. Several approaches had previously been proposed for treatment-resistant depression: reserpine (Poldinger, 1963; Haskovec and Rysanek, 1967; Hopkinson and Kenny, 1975; Zohar et al., 1987), T3 (Earle, 1969; Ogura et al., 1974; Banki, 1977; Goodwin et al., 1982), psychostimulants (Wharton et al, 1971; Ayd and Zohar, 1987), oestrogen supplementation (Shapira et al, 1985; Zohar et al, 1985; Oppenheim et al., 1987) or combination of a tricyclic antidepressant drug (TCA) with a monoamine oxidase inhibitor (MAOI) (Schuckit et al, 1971; Sethna, 1974; Spiker andPugh, 1976; Goldberg and Thormson, 1978). However, until recently, electroconvulsive therapy (ECT) remained the treatment of choice for resistant depression (Medical Research Council, 1965; Davidson et al., 1978). British investigators have recently advanced that lithium addition might soon supersede the use of ECT in treatment-resistant depression (Pai et al., 1986).

Electrophysiological Investigation of the Effects of Antidepressant Treatments on Serotonin Receptors

Long-term treatment with serotonin (5-HT) reuptake blockers, monoamine oxidase inhibitors or 5-HT1A agonists, but not with tricyclic antidepressant drugs, induces a desensitization of rat somatodendritic 5-HT autoreceptors in the rat. This desensitization allows 5-HT neurons to regain progressively their normal firing activity following an initial decrease at the beginning of such treatments. After a long-term treatment with 5-HT reuptake blockers, but not with a monoamine oxidase inhibitor, the terminal 5-HT autoreceptor exhibits a reduced function resulting in a greater amount of 5-HT released per impulse. Repeated administration of tricyclic antidepressant drugs or of electroconvulsive shocks leads to a sensitization of forebrain neurons to 5-HT. Hence, the antidepressant treatments thus far assessed electrophysiologically enhance 5-HT neurotransmission via the modification of different 5-HT receptors. It is proposed that this common final effect of antidepressant treatments on the 5-HT system might be related to their therapeutic efficacy in major depression.

The elderly in the psychiatric emergency service (PES); a descriptive study.

BackgroundThe impact of an aging population on the psychiatric emergency service (PES) has not been fully ascertained. Cognitive dysfunctions aside, many DSM-IV disorders may have a lower prevalence in the elderly, who appear to be underrepresented in the PES. We therefore attempted to more precisely assess their patterns of PES use and their clinical and demographic characteristics.MethodsClose to 30,000 visits to a general hospital PES (Montreal, Quebec, Canada) were acquired between 1990 and 2004 and pooled with over 17,000 visits acquired using the same methodology at three other services in Quebec between 2002 and 2004.ResultsThe median age of PES patients increased over time. However, the proportion of yearly visits attributable to the elderly (compared to those under 65) showed no consistent increase during the observation period. The pattern of return visits (two to three, four to ten, eleven or more) did not differ from that of patients under 65, although the latter made a greater number of total return visits per patient. The elderly were more often women (62%), widowed (28%), came to the PES accompanied (42%) and reported « illness » as an important stressor (29%). About 39% were referred for depression or anxiety. They were less violent (10%) upon their arrival. Affective disorders predominated in the diagnostic profile, they were less co-morbid and more likely admitted than patients under 65.ConclusionAlthough no proportional increase in PES use over time was found the elderly do possess distinct characteristics potentially useful in PES resource planning so as to better serve this increasingly important segment of the general population.