René S. Kahn

m-Chlorophenylpiperazine as a probe of serotonin function

m-Chlorophenylpiperazine (mCPP) is the most extensively used probe of serotonin function in psychiatry. This article reviews its in vitro and in vivo properties in animals, normal human subjects, and psychiatric patients. mCPP is a safe, reliable, direct 5-hydroxytryptamine (5HT) agonist, which may be used to evaluate 5HT receptor sensitivity. It causes a consistent, dose-dependent elevation of ACTH, cortisol, and prolactin levels in both animals and humans, as well as increased body temperature in man. It also causes a variety of behavioral effects, depending on the population studied. These effects are probably 5HT receptor-related, although specific 5HT receptor subtype mechanisms have not yet been established. mCPP may be considered an important addition to armamentarium of 5HT receptor probes, which is especially useful until more selective 5HT receptor agonists have been tested.

Serotonin, dopamine and their interactions in schizophrenia

Interest in a possible role of monoamines other than dopamine (DA) in the pathogenesis of schizophrenia is increasing. This is due in part to the unsatisfactory progress in the treatment of schizophrenia using DA antagonists, particularly in altering the course of illness of the chronic and/or refractory schizophrenic patient. Examination of a possible contribution of serotonin (5-hydroxytryptamine, 5ttT) dysfunction in the pathophysiology of schizophrenia has gained considerable attention in the last few years. Although the earlier studies provided only scant evidence for a role for serotonin in schizophrenia (Bleich et al. 1988), several more recent observations have rekindled interest in serotonergic involvement in schizophrenia. The finding that the 5HT antagonist, ritanserin, alleviates some schizophrenic symptoms and, when added to haloperidol, decreases extrapyramidal side effects (EPS) (Gelders 1989) suggests the usefulness of blocking 5HT receptors in the treatment of schizophrenia. It specifically suggests a role for 5HT in (negative) symptoms in schizophrenia and in reducing the EPS potential of DA antagonists. Its partial efficacy resulted in the development of mixed 5HT2/DA2 antagonists, with the hypothesis that a (small) amount of DA receptor blockade would reduce positive symptoms in schizophrenia, while blockade of 5HT2 receptors would reduce negative symptoms and decrease the EPS induced by blockade of DA receptors (see Leysen et al. this issue). The finding that clozapine, clinically superior to conventional neuroleptics (Kane et al, 1988), is a weak DA2 antagonist but a potent 5HTI~ (Canton et al, 1990) and 5HT 2 antagonist (Meltzer 1989) has further stimulated 5HT-related research in schizophrenia. Thus, as so often in biological psychiatry, interest in the role of a particular neurotransmitter was sparked after (re-)examination of the mechanism of action of drugs. Although recent studies do suggest that examining 5HT function in schizophrenia may be informative and fruitful, it is unlikely that the pathogenesis of schizophrenia would be either dopaminergic or serotonergic in

Brief neuroleptic discontinuation and clinical symptoms in Kraepelinian and non-Kraepelinian chronic schizophrenic patients

Neuroleptic medication was abruptly discontinued in 24 male chronic schizophrenic patients who were subdivided on the basis of their history of illness into Kraepelinian (n = 8) and non-Kraepelinian (n = 16) subgroups. These patients were kept drug free for 6 weeks and then returned to treatment with haloperidol, 20 mg/day. Half of the non-Kraepelinian patients developed exacerbations of their symptoms, which quickly resolved when they were returned to medication, while none of the Kraepelinian patients showed a worsening of symptomatology. On-medication clinical severity failed to predict risk for exacerbation, with severity of exacerbation predicting the amount of improvement when returned to medication. The Kraepelinian patients were found to be much less variable than the non-Kraepelinian patients in their symptoms during both medication manipulations, suggesting that medication truly has a negligible effect on them.

Haloperidol and clozapine treatment and their effect on M-chlorophenylpiperazine-mediated responses in schizophrenia: implications for the mechanism of action of clozapine

Since clozapine is, in contrast to conventional neuroleptics, effective in treatment refractory schizophrenic patients its mechanism of action may be different from that of typical neuroleptics. Clozapine has been shown to display the highest binding affinity of all neuroleptics to one of the serotonin (5-hydroxytryptamine, 5HT) receptor subtypes, i.e., the 5HT1c receptor. Furthermore, clozapine, in contrast to conventional neuroleptics, blocks the effect of 5HT agonists on ACTH and corticosterone release in animals. This study hypothesized that clozapine, but not haloperidol would block ACTH and prolactin release induced by the 5HT agonist,m-chlorophenylpiperazine (MCPP). MCPP (0.35 mg/kg PO) was administered after a 3-week drug-free period, after 5 weeks of haloperidol treatment (20 mg/day) and finally after 5 weeks of clozapine treatment (>400 mg/day) in ten male schizophrenic patients. Clozapine, but not haloperidol, blocked the effect of MCPP on ACTH and prolactin release. These results suggest that clozapine, in contrast to haloperidol, is a functional 5HT antagonist. Since MCPP-induced ACTH and prolactin release may be (partially) 5HT1c mediated, these results suggest that clozapine is a potent antagonist at the 5HT1c receptor.

Effects of ipsapirone in healthy subjects: a dose-response study

A dose-response study of ipsapirone (IPS), a 5HT1a partial agonist, was conducted in healthy male subjects. IPS was administered in doses of 5,10 and 20 mg PO in a placebo-controlled, double-blind design to 15 subjects on 4 test days separated by at least 3 days. Oral temperature, ACTH, cortisol, prolactin, blood pressure, pulse rate and behavioral variables were assessed every 30 min for 3 h after administration of tablets (at 10:00a.m.). IPS at 20 mg significantly decreased temperature and increased cortisol levels. Although IPS increased ACTH levels at 20 mg, this effect was variable and not significant. IPS did not affect prolactin levels nor did it have any behavioral effects. Although 20 mg IPS decreased blood pressure and pulse rate in one subject, overall it had no significant effect on these parameters. IPS at 20 mg PO appears a useful probe to test 5HT1a function when temperature and cortisol are used as response variables. These results replicate earlier studies on the effect of IPS in healthy human subjects.

Nocturnal growth hormone secretion in schizophrenic patients and healthy subjects

Plasma growth hormone concentrations were measured at hourly intervals between 10 p.m. and 8 a.m. the next morning in 15 drug-free chronic schizophrenic male inpatients and 14 healthy males. Growth hormone secretion was significantly lower in the patients as compared with the controls. Growth hormone release peaked around 1 a.m. in the controls, but a growth hormone peak was absent in the patient group. Increased dopamine activity, increased serotonin activity, or both could explain the absence of a nocturnal growth hormone surge in the schizophrenic patients.

White matter maturation in the neonatal brain is predictive of school age cognitive capacities in children born very preterm

To investigate the association between white matter organization in the neonatal brain and cognitive capacities at early school age in children born very preterm.

Effects of indomethacin on plasma homovanillic acid concentration in normal subjects: a study of prostaglandin-dopamine interactions

In laboratory animals, prostaglandins have been shown to act as endogenous neuromodulators of central dopamine (DA) activity. To examine the interaction between prostaglandins and DA in man, the effect of a prostaglandin synthesis inhibitor, indomethacin, was studied on plasma concentrations of the DA metabolite, homovanillic acid (pHVA). Indomethacin (150 mg PO) as compared to placebo significantly elevated mean pHVA concentrations in eight normal subjects. Results of this study support the hypothesis that, as in animals, inhibition of prostaglandin synthesis increases central DA turnover in man.

Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia

The role of the human microbiome in health and disease is increasingly appreciated. We studied the composition of microbial communities present in blood across 192 individuals, including healthy controls and patients with three disorders affecting the brain: schizophrenia, amyotrophic lateral sclerosis, and bipolar disorder. By using high-quality unmapped RNA sequencing reads as candidate microbial reads, we performed profiling of microbial transcripts detected in whole blood. We were able to detect a wide range of bacterial and archaeal phyla in blood. Interestingly, we observed an increased microbial diversity in schizophrenia patients compared to the three other groups. We replicated this finding in an independent schizophrenia case–control cohort. This increased diversity is inversely correlated with estimated cell abundance of a subpopulation of CD8+ memory T cells in healthy controls, supporting a link between microbial products found in blood, immunity and schizophrenia.

The relationship between brain volumes and intelligence in bipolar disorder

OBJECTIVESnBipolar disorder type-I (BD-I) patients show a lower Intelligence Quotient (IQ) and smaller brain volumes as compared with healthy controls. Considering that in healthy individuals lower IQ is related to smaller total brain volume, it is of interest to investigate whether IQ deficits in BD-I patients are related to smaller brain volumes and to what extent smaller brain volumes can explain differences between premorbid IQ estimates and IQ after a diagnosis of BD-I.nnnMETHODSnMagnetic resonance imaging brain scans, IQ and premorbid IQ scores were obtained from 195 BDI patients and 160 controls. We studied the relationship of (global, cortical and subcortical) brain volumes with IQ and IQ change. Additionally, we investigated the relationship between childhood trauma, lithium- and antipsychotic use and IQ.nnnRESULTSnTotal brain volume and IQ were positively correlated in the entire sample. This correlation did not differ between patients and controls. Although brain volumes mediated the relationship between BD-I and IQ in part, the direct relationship between the diagnosis and IQ remained significant. Childhood trauma and use of lithium and antipsychotic medication did not affect the relationship between brain volumes and IQ. However, current lithium use was related to lower IQ in patients.nnnCONCLUSIONSnOur data suggest a similar relationship between brain volume and IQ in BD-I patients and controls. Smaller brain volumes only partially explain IQ deficits in patients. Therefore, our findings indicate that in addition to brain volumes and lithium use other disease factors play a role in IQ deficits in BD-I patients.