Carmen Z. Lemus

Hormonal probes of central serotonergic activity: Do they really exist?

The response of a hormone allegedly under 5-hydroxytryptaminergic (5-HT-ergic) control to a compound stimulating or inhibiting serotonergic activity has been used as a measure of the functional state of central serotonergic systems. The relevant literature is reviewed, and based on that, it is concluded that, as yet, no reliable hormonal 5-HT probe exists. The main problems are nonselectivity of the challengers and noncomparability of individual studies because of variations in dose and route of administration. An acceptable hormonal 5-HT probe should at least have passed the following three tests. The influence of the challenger on catecholaminergic (CA) systems must be rendered unlikely in humans to avoid the pitfalls of, say, the 5-HT precursors whose CA-ergic influences have been overlooked. Dose-response relationships must be established to avoid the confusion caused by different investigators using the challenger in different doses. It must be demonstrated that the effect of the challenger is counteracted by its functional opponent.

The neuroendocrine response to fenfluramine in depressives and normal controls

Disturbances of central nervous system serotonin (5hydroxytryptamine, 5-HT) activity have been hypothesized to be associated with disturbances in mood, anxiety, and aggression regulation (Gardner 1985; van Praag 1985). Although the most direct assessment of central 5HT is via measurement of 5-hyroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) and in postmortem studies of 5-HT and 5-HIAA in the brain, difficulties in using these methods as a practical clinical evaluation of 5-HT are obvious. The development of an easily useable peripheral probe of central 5-HT activity to study 5-HT in psychiatry is essential. The most practical clinical method in studying monoamine (MA) neurotransmitters is the use of hormone challenge methods. Each peripheral hormone is regulated by hypothalmic peptides (inhibitory and/or stimulatory factors), which are in turn regulated by various MA neurotransmitters. As 5-HT is stimulatory to prolactin (PRL) and cortisol in humans (found in most, but not all,

Therapeutic indications for serotonin-potentiating compounds: A hypothesis

The original antidepressants, tricyclics and MAO inhibitors, increase the availability in the brain of both 5-HT and NA. Prompted by clinical findings suggestive of 5-HT disturbances in depression, drugs were developed that increase 5-HT selectively. Data are presented that suggest that broad-spectrum compounds may provide better conditions for antidepressant effects than the 5-HT-selective ones. The hypothesis is proposed that 5-HT potentiators are partial antidepressants, in that they predominantly reduce the anxiety/aggressive component of the depressive syndrome, and deserve to be tested in conditions with heightened anxiety and/or aggression irrespective of the nosological diagnosis. Tentative evidence relates diminished 5-HT metabolism to disordered impulse control. Based on these data, trials of 5-HT potentiators in impulse control disorders unrelated to aggressive drives seem warranted.

Dexamethasone suppression test in schizophrenia. A study and review.

The prevalence of an abnormal response to the 1 mg dexamethasone suppression test (DST) was examined in 40 inpatients suffering from a major depressive disorder (MDD), 17 inpatients suffering from schizophrenia, and 30 normal controls. 23.5% of the schizophrenics were DST nonsuppressors compared to 52.5% of MDD patients and 6.7% of normal controls. The prevalence of abnormal DST in schizophrenics in the literature is reviewed and factors like the presence of depression, doses of dexamethasone, and hospital admission, which may account for the wide variability of prevalence among studies (0-35%), are discussed.

Plasma dexamethasone and cortisol levels in depressed outpatients.

We investigated the 1-mg dexamethasone suppression test (DST) in 41 outpatients with major depressive disorder assessing the role of dexamethasone blood level, age and basal cortisol on DST results. Non-suppressors (approximately 25% of patients) had lower dexamethasone levels, and post-dexamethasone cortisol was negatively correlated with plasma dexamethasone; these findings were more significant after covarying out age and basal cortisol, factors that were also significantly associated to non-suppressors. A subgroup of patients (n = 19) also had 0.75-mg and 2.0-mg DST to evaluate whether a threshold dexamethasone blood level existed; a dexamethasone blood level greater than 1.5 ng/ml converted all non-suppressors to suppressors. Implications of these findings are discussed.

Hormonal response to fenfluramine challenges in clozapine-treated schizophrenic patients

Clozapine is a dibenzodiazepine derivative with proven antipsychotic efficacy in treatme_nt-refractory schizophrenic patients (Kane et a11988). It is considered an atypical neuroleptic due to its low incidence of extrapyramidal side effects (Kane et a11988), its inability to produce catalepsy (Biirki et al 1975) or block apomorphine-induced stercotypy in animals (Ljungberg and Ungerstedt 1978), and its failure to significantly elevate serum prolactin (Prl) levels (Meltzer et al 1979). Serotonin (5-hydroxytryptamine [5-HT]) agonists are known to stimulate Prl release (Martin and Reichlin 1987). This effect is blocked by 5-HT antagonist agents (Martin and Reichlin 1987). PreclinicaI studies suggest that clozapine is a potent 5-HT antagonist (Fink et al 1984; Lee and Tang 1984). We chose a neuroendocrine strategy to study clozapines effect on the serotonergic system of schizophrenic patients. Fentturamine, a 5-HT agonist, was used as a serotonergic probe. Clozapines ability to inhibit the Prl response to fenfluramine would suggest 5-HT antagonistic properties in humans.

Clinical variables and hypothalamic-pituitary-adrenal function in depression The importance of mood reactivity

Forty outpatients with major depressive disorder were studied with the 1 mg DST and the Afternoon Cortisol Test. No relationship was found between hypothalamic-pituitary-adrenal (HPA) axis function and Research Diagnostic Criteria subtypes of depression, with the exception of higher log post-dexamethasone cortisol levels in endogenous depressives. Patients with mood reactivity had lower cortisol values on all assessments. The data suggest that the presence of mood reactivity may be useful as a predictor of normal HPA function in depression.

Behavioral responses to a dopaminergic challenge in obsessive-compulsive disorder

Abstract The behavioral response to an intravenous methylphenidate challenge was evaluated in five patients with obsessive-compulsive disorder. The affective response was heterogeneous, ranging from dysphoria to mood elevation with abreaction. Stereotypic movements were noted. Three of the five subjects experienced a marked worsening (1.6- to 24-fold increase) in their obsessive-compulsive symptoms, and failed to respond to a subsequent treatment trial with fluvoxamine, a 5-HT reuptake inhibitor. These preliminary findings highlight the need to investigate the role of the dopaminergic system in the pathophysiology of obsessive-compulsive disorder.

Behavioural effects of IV MCPP in schizophrenia

The effect of the serotonergic system on psychotic behaviour and sehizophrenia has been recently studied. Meta-chlorophenylpiperazine (MCPP) is a direct-acting 5HT receptor agonist which has been shown to have both neurochemical and behavioural effects in schizophrenic subjects. In this study, we report the behavioural effect of I.V. MCPP administration in a cohort of new-onset and chronic schizophrenics. clozapine trial. Patients were rated for the presence of psychopathological and tardive dyskinesia at regular intervals. Plasma and cerebrospinal fluid homovanillic acid (pHVA, CSF HVA) and cerebrospinal 5hydroxyindoleacetic acid (CSF SHIAA) levels were collected at baseline and treatment week 3. Data from 19 DSM III schizophrenic and schizoaffective disorder patients were examined. The sample was 68% male, 88% treatment refractory, 53% had tardive dyskinesia and the mean age was 29.5k6.3 years. Dividing the sample into clozapine responders vs nonresponders showed that the responders had both a lower baseline CSF HVA levels (pc.08) and a CSF HVA/SHIAA ratio (pi.04). Plasma HVA levels were not associated with CSF HVA values but with CSF SHIAA levels.