H. M. van Praag

Depression, suicide and the metabolism of serotonin in the brain ☆

I have recently summarized the data which indicate the likelihood of a central 5-hydroxytryptamine (serotonin; 5-HT) deficiency in patients with vital depression (Van Praag 1980, 198 la, b). We define vital depression as a syndrome which roughly corresponds with that described as endogenous depression in Anglo-American literature (Van Praag et al. 1965; Van Praag 1978, 1982). The vital depression syndrome is aetiologically non-specific; in other words, it can be provoked by a wide variety of factors: psychosocial, hereditary and acquired somatic factors. The natural course of the syndrome tends to be recurrent (unipolar depressions). When the course is characterized by vital depressive as well as (hypo)manic phases, the term bipolar depression applies. 5-HT is one of the monoamines (MA) found in the brain, where it plays a role as neurotransmitter. Within the context of this paper I will disregard the possible relationships between catecholamines and depression. The bodies of the serotonergic cells are localized mainly in the raphe nuclei. Their axons fan out over large areas of the brain and spinal cord. 5-HT is produced from the essential amino acid tryptophan via a single intermediate compound: 5-hydroxytryptophan (5-HTP). 5-HT is converted to the inactive metabolite 5-hydroxyindoleacetic acid (5-HIAA) with the aid of the enzyme monoamine oxidase (MAO). The concentration of 5-HIAA in the cerebrospinal fluid (CSF) is a gross indicator of the degradation of 5-HT in the brain. By giving the patient probenecid, which inhibits the transport of 5-HIAA from the CNS and CSF to the blood stream, a gross index can be obtained of the 5-HT turnover in the CNS. For theoretical backgrounds and procedure of the probenecid test, see Van Praag (1977a).

Effects ofm-chlorophenylpiperazine in normal subjects: a dose-response study

Abstractm-Chlorophenylpiperazine (MCPP), a direct 5HT receptor agonist, was administered orally to 20 normal subjects in two doses (0.25 and 0.5 mg/kg) in a placebo-controlled design. Behavioral responses; ACTH, cortisol, prolactin and MCPP blood level; temperature and pulse rate were measured over a 210-min period after administration of tablets. Non-linear dose-response relationships between MCPP and ACTH, cortisol and prolactin response were found. On the higher dose, a significant increase in the number of physical symptoms was also noted and three subjects (15%) had a panic attack, while one subject (5%) had a panic attack on the lower dose. No effects on other behavioral variables, pulse rate and temperature were found using either dose. These findings attest to the usefulness of MCPP as a challenge agent to assess 5HT receptor hypersensitivity when given at a low oral dose (i.e. around 0.25 mg/kg), and to assess 5HT receptor hyposensitivity when given at higher oral doses (i.e. around 0.5 mg/kg).

In search of the mode of action of antidepressants. 5-HTP/tyrosine mixtures in depressions.

For a long time antidepressants have been considered to act via enhancement of central monoaminergic activity (due to reuptake or MAO inhibition). An alternative hypothesis holds that their action is based on down-regulation of monoaminergic activity (due to decrease in density or sensitivity of certain receptor populations). In this paper the likelihood of both hypotheses is discussed and the conclusion reached that the first one is the most plausible. The following arguments are discussed: (1) the 5-HT precursor 5-HTP, which is transformed to 5-HT in the brain, has antidepressant properties; (2) there are indications that the same holds true for tyrosine, a catecholamine precursor transformed in the brain to DA and NA; and (3) evidence was found that the effects of 5-HTP in depression are potentiated by tyrosine. Since activation rather than suppression of monoaminergic activity seems to be linked to antidepressant activity, it seems likely that the signs of decreased monoamine metabolism that have been demonstrated in certain types of depression are the expression of a primary metabolic deficit rather than a phenomenon secondary to receptor hypersensitivity. Further clinical studies of 5-HT/CA precursor combinations in depression are justified.

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.

Critical Appraisal of the Evidence

Based on the relation found to exist between low CSF 5-HIAA and suicide attempt, in particular violent suicide attempt, both in depressed and in so-called nondepressed suicide attempters, the conclusion was drawn that decreased central 5-HT metabolism is related to (auto)aggression, rather than to depression. We challenged this conclusion and that for three reasons: Violent suicide attempt accumulates in certain types of depression making it impossible to conclude whether the biological variable relates to (auto)aggression or to that type of depression as such. Nondepressed suicide attempter is a diagnosis that should be based on presuicidal not on postsuicidal data, in order to avoid false-positive diagnoses. Suicide method is not a reliable index of seriousness of the attempt. Risk/rescue ratio should be used instead. Next the data are discussed that do support the hypothesis that diminished 5-HT metabolism in the brain is related to disregulation of aggression. Finally, the hypothesis is launched that both mood and aggression disorders are related to decreased 5-HT metabolism in the CNS. This would provide a biological explanation for the clinical observation that disorders in mood and in aggression often go hand in hand. Biological research of psychiatric disorders gains in informative value as the psychopathological analysis of the phenomena one studies is more comprehensive. Biological suicide research is no exception to this rule.

Indoleamines in Depression and Suicide

Publisher Summary This chapter discusses the evidence in favor of a relationship between depression and central 5-HT dysfunctions. The findings are derived from the patients with depression as the principal diagnosis. Some data originate from the patients suffering from a somatic illness and from depression as well. Both peripheral and central data are discussed. The issue of the specificity of the observed alterations in 5-HT metabolism is also described. It is concluded as in depression, 5-HT metabolism can be disturbed. The same seems to be true for certain disturbances in aggression regulation. It is more likely that the 5-HT disturbances are causally related to the behavioral disorder, than that they are secondary to them or mere coincidences. This conclusion is based on these considerations, including (1) 5-HT precursors, in particular 5-HTP can be effective in depression, (2) 5-HTP exerts prophylactic effects in high frequency uni- and bipolar depression, (3) preliminary findings suggest 5-HT precursors, in particular tryptophan, to possess aggression decreasing potential in schizophrenic patients, (4) in animals the relationship between certain types of aggressive behavior and central 5-HT systems has been well established.

About the course of schizoaffective psychoses

This study involves a program that was developed to determine whether there is a need for the category of schizoaffective disorders. The data suggest that the term schizoaffective pychoses should be upheld as a collective name for the group of the functional “mixed psychoses” between the schizophrenic group and that of the (non-psychotic) manic-depressive syndromes, and that like the group of schizophrenic psychoses, that of the schizoaffective psychoses is a heterogeneous group in terms of symptomatology, short-term treatment response, and long-term outcome.

Effects of haloperidol on human plasma magnesium

The effect of haloperidol treatment on human plasma levels of magnesium (Mg), calcium (Ca) and phosphorus (P) was assessed. Haloperidol treatment significantly reduced plasma Mg but not plasma Ca or P levels. This finding contrasts with studies using other neuroleptics where reductions in both Mg and Ca concentrations were observed. The addition of lithium to haloperidol treatment resulted in an elevation of plasma Mg, but not Ca or P, to levels significantly greater than those at baseline. The reduction of Mg levels by haloperidol may reflect the ions involvement in the pathology of psychosis and/or in the mechanism of generating extrapyramidal side effects.

The effect of milenperone on the aggressive behavior of psychogeriatric patients: a double-blind placebo-controlled study

The antiaggressive action and the side effects of a new neuroleptic, milenperone, were evaluated in 21 oligophrenic patients by means of a double-blind randomized pilot study in comparison with placebo. Only 3 patients appeared to be psychotic, 2 from the milenperone group and 1 from the placebo group. In this study, milenperone was added to the existing psychotropic medication as an adjuvant. The test substance was administered in a dose of 2 X 10 mg daily for 6 weeks. The results were evaluated by means of the Paranoid Belligerence Scale and the improvement of the target symptoms were visualized on the Visual Analogue Line. Although, in the last 3 weeks of the study, the aggressiveness scores had decreased more in the milenperone group than in the placebo group, the difference between both studied groups was not significant. This lack of clear result may probably be ascribed to the high standard deviations, together with the small number of patients per group. The severity and frequency of the side effects remained almost unchanged during the investigation and were independent of the substance administered: milenperone or placebo.

The Effect of Milenperone on the Aggressive Behavior of Psychogeriatric Patients

The antiaggressive action and side effects of a new neuroleptic, milenperone, were evaluated in 20 non-psychotic psychogeriatric patients by means of a double-blind randomized pilot study in comparison with placebo. In this study, milenperone was added to the existing medication as an adjuvant. The test substance was administered in a dose of 2 X 5 mg daily for the first 3 weeks, in a dose of 2 X 10 mg daily for the following 3 weeks. The addition of milenperone to the preexisting medication decreased the aggressiveness scores, significantly on the Paranoid Belligerence Scale, not significantly on the Visual Analogue Line. The improvement of the aggressiveness scores on the Paranoid Belligerence Scale was only significantly apparent when the dose was doubled. In spite of the association with milenperone, the severity and frequency of the side effects did not increase during the investigation.