Godfried M.J. Van Kempen

Pharmacokinetic and pharmacodynamic profile of oral and intravenous meta-chlorophenylpiperazine in healthy volunteers

meta-Chlorophenylpiperazine (mCPP) is a compound that is frequently used in challenge tests of the serotonergic system. Its human pharmacology is largely unexplored. The objective of this study was to investigate the pharmacokinetic and pharmacodynamic profile of mCPP. Eight female and six male healthy volunteers were included in a randomized, double-blind, double-dummy, three-way crossover design of single-dose intravenous (0.1 mg/kg), oral (0.5 mg/kg), and placebo treatment, with 24-hour follow-up. mCPP showed a large variability in clearance (11-92 mL/hr) and bioavailability (14-108%). Two female subjects dropped out because of headache and dysphoria. During the 27 occasions in which mCPP was administered, autonomic physical symptoms were observed in 23 subjects and disturbances of mood in 6 subjects. Oral and intravenous mCPP caused sudden increases in cortisol levels, prolactin levels, and total scores of the Body Sensation Questionnaire. Administration of mCPP also led to concentration-dependent increases of saccadic peak velocity and adaptive tracking performance and to a decrease of electroencephalographic occipital theta activity. No clinically relevant effects on electrocardiogram, temperature, and blood pressure were found. In conclusion, it is doubtful whether mCPP is a useful compound for challenge tests in view of the large pharmacokinetic variability after intravenous and oral administration. The effects of mCPP are consistent with disinhibition of the central nervous system.

Psychopathology and personality characteristics in relation to blood serotonin in Tourette's syndrome and obsessive-compulsive disorder.

Family studies suggest an interrelationship between Gilles de la Tourette Syndrome (GTS) and some forms of obsessive–compulsive disorder (OCD). Some authors consider GTS to be part of a serotonergicallyrmediated cluster of OCD spectrum disorders. The present study was undertaken to compare measures of psychopathology, personality and blood serotonin between GTS and OCD (without tics), and to investigate whether an OCD spectrum hypothesis is supported for GTS. Fifteen GTS without OCD subjects, 21 tic with (+) OCD subjects, 15 OCD without tic subjects and 26 controls (all without serotonergic medication) were evaluated with self-rated and clinician-rated measures of psychopathology and personality. Whole blood serotonin (5-HT) and platelet monoamine oxidase activity (MAO) was measured, and Spearmans correlations were calculated between whole blood 5-HT, MAO and rating scale scores within the entire sample and within subgroups. There were main effects of OCD on anxiety, obsessive–compulsive, neuroticism and extraversion scores. There were main effects of tics on depression, obsessive–compulsive, trait anxiety and neuroticism scores, and on platelet MAO. There were interaction effects on platelet MAO, 5-HT, Yale–Brown Obsessive–Compulsive Rating Scale severity, trait anxiety and Eysenck Personality Questionnaire neuroticism scores. Platelet MAO activity was elevated in tic-free OCD subjects when compared to tic + OCD, GTS without OCD and controls. Whole blood 5-HT was lowered in tic + OCD patients in comparison to GTS without OCD and tic-free OCD subjects. Whole blood 5-HT and obsessive–compulsive severity were negatively correlated within OCD without tic patients and MAO and Leyton Obsessive Inventory scores were negatively related within GTS without OCD patients. The biochemical data of this study suggest that in tic + OCD and in tic-free OCD patients, 5-HT dysregulations play a role, but not necessarily in pure GTS. Serotonergic dysregulations within tic + OCD and tic-free OCD patients are distinct, suggesting differences in underlying pathophysiology. The finding that obsessions and compulsions can be associated with either 5-HT hypofunctionality or hyperfunctionality reveals a major weakness in the OCD spectrum theory, i.e. that the associations between obsessive–compulsive behaviours and 5-HT abnormalities are less specific than suggested by the original obsessive–compulsive spectrum model.

Assay of platelet monoamine oxidase in whole blood

Monoamine oxidase (MAO; EC 1.4.3.4.) was measured in whole blood with kynuramine as the substrate. Optimal circumstances were determined. By use of selective inhibitors, gradient centrifugation, dilution of samples and removal of thrombocytes from whole blood it was shown that this assay of MAO in whole blood is in fact a determination of platelet MAO. No reversible endogenous inhibitors are present in the blood. Because preparation of platelet-rich plasma may lead to considerable losses of specific subpopulations with relatively low or high enzyme activities, the advantage of using whole blood is that the MAO activity is determined in the whole platelet population.

Platelet serotonin and [3H]paroxetine binding correlate with recurrence of suicidal behavior.

Abstract To distinguish state-from trait-dependent associations between serotonergic function and suicidal behavior, platelet serotonergic measures were repeatedly measured, during a 1-year follow-up, in 106 patients who had recently attempted suicide for at least a second time. A major DSM-III-R axis I diagnosis or use of antidepressants were reasons for exclusion. A higher affinity constant (KD) of platelet [3H]paroxetine binding was related to a higher risk of short-term recurrence of a suicide attempt, suggesting a state relationship. Higher levels of platelet serotonin at baseline were a significant predictor of a recurrent suicide attempt within the year of follow-up, suggesting a trait relationship. These associations held equally within the subgroup of 73 patients with a borderline personality disorder. Neither the maximum number of binding sites (Bmax) of [3H]paroxetine nor platelet monoamine oxidase activity correlated with suicidality. The observed association between indicators of platelet serotonin uptake and suicidal behavior suggests a state-and trait-dependency between suicidality and central serotonergic dysfunction.

The effect of m-CPP on tics and obsessive-compulsive phenomena in Gilles de la Tourette syndrome.

Abstract  Rationale: Family genetic and phenomenological studies support an interrelationship between Gilles de la Tourette syndrome (GTS) and obsessive-compulsive disorder (OCD). Some authors consider GTS as part of a serotonergically mediated cluster of OCD spectrum disorders. Objective: To study serotonergic mechanisms in GTS, the effect of the relatively selective 5-HT2c agonist meta-chlorophenylpiperazine (m-CPP) was assessed. Methods: We studied the behavioural effects of m-CPP on tics, obsessions, compulsions and impulsions of GTS. Twelve medication-free GTS patients (ten men, two women) were included in a single dose 0.5 mg/kg oral m-CPP challenge study with a double-blinded placebo-controlled cross-over design. Global symptom scores, target symptom scores as well as biochemical measures were followed up to 24 h after baseline. Results: While m-CPP caused a significant rise in plasma cortisol and prolactin levels, no significant effects were found on the tics, obsessions and compulsions. Impulsions showed a trend to ameliorate. Conclusions: This study does not support a predominant role for 5-HT on the tics in GTS. The trend of impulsions to ameliorate after m-CPP can be interpreted as circumstantial support for impulsivity-related 5-HT hypofunctionality in GTS. However, the large variability of m-CPP plasma concentrations found in this study casts doubts upon the reliability of m-CPP as a probe for challenge studies.

Decreased erythrocyte membrane elevations in patients with a major depressive episode

Washing of erythrocytes from healthy volunteers in an isotonic sodium chloride solution at pH 5.6 results in the occurrence of plasma membrane elevations as observed in freeze-etch electron microscopy. This is prevented by anion permeability inhibiting agents. In the absence of these agents a reduced number of elevations was found in 23 of 36 patients with a major depressive episode. This reduced capacity to form membrane elevations was positively correlated with a genetic vulnerability, defined as an admission to a psychiatric hospital in first-degree relatives.

Evidence of vasopressinergic-noradrenergic mechanisms in depression with above-normal plasma vasopressin concentration with and without psychotic features

Previous studies in the field of melancholic or endogenous depression have resulted in support for a subcategory of depression with above-normal plasma vasopressin (AVP) concentration (ANA). Since an analogous animal model with increased release of above-normal plasma vasopressin exhibits reduced Sympathetic-Nervous-System activity, the present study investigated the plasma norepinephrine concentration and the correlation between plasma norepinephrine and AVP in this ANA depression. As psychotic–melancholic patients may have increased plasma norepinephrine concentration, and noradrenergic activation may stimulate AVP release, potentially confounding effects of psychotic features were also investigated. The data set of the same depressed patient sample that was used before, but limited to those with complete hormonal data (n = 75), was re-analysed. ANA depression (n = 14) had negatively correlating AVP and norepinephrine concentrations. A very small subcategory of ANA depression with psychotic features (n = 3) had high plasma norepinephrine concentration, suggesting that this could be an independent subcategory. This was supported by the combination of relatively low above-normal plasma AVP concentrations with the highest severity scores for depression in this subcategory, which does not correspond with the positive correlation between AVP concentration and severity in non-psychotic ANA depression. The results further support the validity of ANA depression and the analogy with the High Anxiety Behaviour animal model of depression. Further investigations are needed to replicate these findings and to search for genetic and traumatic factors involved.

Increased plasma norepinephrine concentration in psychotic depression.

Objective: We previously found psychotic depression (PSDEP) to have positively correlating plasma norepinephrine (NE) and vasopressin (AVP) concentrations. Since central noradrenergic activity and plasma NE concentration are highly correlated, this suggests an increased noradrenergic activation of the hypothalamus–pituitary–adrenal axis. We hypothesize the increased release of NE in PSDEP to be an associated mechanism. Methods: To test this hypothesis we analyzed the relation between plasma NE and PSDEP in a comparison with non-psychotically depressed patients. Potentially confounding variables were, among others, melancholia and two better validated subcategories in the field of melancholia and endogenous depression, three global dimensions of psychopathology – Emotional Dysregulation, Retardation and Anxiety – smoking habit, and different types of psychotropic and particularly antidepressant treatment. The data from nine patients with PSDEP and 69 patients with non-PSDEP were reanalysed. Results: Analysis of covariance controlling for the effects of tricyclic antidepressant treatment (≥100 mg) and smoking habit showed that PSDEP had an increased concentration of plasma NE. The previously found correlation between plasma NE and AVP was still present after correcting for the effects of confounding variables. Conclusions: The results suggest an increased activity of the sympathetic nervous system in PSDEP that may act as a specific mechanism for increased vasopressinergic activation. This supports the view of PSDEP as a distinct subcategory of major depression.

Hypertonic hemolysis in patients with a mood disorder

Hypertonic hemolysis was increased in patients with a manic episode (n = 6, mean NaCl concentration in mol/L at which 50% of the erythrocytes was hemolyzed (H50) 3.24 +/- 0.10), compared to healthy controls (n = 12, mean H50 3.43 +/- 0.13) (p < or = 0.02) and patients with a nonaffective psychotic disorder (n = 15, mean H50 3.42 +/- 0.18) (p < or = 0.02). Compared to these two control groups, hypertonic hemolysis was decreased in patients with a severe depressive episode (n = 8, mean H50 3.62 +/- 0.19) (p < or = 0.05 and p < or = 0.02, respectively). Within the total depressed patient group, the patients with an increased genetic vulnerability (n = 8, mean H50 3.68 +/- 0.16) showed a decreased hypertonic hemolysis compared to the other depressed patients (n = 14, mean H50 3.40 +/- 0.16) (p < or = 0.002).

Estimation of plasma serotonin using isopycnic centrifugation.

The valid measurement of the concentration of serotonin (5‐HT) in blood plasma is important when using the platelet as a model for the serotonergic neuron. The assay is hampered by the release of 5‐HT by (residual) platelets during the preparation for assay. We developed an isopycnic method that separates cells gently and completely from plasma by centrifuging a diluted Percoll density‐gradient to which whole blood was added. In this study this method was compared with the usual differential centrifugation method. The isopycnic method on average resulted in nine times lower levels of plasma 5‐HT. This difference was linearly related to the number of residual platelets in plasma after differential centrifuging. The proportion of intra‐individual variation decreased three‐fold. Therefore, the use of a Percoll density‐gradient may lead to a more precise and more accurate estimate of the level of plasma 5‐HT. Copyright