Christoph Stuppaeck

Influence of age and gender on risperidone plasma concentrations

There is limited information on gender- and age-specific effects on plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone. The present study investigated dose- and weight-adjusted plasma concentrations of risperidone and its metabolite in three age groups (45 years, 45-60 years, over 60 years). Gender-specific differences were examined in the whole sample and for the premenopausal subgroup. One hundred and twenty-nine patients (18-93 years) were included in the study, 52 (40%) male and 77 (60%) female. Concentrations of risperidone and 9-hydroxyrisperidone were measured at steady-state by high-performance liquid chromatography with electrochemical detection (HPLC-ED). When total plasma concentrations (risperidone plus 9-hydroxyrisperidone) were adjusted for daily maintenance dose (ng/mL/mg C/D ratio), significant differences between all age groups were found. We found a mean increase of the C/D ratio by 34.8% per decade in patients older than 42 years. No significant sex-related differences in the average plasma concentrations were observed for the whole sample and for the premenopausal subgroup. This study shows clear evidence of higher risperidone total plasma concentrations for patients over 40 years of age. This linear increase (over 30% per decade) may then lead to an increased incidence of adverse effects in elderly patients.

A multicenter double-blind trial of paroxetine versus amitriptyline in depressed inpatients

The phenylpiperidine derivative paroxetine is a selective serotonin reuptake inhibitor. In a double-blind 6-week trial, paroxetine was compared with amitriptyline in hospitalized patients suffering from major depression (DSM-III). One hundred fifty-three patients were enrolled in the study in seven centers in Austria and Germany. Results showed similar efficacy of both drugs after 6 weeks. The differences between groups in Mont-gomery-Asberg Depression Rating Scale and Clinical Global Impression ratings did not reach statistical significance at any time. Side effects were distributed similarly but with a significantly higher incidence of anticholinergic effects in patients treated with amitriptyline (p < 0.001), whereas agitation and insomnia were registered more often in the paroxetine group. This study supports the antidepressive efficacy of paroxetine in a sample of severely depressed inpatients.

Hippocampal volume reduction in male schizophrenic patients

Using magnetic resonance imaging of the brain, we examined volumetric measurements of total brain, hemispheres, lateral ventricles and the hippocampus/amygdala complex in male subjects (41 first-episode schizophrenics, 30 chronic schizophrenic patients and 32 healthy controls). We found significantly smaller total brain size in the chronic schizophrenic group, significantly larger lateral ventricles in both patient groups and hippocampal volume reduction bilaterally in first-episode patients (-13.2% left, -12.05% right) and chronic patients (-10.6% left, -10.5% right) compared to controls--irrespective of diagnostic subtype, family history for psychiatric diseases, psychopathology, duration of illness or age at onset.

Risperidone and breast-feeding

We present the case of a breast-feeding woman with acute psychotic symptoms after delivery, which were treated with the antipsychotic agent risperidone. Serum levels of risperidone and 9-hydroxyrisperidone could be detected in both the mother and her infant. Drug-levels in breast milk were ten-fold lower compared to maternal serum. The patient responded well to antipsychotic treatment. Her infant did not display any adverse effects and psychomotor development was normal. In this case, risperidone was a safe treatment option for the breast-feeding mother and her infant. We also provide a brief overview of the clinically relevant data concerning antipsychotics and breast-feeding.

Carbamazepine in the prophylaxis of mood disorders.

Alternatives to lithium are desirable in the prophylaxis of affective disorders, especially in patients who are intolerant of or do not respond to that drug. In the past few years the anticonvulsant carbamazepine has been in the foreground of discussion. Twenty-four patients with affective disorders (17 unipolar depressed, six bipolar, and one unipolar manic) were included in a comparative trial of lithium and carbamazepine; 12 had been pretreated with lithium without a satisfactory effect. All patients received carbamazepine (four received it in combination with lithium) over a mean time span of 20.2 months. Eighty percent of the patients improved with carbamazepine treatment. Side effects were infrequent.

Paroxetine with pindolol augmentation: A double-blind, randomized, placebo-controlled study in depressed in-patients

Pindolol, a 5-HT1A autoreceptor antagonist, given in combination with selective serotonin reuptake inhibitors (SSRIs), may enhance and/or accelerate the therapeutic efficacy of SSRIs. Fifty patients, meeting ICD-10 criteria for major depressive disorder or bipolar depression, were enrolled in our randomized, placebo-controlled, double-blind trial. One group received paroxetine plus pindolol (2.5 mg t.i.d.), and the other group received paroxetine plus placebo. The proportion of patients with sustained response (>or=50% reduction of baseline HAM-D 17 score maintained until the endpoint; p=0.252) and the proportion of patients with remission (HAM-D 17 <or=8 at last visit; p=0.769) did not differ significantly between the two treatment groups. However, a significantly greater proportion of patients who were not previously treated with antidepressants (n=15; p=0.041) and of patients with bipolar depression (n=11; p=0.015) had a sustained response in the paroxetine plus pindolol group compared to the paroxetine plus placebo group; furthermore there was a trend for first episode depressed patients to have a greater response in the paroxetine plus pindolol group (n=12; p=0.071). Summarizing, the entire study population showed no antidepressive benefit from pindolol augmentation. Nevertheless patients with bipolar depression irrespective of previous treatments and duration of illness, and unipolar patients not previously treated demonstrated a significant benefit from pindolol augmentation.

Olanzapine and breast-feeding: changes of plasma concentrations of olanzapine in a breast-fed infant over a period of 5 months

We here report on a psychotic mother and her breast-fed infant who was treated with olanzapine. Consecutively olanzapine concentrations in the milk and plasma of the mother and in the infant were measured with tandem mass spectroscopy over a period of five month. The results show a relatively high plasma level in the infant aged four month, probably referring to an immature hepatic transformation system, especially CYP1A2. In the following four months plasma levels of olanzapine decreased to very low, even undetectable concentrations in the infant. The infant developed normally and showed no side effects during the treatment period.

The Role of Carbamazepine in the Prophylaxis of Unipolar Depression

The prophylaxis of unipolar depression is still a controversial subject. Some authors prefer lithium, others maintenance treatment with antidepressants. The role of carbamazepine remains unclear. Few patients have been described in the literature, and most are lithium nonresponders or rapid cyclers. In an open-label naturalistic study, 15 patients suffering from unipolar depression (DSM-III, 296.2, 296.3) and receiving long-term prophylaxis with carbamazepine were followed for 5 years. Four had been pretreated with lithium without satisfactory effects, 11 were prophylaxis naive. The mean time span patients received carbamazepine was 49.5 months. 73% of the patients gained substantial profit from carbamazepine. Side effects were infrequent.

A review on hyponatremia associated with SSRIs, reboxetine and venlafaxine

Hyponatremia, defined as serum sodium below 135 mmol/l, is a potentially life-threatening condition and was shown to be more frequent in elderly and psychiatric patients. In the last years numerous case reports on SSRI- and venlafaxine-induced hyponatremia were published indicating a higher incidence than previously thought. Only few studies have been performed and the incidence reported varies widely from 4.6/1000 people to 25%. It is still unclear if any single SSRI shows a higher incidence of hyponatremia than the others. Some data suggest that venlafaxine may have a stronger association to hyponatremia than SSRIs. Risk factors include age, female sex, low body mass index, severe physical illness, history of former hyponatremia and co-medications known to induce hyponatremia, especially thiazide diuretics. Symptoms of hyponatremia are usually neuropsychiatric (e.g. restlessness, lethargy, cognitive impairment), and any worsening in psychiatric symptoms in patients with a corresponding risk-profile receiving SSRIs or venlafaxine should give cause to check serum electrolytes. Usually SSRI-induced hyponatremia occurs within approximately 30 days and is reported to improve after withdrawal of the drug. Further controlled studies to confirm the true incidence of hyponatremia due to SSRI or venlafaxine and to define predictors more precisely are needed.

Cardiomyopathy after long-term treatment with lithium – more than a coincidence?

We describe a patient suffering from dilative cardiomyopathy after 16 years of treatment with lithium carbonate. The literature concerning lithium and cardiac adverse reactions is briefly reviewed. There is good evidence for acute cardiac reactions, especially cardiac arrhythmia but a rather speculative association with long-term reactions such as cardiomyopathy. Nevertheless clinicians should be aware of this rare but life threatening conjunction of cardiac disease and lithium treatment.