Low platelet-poor plasma levels of serotonin in adult autistic patients.

BACKGROUND: Hyperserotonemia has been reported in about a third of autistic patients. However, most studies have examined whole blood levels of serotonin (5-HT), the vast majority of which is found in platelets. The aim of this study was to determine 5-HT levels in platelet-poor plasma (PPP) in a group of adult patients with autism. METHODS: Levels of PPP 5-HT were compared between 10 adult drug-free autistic patients and 12 healthy controls. The Ritvo-Freeman Real-Life Rating Scale and the Overt Aggression Scale (OAS) were administered to the autistic group as a measure of symptom severity. RESULTS: Significantly lower PPP 5-HT levels were observed in the autistic group as compared to the controls (p = 0.03). In addition, PPP 5-HT levels were inversely correlated with OAS scores among subjects with autism (r = -0.64, p < 0.05). CONCLUSION: PPP 5-HT ('free') levels appear to be low in autistic patients and may play a role in the pathophysiology and symptomatology of the disorder.

Chronic lithium treatment affects rat brain and serum dehydroepiandrosterone (DHEA) and DHEA-sulphate (DHEA-S) levels.

Lithium (Li) is an established effective treatment for bipolar disorder. However, the molecular mechanism of its action is still unknown. Dehydroepiandrosterone (DHEA) and its sulphate ester (DHEA-S) are adrenal hormones also synthesized de novo in the brain as neurosteroids. Recent studies have suggested that DHEA has mood-elevating properties and may demonstrate antidepressant effects. 3(2)-Phosphoadenosine 5-phosphate (PAP) phosphatase is a novel Li-inhibitable enzyme involved in sulphation processes. In the present study we examined the impact of 10 d Li treatment on serum and brain DHEA and DHEA-S levels in rats. Our results show that Li administration lowered frontal cortex and hippocampus DHEA and DHEA-S levels, in line with our hypothesis assuming that Lis inhibition of PAP phosphatase leads to elevated PAP levels resulting in inhibition of sulphation and reduction in brain DHEA-S levels. Future studies should address the involvement of neurosteroids in the mechanism of Lis mood stabilization.

Three-month treatment course of methylphenidate increases plasma levels of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEA-S) in attention deficit hyperactivity disorder.

Methylphenidate is considered by many to be the treatment of choice for attention deficit hyperactivity disorder (ADHD). Methylphenidate exerts its therapeutic effects through the dopaminergic, serotonergic and noradrenergic systems, however its effects on other neurophysiological systems, such as the neurosteroidal system, remain unknown. Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA-S) are neuroactive steroids with effects on several neurophysiological and behavioral processes. The purpose of the present study was to determine the effect of 3 months of treatment with methylphenidate on circulatory DHEA, DHEA-S, and cortisol in children with ADHD. The study population consisted of 15 boys (aged 11.5 +/- 1.6 years) with ADHD, combined type. Subjects were evaluated before and after methylphenidate treatment with a specific rating scale for the assessment of inattention and impulsivity in ADHD. Results show that treatment led to significant clinical improvement in all subjects. Furthermore, following 3 months of treatment, there was a significant increase in serum levels of DHEA and DHEA-S but not in circulatory levels of cortisol. The mean rate of increase in DHEA levels was 23 and 53.6% in DHEA-S. Our findings suggest that DHEA and DHEA-S may play a role in the therapeutic effects of methylphenidate. Several mechanisms to explain this action are proposed, including involvement of the serotonergic, GABA-ergic and noradrenergic pathways.

Brain neurosteroid changes after paroxetine administration in mice.

Although it is known that selective serotonin reuptake inhibitors (SSRIs), as other antidepressants, elevate mood only after 3-4 weeks of treatment, the mechanism responsible for this delay is not understood. SSRIs have been demonstrated to alter the levels of neurosteroids such as allopregnanolone (THP) which possess anxiolytic and mood-elevating properties. We compared the effect of 9 and 21 days i.p. administration of paroxetine, a potent SSRI, on the synthesis of THP and its precursor, 5alpha-dihydroprogesterone (DHP), in the mouse cortex, hypothalamus and olfactory bulb. Cortex, olfactory bulb and hypothalamus synthesized levels of DHP were significantly raised after 9 days of paroxetine administration, whereas a significant rise in the THP synthesized level was observed only after 21 days of treatment. Peripheral synthesis of DHP, measured by the level in serum, significantly increased after 9 days, but reverted to normal values after 21 days. No increase was detected in serum THP levels either after 9 or 21 days treatment. Differences in peripheral and brain synthesis indicates independence in brain synthesis. The data indicate that paroxetine administration differentially increases [3H]DHP and [3H]THP content, depending on the duration of the treatment. Our results suggest that brain THP may be involved in the antidepressive and anxiolytic activity of paroxetine.

The platelet-poor plasma 5-HT response to carbohydrate rich meal administration in adult autistic patients compared with normal controls.

There are cumulative data indicating involvement of the 5-HT system in autistic disorder. Most studies examining 5-HT function have focused on whole blood 5-HT content. The carbohydrate-rich meal test (CRMT) is a dietary manipulation that could significantly influence platelet-poor plasma (PPP) 5-HT levels and reflect the responsiveness of the serotonergic system in 'free' plasma. In this study, CRMT was used as an indicator of 5-HT responsivity in drug-free adults with autistic disorder (n = 7), compared with normal controls (n = 10). The PPP 5-HT levels were measured at baseline and during 3 h after administration of the CRMT. A significant elevation in PPP 5-HT levels in adult autistic patients was reached 60 min after meal administration (p < 0.03 vs control and p = 0.05 vs baseline) and a significant decrease was noted after 120 min (p < 0.01 vs baseline). In contrast to the biphasic response of the autistic patients, normal controls exhibited a gradual linear increase of PPP 5-HT levels. Our results indicate that in adult autistic patients, the pattern of PPP 5-HT responsivity to a dietary challenge of CRMT is dysregulated compared with normal controls and provide further support for the role of 5-HT in autism.

Obsessive-compulsive disorder in adolescent schizophrenia patients.

OBJECTIVE: The co-occurrence of obsessive-compulsive disorder (OCD) in adult patients with schizophrenia has been increasingly recognized. However, the rate of OCD comorbidity in adolescent schizophrenia patients has yet to be systematically evaluated. METHOD: The rate of DSM-IV OCD was evaluated in 50 adolescent inpatients with schizophrenia or schizoaffective disorder. The severity of schizophrenia and OCD symptoms was assessed with the Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms (SANS), and Yale-Brown Obsessive Compulsive Scale. RESULTS: Thirteen schizophrenia patients (26.0%) also met the DSM-IV criteria for OCD. This subgroup scored significantly higher on the SANS subscale for affective flattening or blunting. The total SANS score positively correlated with the total Yale-Brown Obsessive Compulsive Scale score. CONCLUSIONS: A substantial proportion of adolescent schizophrenia inpatients have concomitant OCD. A prospective study is needed to evaluate the clinical course, response to treatment, and prognosis for this complex disorder.

Clozapine decreases rat brain dehydroepiandrosterone and dehydroepiandrosterone sulfate levels.

We examined the influence of the atypical antipsychotic agent clozapine compared to haloperidol, on levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate ester (both gamma-aminobutyric acid(A) (GABA(A)) receptor allosteric antagonists) in the rat cortex. i.p. injections of clozapine (5 and 15 mg/kg), but not haloperidol (1 mg/kg), for 8 days decreased rat brain cortical dehydroepiandrosterone and dehydroepiandrosterone sulfate levels. These findings support the role of neurosteroids and possibly GABA(A) receptor modulation in the mechanism of action of clozapine.

Plasma serotonin response to carbohydrate-rich food in chronic schizophrenic patients: clozapine versus classic antipsychotic agents.

Researchers have reported a stimulatory effect of carbohydrate-rich intake on platelet-poor plasma (PPP) serotonin (5-HT) levels in healthy human subjects. Dietary manipulation may serve as a safer and less invasive means than pharmacologic challenge to provoke serotonergic responsivity in studies of schizophrenia. In the present study, we used the carbohydrate-rich meal test as an indicator of 5-HT activity in 12 patients with chronic schizophrenia maintained for at least 6 months on clozapine. PPP 5-HT levels were measured at baseline and at 1, 2 and 3 h after administration of the test. Findings were compared with those in schizophrenic patients treated with classic antipsychotic agents for the same duration. The maximal PPP 5-HT response was reached 120 min after meal administration in the clozapine-treated group and 60 min after in the classic antipsychotic-treated group (P<0.05 vs baseline for both). The 5-HT level (as percentage of baseline) at 60 min was significantly lower in the clozapine-treated group (P<0.02), as were individual PPP 5-HT peak values (P<0.05). The individual time to reach the peak response was similar in the two groups. Our results indicate that in patients with chronic schizophrenia 5-HT responsivity to the natural challenge of carbohydrate-rich meals is lower in those treated with clozapine than in those given classic antipsychotic agents. Values in both groups were lower than those in an appropriate historical comparative group of healthy subjects. We suggest that both clozapine and classic antipsychotic agents suppress serotonergic system sensitivity, but to a different degree. Copyright 2001 John Wiley & Sons, Ltd.