H.G.M. Westenberg

Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin

In order to evaluate serotonin (5-HT) function in panic disorder, a double blind placebo controlled study was conducted with ritanserin, a specific 5-HT2 receptor antagonist, and fluvoxamine, a selective 5-HT reuptake inhibitor, in 60 patients with panic disorder. Patients were treated for 8 weeks with 150 mg fluvoxamine, 20 mg ritanserin or placebo; these dose levels were reached after 1 week. In addition, as an index of 5-HT function in panic disorder, plasma concentration of β-endorphin, cortisol and 5-hydroxyindolacetic-acid (5-HIAA) were measured. Furthermore, 5-HT uptake in blood platelets was assessed. Noradrenergic function was assessed by measuring plasma MHPG concentration. In addition, plasma melatonin concentration was measured. Treatment with fluvoxamine resulted in a profound reduction in the number of panic attacks, followed by a decrease in avoidance behavior. Treatment with ritanserin appeared to be ineffective. During treatment no significant changes were observed in plasma concentrations of β-endorphin, cortisol, 5-HIAA and MHPG. With respect to 5-HT kinetics in blood platelets, a substantial increase in Km was observed after treatment with fluvoxamine, whereas Vmax decreased. After treatment with fluvoxamine, plasma concentration of melatonin was significantly increased, which suggests that melatonin synthesis is in part under serotonergic control. The findings of the present study do not support the hypothesis that 5-HT2 receptors are supersensitive in patients suffering from panic disorder, but allow no conclusions about the involvement of other 5-HT receptor subtypes.

Decrease in basal dopamine levels in the nucleus accumbens shell during daily drug-seeking behaviour in rats.

Accumbal dopamine (DA) is generally accepted to participate in the neural mechanisms underlying drug dependence. Recently the involvement of accumbal DA in drug-seeking behaviour has gained more experimental attention. To study an involvement of accumbal DA in drug-seeking behaviour within and between daily self-administration behaviour, changes in extracellular DA concentration in the nucleus accumbens (NAc) shell were measured during the daily dynamics of intravenous heroin and cocaine self-administration. Groups of drug naive rats were allowed to intravenously self-administer heroin (30 microg/infusion) and cocaine (30 microg/infusion) during five consecutive daily 3 h sessions. Extracellular DA concentrations in the NAc were measured before and after a single 3 h session (acute) and before and after 5 consecutive 3 h sessions (repeated). Following acute and repeated heroin and cocaine self-administration the extracellular DA concentration in the NAc shell was increased by two-fold to three-fold over baseline. These changes in DA concentrations are thought to reflect a direct effect of heroin and cocaine on DA neurotransmission in the NAC shell. Measurement of basal DA concentrations before the self-administration sessions revealed that just before the scheduled 5th self-administration session the (absolute) basal DA levels in the NAc in heroin or cocaine self-administering animals were decreased by approximately halve, as compared to drug-naive animals. It is assumed that just before a scheduled next session the (daily) desire for the drug is high. This decrease in basal DA neurotransmission in the NAc shell may, therefore, reflect an involvement of accumbal DA in drug-seeking behaviour during daily self-administration behaviour. The results demonstrate that initiation of i.v. heroin and cocaine self-administration is linked with changes in extracellular levels of DA in the NAc shell. Moreover, the present data suggest that accumbal DA might be involved in processes underlying the motivational aspects involved in daily drug-seeking behaviour, and that neuroadaptive changes in the mesolimbic DA system due to repeated drug intake lead to an tonic decrease in overall DA activity in the NAc.

Mirtazapine in social anxiety disorder: a pilot study.

Fourteen patients with social anxiety disorder (generalized type), according to DSM-IV criteria, were treated with mirtazapine 30 mg for 12 weeks. Twelve patients completed the study. Two patients (14.3%) dropped out due to side-effects. Generally, mirtazapine was well tolerated. Five out of 12 patients (41.7%) were classified as responders, based on a Clinical Global Improvement score of 1 or 2 and a reduction of the Liebowitz Social Anxiety Scale (LSAS) of 40%. The mean total score on the LSAS, as well as the anxiety and avoidance subscores, decreased significantly. This open pilot study suggests that further investigations are warranted to prove the efficacy of mirtazapine in generalized social anxiety disorder.

Anhedonia, suicide ideation and Dexamethasone nonsuppression in depressed patients

In the search for a valid analysis of a number of operationalised symptoms common to depressive behaviour, a study was performed comprising 46 patients showing depressive symptoms, according to operationalised criteria and as part of which all agreed to undergo the following tests: (a) psychiatric: Present State Examination; (b) psychological: Hamilton Rating Scale, Montgomery-Asberg Rating Scale, State-Trait Anxiety Inventory, Beck Suicide Ideation Scale, Chapman Anhedonia Scale, Mood Scale, Sleep Quality Scale, Activities Scale, Social Support Scale, Questionnaire on Recently Experienced Events and the Paykel Life Events Interview; and (c) biochemical: Dexamethasone Suppression (DEX) Test. After gathering different depressive subgroups, based on operationalised symptoms, a dichotomy was made in the distributions of the (an)hedonia, suicide ideation and DEX-(non) suppression scores. This study may indicate that anhedonia, suicide ideation and DEX-nonsuppression are the opening to the identification of a subgroup of depressed patients. This symptom complex could not definitely be identified on the basis of existing DSM-III diagnostic entities, because of the known fact that this method of classification is not appropriate for our purposes in revealing pathophysiological processes. It is suggested, therefore, that these symptoms might prove to be the anchor-point from which to reach a better insight into the aetiology and pathogenesis (i.e. the final common pathway) of depression.

Biological dissection of anxiety disorders : the clinical role of selective serotonin reuptake inhibitors with particular reference to fluvoxamine

The selective serotonin reuptake inhibitor (SSRI) fluvoxamine has been used in an attempt to understand whether there is a biological distinction among anxiety disorders. A comparison of fluvoxamine with the specific noradrenaline reuptake inhibitor maprotiline in patients with panic disorder showed fluvoxamine to be a potent anti-panic agent, whereas maprotiline had no effect on the frequency of panic attacks. This result supported the hypothesis of serotonergic involvement in the pathogenesis of panic disorder. In a second study, unlike fluvoxamine, the 5-HT2A/2C antagonist ritanserin had no effect on the number of panic attacks, or phobic avoidance. This suggested that the efficacy of antidepressants in panic disorder was not a result of down-regulation of postsynaptic 5-HT2 receptors. Most studies suggest that the efficacy of antidepressants in obsessive-compulsive disorder (OCD) is not related to their antidepressant or mood-enhancing effects. Fluvoxamine has also been shown to reduce general and phobic anxiety in social phobia patients. In conclusion, serotonergic systems are implicated in the pathophysiology of global anxiety irrespective of the nosological background, and SSRIs, exemplified by fluvoxamine, appear to be effective in panic disorder, OCD and probably also social phobia.

Remoxipride in schizophrenia. A preliminary report.

ABSTRACT Remoxipride, a substituted benzamide with preferential action on mesolimbic dopaminergic brain functions, was investigated in an open study in 10 schizophrenic patients. After 1 week with placebo, patients received remoxipride in a increasing doses from 150 to maximal 450 mg daily for 6 weeks. In six patients a clinically relevant reduction of psychotic symptomatology as assessed with the BPRS was observed. Few adverse effects were noted; extrapyramidal symptoms, if present, decreased during treatment, while the reported side effects were only mild. No consistent changes in plasma levels of prolactin and HVA were found.

Double blind comparative study of remoxipride and haloperidol in acute schizophrenic patients

In the present 6-week double-blind, randomised, multicentre study, the atypical neuroleptic remoxipride was compared to haloperidol in acute schizophrenic patients (DSM-III). Seventy-one patients entered the study, 36 in the remoxipride group and 35 in the haloperidol group. There were ten early withdrawals, four in the remoxipride group and six patients in the haloperidol group. The Present State Examination (PSE) profile revealed a similar reduction in the symptom clusters of psychosis in both treatment groups. Forty-seven per cent of the patients in the remoxipride group and 34% of the patients in the haloperidol group showed clinically relevant improvement (reduction of BPRS total score ≥ 50%). All extrapyramidal symptoms except “glabella tap” occurred significantly less frequently in the remoxipride group as compared to the haloperidol group. Substantially lower incidences of EPS were found by active questioning in the remoxipride group compared to the haloperidol group. In addition, considerably lower incidences were observed in the remoxipride group with respect to drowsiness/somnolence, tiredness/fatigue and concentrating difficulty. At the end of treatment 66% of the patients in the haloperidol group and 22% in the remoxipride group were using anticholinergics. No consistent changes were found in the mean plasma HVA level in either treatment group. In responders (reduction of BPRS total score ≥ 50%) lower baseline HVA levels were observed in both treatment groups. This study indicates that the newly developed neuroleptic remoxipride is an effective antipsychotic compound, which is clinically safe and well tolerated. In particular, few EPS were induced by remoxipride, as compared to haloperidol.

Clinical, biochemical, and hormonal aspects of treatment with des-tyr1-gamma-endorphin in schizophrenia

Des-tyr1-gamma-endorphin (DT gamma E) was administered intramuscularly in a dose of 1 mg/day for 10 days to 18 neuroleptic-free schizophrenic patients in a double-blind crossover design. Six patients showed either a slight or no antipsychotic response; seven patients showed a moderate antipsychotic response; and the remaining five patients showed a marked antipsychotic response. DT gamma E led to a decrease of plasma prolactin levels in patients treated with DT gamma E in the first period of experimental treatment as compared to those treated with placebo. Neither plasma levels of growth hormone and cortisol nor cerebrospinal fluid concentrations of homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylglycol were affected by DT gamma E. Patients suffering from a hebephrenic or paranoid type of schizophrenia and those presenting relatively fewer negative symptoms were most susceptible to treatment with DT gamma E. These data confirm and extend previous findings that DT gamma E has antipsychotic properties in a number of schizophrenic patients.

Serotonergic compounds in panic disorder, obsessive-compulsive disorder and anxious depression: A concise review

The recognition that antidepressants are effective in panic and anxiety disorders had led to the evaluation of drugs selective for serotonin uptake in an attempt to dissect the neurotransmitters responsible for panic disorder. Fluvoxamine is the best studied of the selective serotonin reuptake inhibitors (SSRIs) and recent double‐blind studies have confirmed earlier findings showing a reduced number and duration of panic attacks. In addition, fluvoxamine attenuates the ‘accessory symptoms’ of panic disorder such as depression and anxiety. Fluoxetine has only been evaluated in open trials, although these results are generally positive. Paroxetine has shown similar efficacy to clomipramine in a large, controlled study, although the other SSRIs have seldom been investigated. Fluvoxamine lacks the activating properties possessed by some SSRIs and this also makes it a useful candidate for the treatment of anxious depression. The efficacy of fluvoxamine in obsessive‐compulsive disorder has been established in several double‐blind, placebo‐controlled trials. In clinical terms, fluvoxamine is approximately as effective as clomipramine, but with a decidedly better adverse event profile. Fluoxetine has also proved effective in obsessive‐compulsive disorder, although a recent meta‐analysis suggests that fluvoxamine may be somewhat more effective. The other SSRIs have not been sufficiently well studied to justify conclusive statements.

The effects of haloperidol on the eeg spectrum

A placebo-controlled study with six normal volunteers was carried out using 1 mg haloperidol IM. In some EEG frequency bands, the power density due to haloperidol appeared to increase or decrease depending on the subject. Nevertheless, if the results of the six subjects are taken together, the effects of haloperidol are in agreement with the literature. No correlation was found between plasma concentration of haloperidol and EEG response. Some methodological problems are discussed.