Efficacy and tolerance of D-cycloserine in drug-free schizophrenic patients.
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Adolescent↗
Biomedical subjects
H G Westenberg
Publications and source records attributed to H G Westenberg.
Effect of the cholecystokinin-B receptor antagonist L-365,260 on lactate-induced panic attacks in panic disorder patients.
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Adult↗
Developments in the drug treatment of panic disorder: what is the place of the selective serotonin reuptake inhibitors?
Panic disorder is becoming better recognised and understood as a chronic, debilitating but treatable condition. Drug treatment options shown by adequate research to be beneficial in this condition include mainly the benzodiazepine alprazolam, the tricyclic antidepressants (TCAs) imipramine and clomipramine, the monoamine oxidase inhibitor (MAOI) phenelzine, and the newer selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and paroxetine. Alprazolam, although approved for use in panic disorder in the US and very widely used, is associated with a risk of dependence and withdrawal syndromes. Given that depression frequently occurs as a comorbid condition with panic disorder the use of antidepressants is a logical choice. Among the antidepressants, MAOIs are little-used in panic disorder, mainly because of their potential for precipitating hypertensive crises if tyramine is ingested. TCAs are widely used and are effective but they are associated with initial activation, or 'jitteriness', have a 4-6-week time lag before onset of beneficial effect and produce troublesome side effects in a high proportion of patients, particularly during long-term use. TCAs are also cardiotoxic in overdosage, and panic disorder patients with comorbid depression are at high risk of attempted suicide. Serotonin dysregulation has been implicated in the pathogenesis of anxiety disorders in general, and panic disorder in particular. Among the TCAs, those with an effect on serotonin reuptake are most effective in panic disorder. SSRIs are specifically active on serotonin reuptake and do not have anticholinergic effects or act on the noradrenergic system. There is a clear pharmacological rationale for believing that SSRIs should be as effective as TCAs in panic disorder and better tolerated. Accumulating clinical research evidence supports this hypothesis. Further comparative studies with standard agents and additional long-term studies to support the initial long-term data with paroxetine are needed to confirm SSRIs as drug treatment of choice in panic disorder.
Antidepressive Agents, Tricyclic↗
Responders and non-responders to drug treatment in social phobia: differences at baseline and prediction of response.
Differences between responders and non-responders to drug therapy were investigated in social phobia. Two previously published studies were pooled to obtain data of 30 patients who were treated for 12 weeks with brofaromine or fluvoxamine. Four criterion variables were used to divide patients in responders and non-responders. Depending on the criterion variable up to 72% of the patients were regarded as responders. Non-responders differed from responders in that they had a higher heart rate and a higher blood pressure. They were also characterized by higher scores on several psychometric scales, indicative of illness severity.
Adult↗
Pentagastrin has panic-inducing properties in obsessive compulsive disorder.
The effects of the CCKB-receptor agonist pentagastrin, a synthetic analogue of the cholecystokinin tetrapeptide (CCK-4), were studied in seven patients suffering from obsessive compulsive disorder (OCD) and seven healthy controls. All subjects were challenged with an IV dose of 0.6 micrograms/kg pentagastrin or placebo under double blind placebo controlled conditions, on two separate occasions, with a minimum interval of 1 week. Six (86%) out of seven OCD patients experienced a panic-like reaction after pentagastrin administration, against only two (29%) in the control group. These differences failed to reach statistical significance, probably due to the small sample size. No increases were observed in obsessions or compulsive behaviors as assessed with the Yale-Brown Obsessive Compulsive Challenge Scale, neither in the pentagastrin, nor in the placebo condition. These findings suggest that pentagastrin has panic-inducing properties in OCD patients, without affecting the core symptoms. The panic-inducing properties of pentagastrin are not specific for panic disorder patients, which might be indicative of a common neurobiological dysfunction in panic disorder and OCD at the level of CCK-B receptors.
Adult↗
Effects of the 5-HT1A receptor agonist flesinoxan in panic disorder.
The effects of flesinoxan, a potent and selective 5-HT1A agonist, were studied in two pilot studies in panic disorder patients to explore the role of 5-HT1A receptors in the mechanism of action of antipanic agents. This paper reports on the results of these two studies with flesinoxan. In study I, using a single-blind crossover design, five patients were treated for 1 week with placebo, 4 weeks with flesinoxan (up to 2.4 mg per day), and 2 weeks with placebo. In study II, 15 patients were enrolled in a double-blind, three-armed study with placebo and two dosages of flesinoxan. After a single-blind placebo run-in phase of 1 week, patients were treated for 8 weeks with placebo, 0.6 or 1.2 mg/day flesinoxan. In pilot study I patients' condition worsened during the 4-week flesinoxan treatment period. Anxiety was frequently reported as an adverse event. Symptoms returned to the pre-treatment level during the 2-week placebo washout period. In pilot study II, no treatment effects in either group were observed. Anxiety as an adverse event was less prominent than in the first pilot study. A lowering of mood was seen in some patients. The sample sizes of these two pilot studies are too small to draw firm conclusions on the efficacy of flesinoxan in panic disorder, but the present data are not encouraging in this respect. The worsening of symptoms seen with the highest dose of flesinoxan is intriguing and might give a clue to the understanding of the mechanism underlying similar effects seen with antidepressants in panic disorder patients.
Adult↗
MHPG and heart rate as correlates of nonresponse to drug therapy in panic disorder patients. A preliminary report.
Little is known about biological predictors of treatment response in panic disorder (PD). In the present study heart rate, blood pressure, plasma cortisol and plasma MHPG were investigated at baseline in a sample of 44 PD patients as possible predictors for nonresponse to treatment. We used a strict definition of nonresponse to find patients who did not respond at all after 12 weeks of treatment with brofaromine or fluvoxamine. Patients were considered nonresponders when they fulfilled two criteria: they did not show a 50% reduction of agoraphobic avoidance and they still experienced panic attacks at endpoint. The variables that differed significantly between the groups were used to predict nonresponse to drug therapy. Using this strict definition of nonresponse, 15 patients (32.6%) were considered nonresponders. These patients were characterised by a higher plasma MHPG concentration and a higher heart rate at baseline. These variables were subsequently used to predict nonresponse.
Adult↗
Behavioral, neuroendocrine and biochemical effects of different doses of 5-HTP in panic disorder.
To investigate the role of serotonin (5-HT) in the pathophysiology of panic disorder (PD) a challenge test with L-5-hydroxytryptophan (5-HTP) was conducted. Seven patients suffering from PD and seven healthy controls received an i.v. challenge with 10 mg, 20 mg and 40 mg 5-HTP and placebo in random order on four different occasions. Before, during and until 2 h after 5-HTP administration anxious and depressive symptomatology was assessed. In addition, plasma levels of 5-HTP, cortisol, and 5-HIAA were measured at several timepoints. During and after infusion of placebo or any of the different dosages of 5-HTP, none of the patients or controls experienced a panic attack or showed an increase in anxiety or depressive symptoms. There was a dose-related increase in side effects, like nausea, dizziness and fatigue. Only infusion with 40 mg 5-HTP led to an increase in plasma cortisol in both patients and controls. The observed increase in plasma cortisol level was higher for patients compared to controls only at 30 min after infusion. In conclusion, stimulation of the serotonergic neuronal system by three different dosages of 5-HTP did not induce panic or anxiety in PD patients and healthy controls. The 5-HT hypersensitivity hypothesis of PD could not be confirmed in the present study.
5-Hydroxytryptophan↗
The panic-inducing properties of the cholecystokinin tetrapeptide CCK4 in patients with panic disorder.
We studied the effect of the cholecystokinin tetrapeptide (CCK4), a potent CCKB antagonist, in patients with panic disorder. Two different dosages (25 and 50 micrograms) of CCK4 and saline were tested in 12 patients who were randomly allocated to 2 of the 3 possible treatment groups. Patients were tested on 2 separate occasions, 1 week apart, using an unbalanced single-blind incomplete block design. A total of 24 intravenous injections were carried out. The panic rate with 25 micrograms CCK was 44% (4/9) and 71% (5/7) with 50 micrograms. None of the patients panicked with saline (0/8). Patients' symptom responses were very similar to their spontaneous panic attacks. Taking the Panic Symptom Scale (PSS) as outcome variable, we found that CCK4 provoked symptoms of panic in a dose-dependent fashion. The behavioral response to CCK4 was not accompanied by activation of the hypothalamic-pituitary-adrenal (HPA) axis as measured by the prolactin and cortisol responses. Moreover, CCK4-induced panic symptoms were not correlated with plasma increases in the principal noradrenergic metabolite, 3-methoxy-4-hydroxy-phenylglycol (MHPG), suggesting that activation of the locus coeruleus may not be critical for CCK4-induced panic.
Adult↗
Cholecystokinin in anxiety.
Cholecystokinin (CCK) plays an important role in both the alimentary tract and the central nervous system (CNS). At present it seems to be the most abundant neuropeptide in the CNS. This paper reviews the CCK neuronal system and its interactions with gamma-aminobutyric acid (GABA) and serotonin (5-hydroxytryptamine; 5-HT). In addition, its putative role in anxiety will be discussed on the basis of animal data and studies in healthy volunteers and panic disorder patients. According to these investigations, the CCK4 challenge test fulfills most criteria for an ideal panicogenic agent and evidence has been found that CCKB receptor antagonists might possess anxiolytic properties in man.
Animals↗
Flesinoxan dose-dependently reduces extracellular 5-hydroxytryptamine (5-HT) in rat median raphe and dorsal hippocampus through activation of 5-HT1A receptors.
The effects of systemic administration of the serotonin (5-hydroxytryptamine) 5-HT1A receptor agonists flesinoxan and 8-hydroxy-2-(di-n-propylamino)tetralin on extracellular 5-HT were measured using microdialysis probes in both median raphe nucleus and dorsal hippocampus. Both 5-HT1A agonists dose-dependently decreased dialysate 5-HT levels from both brain regions. The effects of flesinoxan in the median raphe (0.3 mg/kg) and dorsal hippocampus (1.0 mg/kg) could be blocked by the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexane carboxamide trihydrochloride (WAY 100,635) at a dose of 0.05 mg/kg s.c. The antagonist itself had no effect at this dosage. Local perfusion of flesinoxan for 30 min through the dialysis probe into the median raphe region at concentrations of 20, 100, and 1,000 nM resulted in a significant decrease in dialysate 5-HT content from both regions. The effect of 100 nM flesinoxan could be blocked by coperfusion of 1,000 nM WAY 100,635. The data indicate that flesinoxan is a potent 5-HT1A receptor agonist and also support the notion that somatodendritic 5-HT1A autoreceptors regulate both terminal and somatodendritic 5-HT release.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
A double-blind comparative study of brofaromine and fluvoxamine in outpatients with panic disorder.
Previous studies have shown that both selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) are effective in the treatment of panic disorders (PD). In this study, the SSRI fluvoxamine (Fluv) was compared with the MAO-A-I brofaromine (Brof). Thirty patients with the diagnosis of PD with or without agoraphobia were treated with either Fluv or Brof (150 mg daily) in a double-blind design. After 12 weeks of treatment, 93% of the Brof group and 87% of the Fluv group considered themselves much or very much improved. Taking a reduction in the Hamilton Rating Scale for Anxiety score of 50% or more, 33% of the Fluv patients and 47% of the Brof patients were responders to treatment. After an increase in anxiety in the 1st week, which was more severe in Fluv-treated patients than for Brof, a clinically relevant decrease in anxiety symptoms and reduction in panic attacks and avoidance behavior was observed. There was no significant difference between the treatment groups. The most prominent side effects were middle-sleep disturbance (Brof), tiredness (Fluv), and nausea after taking the medication (Brof and Fluv). During a double-blind follow-up period of another 12 weeks, a further improvement was found in both treatment groups without significant differences between the two groups. The selective and reversible MAO-A-I brofaromine and the SSRI fluvoxamine are equally effective in the treatment of PD. Both compounds lead to a reduction in the number of panic attacks and a subsequent reduction in agoraphobic avoidance.
Adult↗
Immunoglobulin production in vitro in major depression: a pilot study on the modulating action of endogenous cortisol.
To investigate the possible differential sensitivity of hydrocortisone (HCO) on immunoglobulin (Ig) production in depression in relation to endogenous cortisol levels, blood was obtained at 8 AM and 4 PM from 10 inpatients with major depression according to DSM-III-R criteria and 10 age- and sex-matched healthy subjects. Peripheral blood lymphocytes were cultured in the presence of graded concentrations (10(-9)-10(-5) M) of HCO to study the effect on immunoglobulin (IgG and IgM) synthesis. In addition, peripheral blood lymphocytes were cultured in the presence of pokeweed mitogen (PWM) to study any additional effect of graded concentrations of HCO (10(-9)-10(-5) M) on IgG and IgM synthesis. Mean plasma cortisol levels at both time points were higher in patients compared to controls. HCO--preferentially at concentrations of 10(-8)-10(-6) molar--stimulated IgG and IgM production in controls, except for IgM production in the 8 AM samples, when the cells were cultured in the absence of PWM. Under these culture conditions, HCO stimulated IgG but not IgM synthesis in depressed patients. PWM-driven IgG and IgM synthesis in controls was stimulated by HCO in both the 8 AM and the 4 PM samples. In patients PWM driven IgG synthesis was stimulated by HCO in the 8 AM but not in the 4 PM samples. PWM-stimulated IgM synthesis was not augmented by HCO in depressed patients. We conclude that a differential sensitivity to the effects of HCO exists in in vitro IgG and IgM synthesis between depressed patients and controls. Furthermore, we suggest that immunocompetent cells of depressed patients possess corticosteroid-resistant properties.
Adult↗
Phobic symptoms as predictors of nonresponse to drug therapy in panic disorder patients (a preliminary report).
Factors that predict nonresponse to drug therapy (brofaromine or fluvoxamine) were investigated in a sample of 44 panic disorder patients. We used a strict definition of nonresponse to find patients who did not respond at all after 12 weeks of treatment. Using this definition, 15 patients (32.6%) were considered nonresponders. Nonresponders had a higher score on the Blood-Injury subscore of the Fear Questionnaire (FQ) and more often had high scores on several FQ subscores, indicative of comorbid phobic symptoms. These variables were subsequently used to predict nonresponse.
Adult↗
Recent developments in the psychopharmacology of social phobia.
The past 2 decades have witnessed an upsurge in the interest in anxiety disorders. Much research effort has been dedicated to panic disorder and obsessive-compulsive disorder. However, it is only very recently that we have begun to understand some of the basic principles about the psychopharmacology of social phobia. Drug classes thus far studied include beta-blockers, nonselective and irreversible monoamine oxidase inhibitors (MAOIs), and benzodiazepines. Beta blockers appear to be of use in specific social phobias, such as public speaking, whereas they are of little use in generalized social phobia. There is considerable evidence suggesting that MAOIs are effective in reducing both social anxiety as well as social avoidance in generalized social phobia. A disadvantage of the conventional irreversible MAOIs is their risk for hypertensive crises when combined with dietary tyramine. Thus far only a small number of studies with selective MAO-A inhibitors, such as moclobemide and brofaromine, have been conducted in social phobia, and the results indicate that both compounds are effective. Drugs exerting selective and specific actions on certain components of, for example, the serotonergic system, can now be studied, and it is hoped that the role of 5-hydroxytryptamine) and other neuronal systems in social phobia can be elucidated. In order to gain more information about selective serotonergic drugs, the first double-blind placebo-controlled study with fluvoxamine was recently published. Preliminary results indicate a reduction in social anxiety after a prolonged treatment period. Finally, the role of peptides in the treatment of social phobia is critically reviewed. The MSH/ACTH analog Org 2766 was investigated in patients suffering from social phobia.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Differential effects of the D1-DA receptor antagonist SCH39166 on positive and negative symptoms of schizophrenia.
In the present open study the effects of the D1-dopamine antagonist SCH 39166 on positive and negative symptoms of schizophrenia (DSM-IIIR) were investigated. SCH 39166 was given orally according to a fixed dosage schedule (day 1: 25 mg b.i.d; day 4: 50 mg b.i.d.; day 7: 100 mg b.i.d.; day 18: 200 mg b.i.d.; day 21: 225 mg b.i.d.). Seven patients completed 2 weeks, and five patients completed the study. The reason for premature withdrawal was lack of efficacy or refusal to take SCH 39166. In none of the patients a reduction of the BPRS or CGI score was found. As measured with the PANSS, a significant reduction was observed in the score of the negative subscale, whereas the positive symptoms scale and general psychopathology score remained unaffected. Akathisia, rigidity and hypokinesia were reported occasionally, although only mild in severity. The results of the present study do not support the hypothesis that D1-dopamine antagonists are clinically effective antipsychotics in schizophrenia, considering the fact that SCH 39166 had no effect on positive symptoms. The present study provides circumstantial evidence for an effect of SCH 39166 on negative symptoms.
Administration, Oral↗
Chronic treatment with fluvoxamine by osmotic minipumps fails to induce persistent functional changes in central 5-HT1A and 5-HT1B receptors, as measured by in vivo microdialysis in dorsal hippocampus of conscious rats.
This study investigated the alterations of the 5-HT1A and 5-HT1B autoreceptor function following chronic treatment with fluvoxamine using osmotic minipumps. The 5-HT1A and 5-HT1B autoreceptor function were studied using microdialysis in the dorsal hippocampus. The effect of the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, SC) and the 5-HT1B receptor agonist RU-24969 (100 nM through the dialysis probe for 30 min) on 5-HT release was compared with rats chronically treated with saline. 8-OH-DPAT decreased 5-HT release to 55% and 60% of baseline, while RU-24969 decreased 5-HT release to 66% and 70% of baseline value in the saline and fluvoxamine group, respectively. In both cases, differences between the saline and fluvoxamine groups were not statistically significant. Plasma levels of fluvoxamine after 21 days of treatment ranged from 3 to 5 ng/ml. Fluvoxamine concentration in rat brain during treatment was estimated between 100 and 200 nM, which approximates to the IC50 value of fluvoxamine on the 5-HT transporter in synaptosomes and is 50 times higher than the Kd value for the 5-HT reuptake site. In conclusion, no evidence was found for changes in 5-HT1A,B receptor function using 8-OH-DPAT and RU-24969 as probes after continuous treatment with fluvoxamine by means of osmotic minipumps.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Effects of single and repeated oral administration of fluvoxamine on extracellular serotonin in the median raphe nucleus and dorsal hippocampus of the rat.
The delay in clinical effects of selective serotonin reuptake inhibitors (SSRIs) suggest the existence of adaptive phenomena, such as receptor sensitivity changes. To examine the effects of repeated administration of SSRIs on serotonin neurotransmission, we investigated the effects of acute and chronic administration of the SSRI fluvoxamine on the extracellular levels of 5-HT in the median raphe nucleus and dorsal hippocampus of conscious rats by means of brain microdialysis. A single oral dose of fluvoxamine (30 mg/kg) augmented extracellular 5-HT in the median raphe and dorsal hippocampus to 270 and 191% of baseline level, respectively. Administration of fluvoxamine (30 mg/kg) or vehicle for 14 days did not affect 5-HT baseline levels. Moreover, the increase in extracellular 5-HT in the median raphe nucleus and dorsal hippocampus after an oral dose of fluvoxamine (30 mg/kg) in rats chronically treated with fluvoxamine was not different from rats treated with vehicle. Using RU 24969 as a probe for the sensitivity of the 5-HT1B autoreceptors in the dorsal hippocampus, no change in receptor sensitivity could be observed. These results demonstrate that repeated oral treatment with fluvoxamine does not affect extracellular 5-HT in the median raphe and dorsal hippocampus, suggesting that presynaptic functional changes of 5-HT in the brain areas tested are not implicated in the observed delayed onset of action of this SSRI in humans.
Administration, Oral↗