We studied the effects of pentagastrin, an analogue of the cholecystokinin tetrapeptide (CCK4), in 15 patients with panic disorder and 15 healthy controls. Three different intravenous dosages of pentagastrin (0.1, 0.3 and 0.6 μ/kg) and placebo (saline) were investigated. Subjects were randomly allocated to two of the four dosage groups and tested on two separate occasions, one week apart, using a double-blind incomplete block design. A total of 59 intravenous injections were carried out. The panic rate with pentagastrin, irrespective of the dosage, was 55% (12/22) for patients and 5% (1/22) for controls. None of the subjects panicked with saline. The frequency of panic attacks between the three pentagastrin doses in patients was not different. One control subject had a panic-like attack at the highest dose of pentagastrin. These findings concur with previous studies on the panicogenic effect of CCK4 and pentagastrin and suggest a greater sensitivity for CCK agonists in patients suffering from panic disorder than in healthy controls.

One of the theories on the biology of panic disorder which received much attention is the locus coeruleus hypothesis. This hypothesis states that there exists an episodic overactivity of noradrenergic systems in panic disorder. Experiments with yohimbine form the cornerstone of this theory, and additional supporting evidence is provided by challenge studies with isoproterenol and treatment studies with clonidine. These studies are critically reviewed and it is argued that based upon the studies with yohimbine one cannot conclude that there is a specific noradrenergic abnormality in panic disorder, since yohimbine also affects dopaminergic and serotoninergic neurons in the brain.

In an alternative theory on the relationship between noradrenaline and anxiety it is postulated that increases in anxiety, irrespective of the diagnostic category, are related to increases in locus coeruleus activity.

In this first part of a review on biological psychiatric aspects of obsessive-compulsive disorder (OCD), firstly a short introduction is given about historical, diagnostic and epidemiological issues concerning OCD. Subsequently pharmacologic treatment-studies are discussed. Only serotonin (5-HT) reuptake blockers are proven to be effective. There is accumulating evidence that this therapeutic effect is not due to antidepressant effects. The results of the treatment-studies strongly suggests that 5-HT is involved in OCD. CSF-studies seem to confirm this. Possibly the therapeutic effect is related with adaptive changes of 5-HT receptors. There is evidence that in a subgroup of O CD-patients the dopaminergic system is involved.

In this review the most important hypotheses for the occurrence of the clinical picture of hepatic encephalopathy are discussed. As possible pathogenetic mechanisms are raised: dysfunction of the serotonergic system due to an increased tryptophan uptake in the brain, an elevated intracerebral ammoniac concentration and glutamine synthesis, and a heightened intracerebral GABA-activity.

The dysregulation of the serotonergic system as a consequence of the increased intracerebral tryptophan uptake is described as one of the most important pathogenetic mechanisms. The elevated intracerebral ammoniac concentration and the elevated intracerebral glutamine synthesis play in this a facilitating role. The similarity in symptomatology of the clinical picture of HE and the serotonergic syndrome support this hypothesis. Due to contradictory research findings the role of the GABA-ergic system and the occurrence of HE remains unclear.

The last two 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 so far studied include beta-blockers, non-selective and irreversible MAO-inhibitors (MAOI's) and benzodiazepinen. Beta-blockers appear to be of use in specific social phobias, like public speaking. There is considerable evidence suggesting that MAOI's are effective in reducing both social anxiety as well as social avoidance. A disadvantage of the conventional irreversible MAOI's is their risk for hypertensive crises when combined with dietary tyramine.

So far only a small number of studies with selective MAOI-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 e.g. the serotonergic system can now be studied and it is hoped that the role of serotonin 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 in social phobia is here reported. Preliminary results indicate a reduction of social anxiety.

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. No anxiolytic effects of this peptide could be observed.

In biological psychiatry, the biopsychosocial model is broadly supported. This does not mean a rejection of materialism, but of reductionism. Psychological (and social) psychiatry is deemed to be a necessary supplement to biological psychiatry.

This is one of the lessons made avalaible by Freud. In addition, there are other lessons to be taken from his work. From his view on the mind-body relationship a useful strategy for theory construction can be abstracted:

1. specify the relevant (neuro)physiologiocal mechanims,

2. specify the relevant mental mechanisms,

3. look for that output of the neurophysiological mechanisms that can also serve as the input of the mental mechanisms, and conversely. Especially the third directive will be of use for adherents of the biopsychosocial model.

We may also learn from Freud's mistakes. He rightly used his interactionistic but non-dualistic arguments for the vindication of a relatively autonomous psychological psychiatry. However, he wrongly delayed biological-psychiatric tasks to an indefinite future.

Indications for lithium in the treatment of bipolar disorders are acute mania, depression and preventive treatment. In the case of insufficient efficacy or adverse effects the first alternative for lithium in acute mania is carbamazepine. However, the role of carbamazepine in preventive treatment is still uncertain. Well designed prospective research is hardly done. Clearly positive reports on the efficacy of carbamazepine concern specific lithium-resistant groups such as the ‘rapid-cyclers’. Valproic acid has been found effective in a few studies in bipolar disorders, especially in acute mania. Clonazepam is sometimes mentioned as a possible alternative, however recent research seriously questions the efficacy of clonazepam in bipolar disorders. Calcium-antagonists, especially verapamil, may have some efficacy in the treatment of acute mania, their role is still very uncertain.

In this second part of a review on OCD, challenge-tests are discussed and an overview is given of neuro-imaging studies. Subsequently some hypotheses concerning the pathogenesis of OCD are reviewed. The serotonin (5-HT) agonist metachloro-phenylpiperazine (mCPP) was found to lead to an increase in obsessive-compulsive symptoms. These studies revealed a dissociation between the behavioral and the neuroendocrine responses: OCD-patients showed a blunted hormonal respons compared to controls. Possibly different receptor subtypes are involved. One study is reported with a 5-HT1a agonist as a probe. This study lends no support to an involvement of the 5-HT1a receptor. Tests with noradrenergic probes showed unequivocal results.

Research on the neuroanatomic substrate of OCD is critically reviewed. PET-scan studies point to a possible role of the (orbito-)frontal cortex and the basal ganglia in OCD. Keywords: obsessive-compulsive disorder, OCD, challenge-test, serotonin (5-HT), mCPP, PET-scan.

Two subjects are described suffering from longlasting behavioral disorders, who appeared to have both an abnormal karyotype, 47XXY and 47XYY respectively. The relationship between psychopathological disorders and the type of karyotypes is discussed. It is concluded that both biological and environmental factors are involved in the development of behavioral disorders that are observed frequently in this kind of subjects.