Skin conductance is a psychophysiological parameter that reflects fundamental processes such as attention and arousal. The present study explored whether deviations in skin conductance activity are associated with severity of schizophrenic symptoms. For this purpose, Skin Conductance Responses (SCRs) to discrete stimuli (80 dB noises) and Skin Conductance Levels (SCLs) of 37 schizophrenic patients and 31 healthy volunteers were recorded. In accordance with previous studies, schizophrenic patients were found to be hyporesponsive compared to healthy controls. More specifically, almost half of the patients (46%) did not react with any SCR to the first 3 stimuli, whereas only 10% of the control group exhibited such a non-responding. Accordingly, the mean amplitude of the first 3 SCRs – as measured in u Siemens – was found to be significantly lower in patients compared to controls. As well, mean SCL was found to be (marginally) elevated in the patient group. This was especially the case for patients who did exhibit SCRs. In the patient group, a negative correlation was found between amplitude of SCRs and symptom severity. This association was mainly carried by a significant correlation between positive symptoms and reduced SCRs. The clinical relevance of these findings is discussed in detail.

Therapy-resistance for positive symptoms is one of the most important problems that occurs with the medical treatment of schizophrenia. In the past years, clozapine has proven its effectiveness in this area and has been included in the treatment protocols and guidelines. Because of the risk of agranulocytosis with this compound and the intensive laboratory controls to be done, several studies have been performed with the new antipsychotics risperidone and olanzapine as alternative treatments. A review of the literature suggests that both drugs are as effective as the classic antipsychotics for therapy-resistant patients. A switch to risperidone or olanzapine possibly would be a alternative for those patients who have favourable effects on a low dose of clozapine. Furthermore the new antipsychotics have less side effects and ameliorating effects on negative and cognitive symptoms, so contributing to overall improvement in chronic schizophrenic disorders. However, in case of persistent positive symptopathology, clozapine remains the golden standard. The new antipsychotics should be included in treatment protocols before clozapine.

Alprazolam (a benzodiazepine in the group of the triazolo-benzodiazepines) is a potent drug for the treatment of panic disorder. This is possible due to four different interactions with neurotransmitter systems. First, it facilitates, as all diazepines, the inhibitory acitivity of gamma-amino-butyricacid (GABA). The chemical structure differs from the benzodiazepines by incorporation of the triazoloring. Due to this triazoloring, the drug has three additional modes of action. These modes of action inhibit the locus coeruleus which plays a role in the origin of panic disorder. A first specific action is a stimulation of the serotonergic system. Triazolobenzodiazepines are also α2-adrenoreceptor agonists. Both mechanisms are responsible for inhibition of the locus coeruleus. Triazolo-benzodiazepines inhibit the platelet-activating-factor (PAF). PAF stimulates the corticotropin-releasing-hormone (CRH). This hormone stimulates the locus coeruleus. CRH in patients with panic attacks is elevated. This could be a result of hyperactive metabolism of the right parahippocampal area, which is observed in patients with panic attacks. Triazolo-benzodiazepines decrease the activity of the locus coeruleus because of a low CRH-level due to inhibited PAF.

Advances towards the understanding of the etiological mechanisms involved in mood disorders provide interesting yet diverse hypotheses and promising models. In this context, molecular genetics has now been widely incorporated into genetic epidemiological research in psychiatry. Affective disorders and, in particular, bipolar affective disorder (BPAD) have been examined in many molecular genetic studies which have covered a large part of the genome, specific hypotheses such as mutations have also been studied. Most recent studies indicate that several chromosomal regions may be involved in the aetiology of BPAD. Other studies have reported the presence of anticipation in BPAD. This phenomenon describes the increase in clinical severity and decrease in age of onset observed in successive generations. This mode of transmission correlates with the presence of specific mutations (Trinucleotide Repeat Sequences) and may represent a genetic factor involved in the transmission of the disorder. In parallel to these new developments in molecular genetics, the classical genetic epidemiology, represented by twin, adoption and family studies, provided additional evidence in favour of the genetic hypothesis in mood disorders. Moreover, these methods have been improved through models to test the gene-environment interactions. While significant advances have been made in this major field of research, it appears that integrative models, taking into account the interactions between biological (genetic) factors and social (psychosocial environment) variables offer the most reliable way to approach the complex mechanisms involved in the etiology and outcome of mood disorders.

Since 1863 psychiatry is dominated by the nosological conceptual paradigm that was further stimulated by the introduction of the DSM-III. This has resulted in an ignorance of the European psychiatric diagnostic tradition and a loss of the necessary critical observations and descriptions of psychopathology. This unfortunate process may be observed in the diagnosis of psychiatric disorders in mentally retarded patients where entities such as atypical psychoses, unstable mood disorder and motivational deficit syndrome are not recognized in general. The enormous increase of neuroscienti-fic knowledge, particularly the impact of genetic and intracellular mechanisms in the pathophysiology of psychiatric disorders, warrants the use of a more dimensional and functional psychiatric paradigm. It concerns the effect of gene transcription on the expression of neurotransmitters and receptors that may account for an increased vulnerability or a relapsing course. A so called anticipatory treatment approach is therefore advocated.

Reported (ir)reversibility of neurological and psychiatric symptoms induced by Phenytoin intoxication is being discussed by means of a case report concerning a 40-year old man who sets fire to his house during a psychosis. Observation after admission to a general psychiatric hospital, following a short period of detention, leads to diagnosing neurological and psychiatric symptoms due to chronic Phenytoin intoxication. Discontinuation of Phenytoin supply induces partial remission of the symptoms. Literature on the subject is being revised.

Serotonin (5-HT) has been implicated in the pathophysiology of bipolar disorders. Acute tryptophan depletion (ATD), which decreases serotonergic turnover, is an established paradigm to study serotonergic vulnerability in affective disorders. Literature on the application of ATD as a research tool in bipolar patients is limited to three studies, which revealed inconsistent results on mood modification. These inconsistencies may be attributed to differences in methodological procedures and / or characteristics of included patients. Patient selection, methodological aspects and procedures of these studies are critically considered and recommendations given. A research protocol to test the 5-HT vulnerability in bipolar disorder is proposed.

Repeated exposure of rats to cocaine, amphetamine, opiates, nicotine and alcohol causes a very long-lasting (months) increase in the behavioral effects of these addictive drugs and drug-associated environmental stimuli (sensitization). This hypersensitivity is associated with persistent changes in the reactivity of neurons of the motivational (mesocorticolim-bic) system in the brain. Using an animal model for relapse, recent studies in our laboratory show that relapse to drug-seeking behavior (following extinction of intravenous cocaine or heroin self-administration) depends on the occurrence of sensitization. Accordingly, sensitization and conditioning seem to be more important for the persistence of drug and alcohol addiction then the occurrence of withdrawal phenomena. Biochemical research on the molecular and cellular basis of behavioral sensitization and behavioral studies on readjustment of stimulus responsiveness in rats, is of great importance for the development of an adequate pharmacotherapy of addiction.

A huge number of natural and synthetic compounds modulate the function of the γ-aminobutyric acid type A receptor (GABAA-R) by interacting with several allosteric binding sites which may differ in the various GABAA-R subtypes. The benzodiazepine receptor (BDZ-R) is the most intensively studied allosteric site. It is the first allosteric modulatory site on a neurotransmitter receptor that has been found to mediate two opposite functions: facilitation and depression of GABAA-R function. The effects of BDZ-R ligands on behavior range from agonistic (anxiolytic, anticonvulsant, myore-laxant/ataxic and hypno-sedative effects) to inverse-agonistic (anxiety and panic, hypervigilance and convulsions). Of particular interest for the future are BDZ-R partial agonists, as they lack several of the undesired properties of classic full agonists. Furthermore the GABAA-R system shows a high plasticity. This polymorphism raises the possibility that ligands selective for distinct subtypes of BDZ-R may emerge as useful drugs. In both cases the possibility exists of achieving very subtle manipulations of GABAA-R function by using allosteric modulators.

Epidemiological and pathobiological findings in bipolar disorder [BP] have often been limited by selection bias and lack of epidemiological representativeness. In a rural, circumscribed catchment area, ‘all’ patients with BP were identified and assessed. On preliminary analysis, morbid risk [MR] for BP over the area as a whole was 5.0 ± 0.6/1000. The distribution of MR for BP over geographical subregions showed no significant deviation from a statistical model for random occurrences in space by place at birth, in contrast to schizophrenia [SZ], and varied only modestly among males by place at onset. These results imply different etiological factors acting in BP in comparison with SZ, particularly with regard to the role of early versus later life events. In preliminary analyses of psychotic and cognitive features, current severity of positive symptoms was predicted in BP only by increasing dominance of the left hand; negative symptoms by duration of illness and current anticholinergic exposure; poorer general and frontal cognitive function by older age at onset of illness, increasing duration of illness, and current anticholinergic exposure. The finding on handedness suggests disturbance of cerebral asymmetry associated with positive symptoms in BP, while both negative symptoms and cognitive impairment may involve progressive processes. Further analysis of this epidemiologically complete population, including systematic comparisons of BP with schizoaffective disorder and SZ, continues.

Zinc is a trace element which plays a fundamental role in a wide range of biochemical processes in living organisms. Zinc is an essential component of various proteins and is an important factor for physiological function of the mammalian nervous and immune systems. In the central nervous system (CNS), zinc is found at high concentrations in hippocampal neurons. These neurons possess mechanisms for zinc uptake and storage in synaptic terminals and for the stimulation of zinc release along with neurotransmitters. In the central nervous system, zinc modulates predominantly the excitatory (glutamatergic) and inhibitory (GABAergic) amino acid neurotransmission pathways. In the immune system, zinc is necessary for the physiological activity of the thymus and T-cell-dependent responses. Zinc deficiency impairs the activities of the neuroendocrine and immune systems in mammalian organisms. This paper reviews the alterations in the blood and brain zinc concentrations in relation to the neuroimmune pathophysiology and treatment of depression. Major depression is related to lowered serum zinc concentrations, which may be caused by the acute phase and the inflammatory response in that illness. Repeated administration of antidepressants selectively increases and redistributes brain zinc in the hippocampus. Since zinc is an inhibitor of the glutama-te/NMDA receptor, these data are in accordance with the glutamate hypothesis of antidepressant action.

The mode of action of serotonin in depression is unclear. We tested the modulation of hippocampal long-term plasticity, a model for learning and memory, by 5-HT and found a selective impairment of long-term depression resulting in a positive modification of synaptic network properties. We hypothetize a role for long-term plasticity in emotional regulation and the pathophysiology of affective disorders.

This article describes a number of studies by our research group to find brain structures that may be involved in the symptoms of idiopathic depression, depression in Alzheimer's disease and depression in Parkinson's disease. Until recently, idiopathic depression has generally been related to deficiencies of aminergic systems. In Alzheimer patients we found a strong decrease in the number of neurons in the locus coeruleus and brain noradrenaline concentrations, but in depressed Alzheimer patients we did not find an extra de crease. This is in agreement with the finding that there is no cell loss in the locus coeruleus in idiopathic depression. We did find, however, that the number of corticotropin-releasing hormone-, vasopressin- and oxytocin expressing neurons, the number of corticotropin-releasing hormone neurons co-expressing vasopressin and the amount of corticotropin-releasing hormone -mRNA in idiopathic depression were strongly increased in the paraventricular nucleus of the hypothalamus. This result supports the hypothesis on the pathogenetic involvement of the hypothalamo-pituitary-adrenal axis in depression and is of clinical relevance, since it may provide a theoretical rationale for antidepressive therapy with CRH antagonists.

Classical antipsychotic drugs increase the level of serum prolactin. The atypical antipsychotic clozapine barely increases prolactin levels. An open naturalistic study in the University Hospital of Groningen suggests that treatment with risperidone in comparison to classical antipsychotics seems to increase the risk of erectile and ejaculatory disorders in male patients and to menstrual disturbances in female patients. In the literature reviewed, risperidone is associated with higher prolactin levels in comparison to classical antipsychotics. It is still unclear which mechanism is responsible for the increase of serum prolactin levels and sexual dysfunctions in patients using risperidone. Dopaminergic and serotonergic receptor blockade seems to play an important role. Other mechanisms are discussed.