Herman M. van Praag

Denosologization of biological psychiatry or the specificity of 5-HT disturbances in psychiatric disorders

5-Hydroxytryptamine (5-HT) disorders have been reported to occur in a variety of psychiatric disorders. The situation has been called chaotic, the disturbances non-specific. We reject this viewpoint. 5-HT disturbances are non-specific only from a nosological/categorical viewpoint; they seem rather specific from a functional/dimensional point of view, correlating as they do with particular psychopathological dimensions, i.e. aggression-, anxiety- and possibly mood-disregulation, across diagnosis. The evolution of 5-HT research in psychiatry illustrates the importance of what we have called the functional approach, implying dissection of a given psychopathological syndrome in its component parts, i.e., the psychological dysfunctions, and searching for correlations between biological and psychological dysfunctions. The rigid preoccupation of biological psychiatry with the search for markers of disease entities has hampered progress. The functional approach should be incorporated in biological psychiatry, not as an alternative for the nosological approach but as its complement.

Serotonin and anxiety revisited

Serotonin (5hydroxytryptamine; 5-HT) was first discovered in 1948 in blood platelets and a few years later in the brain. Since then, investigations of 5-HT involvement in mental disorders have contributed to major advances in psychiatry. 5-m distances were initially linked to the p~ogenesis of depression. A subgroup of depressed patients was noted to have decreased 5-HT metabolism in the central nervous system (CNS) (van Praag and Korf 1971). Further studies indicated that lowered 5-HT metabolism correlated with particular dimensions of psychopathology that may occur within depressive disorders but likewise within other syndromes. One of these dimensions is dyscontrol of aggression, leading to suicide or to outwardly directed aggression (van Praag 1986). A second psychopathological dimension appears to be related to anxiety. Evidence relevant to this latter conclusion will be summarized in this article. Most data on the relationship of 5-HT to anxiety are derived from animal studies. Research using human subjects has only recently begun. We think that the substanti~ body of animal findings and the exciting new human data warrant a reexamination of the role of 5-HT in the pathogenesis of anxiety. We will propose a 5-HT hypothesis of anxiety that takes into account 5-HT availability as well as receptor sensitivity. H-IT Systems in the Brain The raphe nuclei in the brain stem, encompassing the dorsal raphe and medial raphe nuclei, contain the cell bodies of 5-HT-producing neurons. From there, six major projections ascend to the forebrain, two tracts within the median forebrain bundle and four outside of it. Cortex, hypothalamus, thalamus, basal ganglia, substantia nigra, caudate, putamen, amygdala, hippocampus, septum, tegmentum, and mamillary bodies are all innervated by 5-HT neurons (Azmitia and Segal 1978). Two major subcategories of 5HT receptors have been identified in the CNS, labeled 5-HTr (Perot&a 1984) and 5-HT2 (Leysen et al. 1984). 5-HTr receptors are further su~Iassifi~ as 5-HTr,, 5-HTu,, 5HTr,, and 5-HTrd receptors. 5-HT,, receptors display a very high affinity for 8-hydroxyNJV-dipropyl-2-aminotetralin (80HDAP) and are found in the human frontal cortex and

The measurement of suicidality, aggressivity and impulsivity.

1. From an evolutionary point of view aggressive behavior increases the chances of individual survival as well as inclusive fitness. 2. There are brain structures and biochemical systems that are involved in the regulation of aggressive behavior. 3. Genetic studies have revealed genetic contributions to aggressive as well as impulsive behaviors. 4. Research has demonstrated correlations between measures of suicidality, violence and impulsivity. 5. A two-step model of countervailing forces has been developed that identifies amplifiers and attenuators of the aggressive impulse. This model has enabled us to determine a set of variables that influence suicide but not violence and another set that influences violence but not suicide.

Neuroendocrine evidence for serotonin receptor hypersensitivity in panic disorder

Normal controls (NC) (n=15), patients with panic disorder (PD) (n=13) and patients with major depression (MD) (n=17) were challenged with a single, oral dose (0.25 mg/kg) of the selective 5HT agonist m-chlorophenyl-piperazine (MCPP) or placebo. Blood samples were assayed for cortisol and MCPP levels every 30 min. The PD group had an augmented cortisol release when compared to the other two groups. Finally, a significant correlation was found across all subjects between clinical anxiety level and cortisol release on MCPP. These data support the hypothesis of 5HT receptor hypersensitivity in PD.

Activation of 5-HT3 receptor by 1-phenylbiguanide increases dopamine release in the rat nucleus accumbens

The serotonin-3 (5-HT3) agonist 1-phenylbiguanide (0.1-1.0 mM in perfusate) caused a robust, dose-dependent enhancement of extracellular dopamine content in nucleus accumbens as measured by in vivo microdialysis. This action was antagonized by co-perfusion of the 5-HT3 antagonists zacopride and GR38032F (1 mM in perfusate). Similar effects were observed in 5-HT-denervated rats. These findings suggest that there is a potent modulation of dopamine (DA) release in the nucleus accumbens mediated via 5-HT3 receptors, which appear to be located presynaptically on DA terminals of the mesolimbic DA pathway.

Interrelationships among anxiety, aggression, impulsivity, and mood: a serotonergically linked cluster?

Serotonin abnormalities appear to be related to a variety of psychopathological dimensions such as anxiety, depressed mood, impulsivity, and aggression dysregulation. We hypothesized that the psychopathological dimensions related to serotonin would be significantly intercorrelated since they seem to have a common biological basis. Sixty psychiatric inpatients were examined on a series of psychometric tests measuring suicidality, violence potential, impulsivity, depressive mood, and anxiety. The scores on all of these measures tended to be significantly correlated with one another. These findings support the additional hypothesis that biological markers may be more closely related to basic psychological dimensions than to nosological categories.

Behavioral indications for serotonin receptor hypersensitivity in panic disorder

Immediate placebo-corrected behavioral responses to m-chlorophenylpiperazine (MCPP), a selective serotonin agonist, are reported in 11 normal controls, 10 patients with panic disorder, and 10 patients with major depression. Whereas the normal and depressed groups showed no noteworthy behavioral response, panic disorder patients became more anxious, depressed, and hostile, and 60% had panic attacks. These data suggest a hypersensitive postsynaptic serotonin receptor system in some panic disorder patients.

Hormonal probes of central serotonergic activity: Do they really exist?

The response of a hormone allegedly under 5-hydroxytryptaminergic (5-HT-ergic) control to a compound stimulating or inhibiting serotonergic activity has been used as a measure of the functional state of central serotonergic systems. The relevant literature is reviewed, and based on that, it is concluded that, as yet, no reliable hormonal 5-HT probe exists. The main problems are nonselectivity of the challengers and noncomparability of individual studies because of variations in dose and route of administration. An acceptable hormonal 5-HT probe should at least have passed the following three tests. The influence of the challenger on catecholaminergic (CA) systems must be rendered unlikely in humans to avoid the pitfalls of, say, the 5-HT precursors whose CA-ergic influences have been overlooked. Dose-response relationships must be established to avoid the confusion caused by different investigators using the challenger in different doses. It must be demonstrated that the effect of the challenger is counteracted by its functional opponent.

Correlates of suicide and violence risk: III. A two-stage model of countervailing forces

Questionnaires and self-report scales were administered to 100 psychiatric inpatients. The scales measured such variables as depression, hopelessness, impulsivity, mental and life problems, family violence, personality characteristics, and dyscontrol tendencies. These were correlated with indices of suicide risk and violence risk. Most variables were found to correlate significantly with both suicide and violence risk. Partial correlation analyses revealed that 10 variables correlated significantly with suicide risk but not violence risk, while four variables correlated significantly with violence risk but not suicide risk. A two-stage model of countervailing forces, incorporating concepts from both psychoanalysis and ethology, is presented as a way of interpreting the results.

Central serotonin metabolism and frequency of depression

Central serotonin (5-hydroxytryptamine; 5-HT) metabolism can be disturbed in a subgroup of patients with vital (endogenous, primary) depression. Presumably these disturbances do not result from the depression and have a predisposing rather than a causative relationship to it. This latter statement is based on two observations. First, in a majority of patients, the 5-HT disturbances persist after depression has abated. Secondly, 5-hydroxytryptophan seems to have prophylactic value, in particular in patients with persistent abnormalities in central 5-HT metabolism. In this study we approached the hypothesis that 5-HT disturbances are a predisposing factor to the occurence of depression from still another perspective. If this hypothesis is correct, then depressive patients with persistent 5-HT disturbances should have higher frequencies of depression than depressive patients without demonstrable 5-HT disturbances. This was indeed demonstrated. The same was true for family members of probands with low levels of 5-hydroxyindoleacetic acid. No cerebrospinal fluid data are available for family members. The reported findings strongly support the predisposition hypothesis.