Scott Wetzler

m-Chlorophenylpiperazine as a probe of serotonin function

m-Chlorophenylpiperazine (mCPP) is the most extensively used probe of serotonin function in psychiatry. This article reviews its in vitro and in vivo properties in animals, normal human subjects, and psychiatric patients. mCPP is a safe, reliable, direct 5-hydroxytryptamine (5HT) agonist, which may be used to evaluate 5HT receptor sensitivity. It causes a consistent, dose-dependent elevation of ACTH, cortisol, and prolactin levels in both animals and humans, as well as increased body temperature in man. It also causes a variety of behavioral effects, depending on the population studied. These effects are probably 5HT receptor-related, although specific 5HT receptor subtype mechanisms have not yet been established. mCPP may be considered an important addition to armamentarium of 5HT receptor probes, which is especially useful until more selective 5HT receptor agonists have been tested.

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

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.

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.

The Psychology of Gastric Bypass Surgery

Background: This article discusses the importance of psychological evaluation of gastric bypass (GBP) surgery candidates and post-surgical psychological support services, using the Center for Weight Reduction Surgery at Montefiore Medical Center as a model. The study of psychological predictors of post-operative outcome is in its beginning stages, and the small body of literature on this topic is reviewed. Methods: 115 GBP surgery candidates completed a clinical interview and a self-report measure, the MMPI-2. Results and Conclusions: A high prevalence of psychopathology and personality disturbance was found in this population.The impact that psychological disturbance may have on post-operative outcome is discussed.The authors also provide a qualitative analysis of the psychological themes commonly found among this population, as well as psychosocial interventions that have been found helpful.

Effects ofm-chlorophenylpiperazine in normal subjects: a dose-response study

Abstractm-Chlorophenylpiperazine (MCPP), a direct 5HT receptor agonist, was administered orally to 20 normal subjects in two doses (0.25 and 0.5 mg/kg) in a placebo-controlled design. Behavioral responses; ACTH, cortisol, prolactin and MCPP blood level; temperature and pulse rate were measured over a 210-min period after administration of tablets. Non-linear dose-response relationships between MCPP and ACTH, cortisol and prolactin response were found. On the higher dose, a significant increase in the number of physical symptoms was also noted and three subjects (15%) had a panic attack, while one subject (5%) had a panic attack on the lower dose. No effects on other behavioral variables, pulse rate and temperature were found using either dose. These findings attest to the usefulness of MCPP as a challenge agent to assess 5HT receptor hypersensitivity when given at a low oral dose (i.e. around 0.25 mg/kg), and to assess 5HT receptor hyposensitivity when given at higher oral doses (i.e. around 0.5 mg/kg).

The MCPP challenge test in schizophrenia: Hormonal and behavioral responses

In a neuroendocrine challenge paradigm, the present study investigated responses of schizophrenic patients to m-chlorophenylpiperazine (MCPP), a serotonin (5-hydroxytryptamine, 5HT) agonist. In an oral dose of 0.25 mg/kg, MCPP was administered in a placebo-controlled double-blind design to male schizophrenic patients (n = 7) and normal male controls (n = 8). Behavioral (Positive and Negative Syndrome Scale; PANSS) and hormonal (cortisol, prolactin) variables were measured over the subsequent 210 min. The schizophrenic patients experienced an overall exacerbation of psychopathology on MCPP as compared with placebo (p less than 0.05), with specific worsening of PANSS-positive symptoms (p less than 0.025) and PANSS activation (p less than 0.001). In addition, the schizophrenic patients showed significantly lower cortisol (p less than 0.05) and prolactin (p less than 0.05) responses than the normal subjects. The schizophrenic patients had lower peak MCPP blood levels than the normal subjects, although this difference was not statistically significant. The findings are discussed in terms of 5HT receptor(s) sensitivity and the pharmacokinetics of MCPP in schizophrenia.

Five percent carbon dioxide challenge: Valid analogue and marker of panic disorder?

The administration of 5% carbon dioxide (CO2) to patients with panic disorder (PD) induces a behavioral response similar to a naturally occurring panic attack. This article reviews the literature on the nature and incidence of this response. We conclude that the 5% CO2 challenge test is a valid and useful laboratory analogue of naturally occurring panic attacks, and shows promise as a marker to identify a subset of PD patients. Though further research on reliability, validity, and dose-response effects must be conducted, the CO2 challenge test provides important information regarding the phenomenology of panic states.

Serotonin function in panic disorder: intravenous administration of meta-chlorophenylpiperazine

A placebo-controlled study of the direct serotonin receptor agonist meta-chlorophenylpiperazine (MCPP), intravenously infused over 90 s in a 0.06 mg/kg dose, was conducted in 10 patients with panic disorder and 9 normal control subjects. Cortisol, MCPP serum levels, and behavioral responses in both groups. Differences between intravenous and oral administration of MCPP are discussed, and the present findings are related to the serotonergic hypothesis of panic disorder.