Central Serotonergic Neurotransmission Research Articles

Cluster Headache Patients Show Marked Intensity Dependence of Cortical Auditory Evoked Potentials during and outside the Bout

Central serotonergic neurotransmission was assessed using intensity dependence of cortical auditory evoked potentials (IDAP) in cluster headache (CH) patients during both the active and interictal period. In 15 episodic CH patients and 13 controls previously described methods were used and amplitude-stimulus intensity function (ASF) slopes were computed. In the cluster group mean ASF slope was significantly steeper than in the control group both during the active period (1.53+/-0.90 vs. 0.77+/-0.85, P=0031) and interictally (1.85+/-1.20 vs. 0.77+/-0.85, P=0012). In the cluster group IDAPs of active and interictal period did not differ significantly (P=0378). Duration of the disease or the present bout, distance from the last attack did not correlate with ASF slopes. In conclusion, our results are compatible with decreased level of serotonergic neurotransmission in raphe-cortical pathways. Diminished serotonergic activity in raphe-hypothalamic serotonergic pathways might be hypothesized influencing the activity of hypothalamic neurons and thus play a role in the genesis of cluster headache.

A randomized, controlled crossover trial of ondansetron in patients with primary biliary cirrhosis and fatigue†

Fatigue is common in primary biliary cirrhosis (PBC). Altered central serotonergic neurotransmission may be involved in its pathogenesis. This multicenter, randomized, double-blind, placebo-controlled, crossover trial evaluated the efficacy of ondansetron, a selective 5-HT3 receptor subtype antagonist, for treating fatigue in PBC. A crossover design was chosen, allowing subjects to serve as their own controls-appropriate to evaluate fatigue, a subjective symptom. Sixty patients with clinically stable PBC, a Fatigue Severity Score (FSS) > 4, and no other identifiable cause for fatigue were enrolled. Subjects were randomized to receive ondansetron (4 mg) or placebo orally 3 times daily for 4 weeks (period 1). Subjects then crossed over, after a minimum 1-week washout period, for a further 4 weeks of ondansetron or placebo (period 2). Fatigue was measured at the beginning and end of each period by using the FSS and Fatigue Impact Scale (FIS). Six patients withdrew; the remaining 54 subjects had a mean baseline FSS of 5.55 (+/-0.1). Response to study medication in period 1 versus period 2 was not uniform; thus, it was necessary to analyze the trial periods separately. In period 1, there was no significant additional fatigue reduction on ondansetron over placebo. During period 2, FSS and FIS decreased significantly on ondansetron versus placebo (P = .001). However, period 2 results were invalidated because drug side effects unblinded subjects (constipation affected 63.0% of patients taking ondansetron, versus 13.3% on placebo). In conclusion, ondansetron administration did not confer clinically significant fatigue reduction when compared with placebo in our study population.

The intensity dependence of the auditory evoked N1 component as a predictor of reponse to Citalopram treatment in patients with major depression

The intensity dependence of the auditory evoked N1 ERP component (IDAP) has been suggested as an indicator of central serotonergic neurotransmission with relevance to pharmacological treatment. We report the results of a study evaluating the IDAP in 16 in-patients fulfilling DSM-IV criteria for major depressive episode in the course of treatment with the SSRI Citalopram. Our data revealed a significant correlation between the intensity slopes of the N1 amplitude prior to Citalopram treatment and treatment response: patients with higher intensity slopes of N1 amplitude showed a significantly stronger decrease of HDRS-Score after Citalopram treatment than patients within the lower intensity slope ranges. Our results indicate an association of N1 amplitude intensity dependence with response to antidepressant treatment with Citalopram.

Loudness dependency of the primary auditory cortex as an indicator of central serotonergic transmission: Combination of EEG and fMRI

Converging arguments from preclinical and clinical studies support the hypothesis that the loudness dependence of the auditory evoked N1/P2-response (LDAEP) is regulated by the level of central serotonergic neurotransmission. More specific, studies in behaving cats suggest that inhibition or activation of the serotonergic neurons in the dorsal raphe nucleus influences the loudness dependency only in the primary but not in the secondary auditory cortex (Juckel et al., 1999). With dipole source analysis or tomographic current source density analysis, activity of the primary and the secondary auditory cortex can be separated at least in parts (Mulert et al., 2002). The goal of the present investigation was to use the high spatial resolution of fMRI to get a more precise covering of the activity of the primary auditory cortex than it is possible with EEG based localisation approaches.

Genetics of suicide: an overview.

Risk for suicide may have heritable contributions. Evidence supporting this hypothesis includes strong and consistent findings from more than 20 controlled family studies indicating nearly 5-fold greater relative risk of suicidal acts among relatives of index cases with suicidal behavior compared to relatives of nonsuicidal controls. Relative risk was greater for completed suicide than for attempts. Contributions of genetic instead of environmental factors are indicated by a higher average concordance for suicidal behavior among co-twins of suicidal identical twins compared to fraternal twins or to relatives of other suicidal subjects, in at least seven studies. Three studies indicate significantly greater suicidal risk, particularly for completed suicide, among biological versus adoptive relatives of suicidal or mentally ill persons adopted early in life. Molecular genetics studies have searched inconclusively for associations of suicidal behavior with genes mainly for proteins required for central serotonergic neurotransmission. Complex interactions of environmental with heritable risk and protective factors for suicide and psychiatric illnesses or vulnerability traits are suspected, but specific intervening mechanisms remain elusive. Familial or genetic risks for psychiatric factors strongly associated with suicide, such as major affective illnesses and alcohol abuse, as well as impulsive or aggressive traits, have not consistently been separated from suicidal risk itself.

Immunocytochemical study of the forebrain serotonergic innervation in Sardinian alcohol-preferring rats.

The anxiolytic effect of ethanol is generally considered to be causally related to the development of alcohol dependence, and serotonin (5-HT) has been involved in both alcohol abuse and anxiety disorders. Several lines of evidence suggest an inverse relationship between alcohol abuse and central serotonergic neurotransmission. When tested in the elevated plus-maze, selectively bred Sardinian alcohol-preferring (sP) rats display a higher degree of anxiety than Sardinian alcohol-non-preferring rats (sNP); this behavior is reversed by voluntary ethanol intake. The present study examined whether sP rats differed with respect to the 5-HT innervation in different forebrain areas. We performed an immunohistochemistry study using an antibody raised against serotonin transporter (SERT), a marker for 5-HT fibers, coupled with an unbiased stereology, the method used to count the number of 5-HT neurons in the raphe nuclei. The SERT-positive innervation density was found to be significantly lower in the medial-prefrontal cortex and in the shell of the nucleus accumbens of the ethanol-naive sP rats (sP-N) when compared with the sNP and unselected Wistar rats. No differences were found in the caudate putamen and hippocampus. The stereological analysis showed a significant difference in the number of 5-HT neurons in the dorsal but not in the median raphe of sP-N rats, compared with sNP and Wistar rats. Analysis of the cell body cross-sectional area revealed no differences among the three lines of rats either in the dorsal or in the median raphe. In sP rats that had voluntarily drunk ethanol for 14 consecutive days (sP-exp), no differences were found in the 5-HT innervation relative to sP-N animals. These results indicate a selective reduction of innervation in the medial portion of the mesocorticolimbic 5-HT system in sP rats, suggesting that this genetically determined difference may be involved in the contrasting alcohol preference and consumption of sP and sNP animals.

Ethanol consumption and serotonin-1A (5-HT1A) receptor function in heterozygous BDNF (+/-) mice.

Heterozygous brain-derived neurotrophic factor (BDNF) (+/-) mice display abnormalities in central serotonergic neurotransmission, develop decrements in serotonergic innervation of the forebrain, and exhibit enhanced intermale aggressiveness. As disturbances of serotonin neurotransmission are implicated in alcohol abuse and aggression, we have examined in BDNF (+/-) mice alcohol drinking behavior, as well as central 5-hydroxytryptamine (5-HT)1A receptor function at the level of 5-HT1A receptor-G protein interaction. BDNF (+/-) mice displayed increased ethanol intake in a two-bottle choice procedure. There was no difference in the preference ratio for non-alcoholic tastants (i.e. quinine or saccharin) between genotypes. In the brains of alcohol-naive mice, we measured [35S]GTP gamma S binding stimulated by the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-dipropyl-aminotetralin hydrobromide (8-OH-DPAT; 1 microM). In BDNF (+/-) versus wild-type (WT) mice, 5-HT1A receptor-stimulated [35S]GTP gamma S binding was significantly attenuated in the median raphe nucleus. There was a decrease in (+/-)8-OH-DPAT-stimulated [35S]GTP gamma S binding in the dorsal raphe, which did not reach statistical significance. In the hippocampus, 5-HT1A receptor-stimulated [35S]GTP gamma S binding was significantly attenuated in BDNF (+/-) mice. 5-HT1A receptor-stimulated [35S]GTP gamma S binding was attenuated in the anterior cingulate cortex and lateral septum, although these reductions did not reach statistical significance. 5-HT1A receptor number was not different between genotypes in any area of brain examined, suggesting that 5-HT1A receptor function, specifically the capacity of the 5-HT1A receptor to activate G proteins, is attenuated in BDNF (+/-) mice.

Emerging evidence for a central epinephrine-innervated alpha 1-adrenergic system that regulates behavioral activation and is impaired in depression.

Currently, most basic and clinical research on depression is focused on either central serotonergic, noradrenergic, or dopaminergic neurotransmission as affected by various etiological and predisposing factors. Recent evidence suggests that there is another system that consists of a subset of brain alpha(1B)-adrenoceptors innervated primarily by brain epinephrine (EPI) that potentially modulates the above three monoamine systems in parallel and plays a critical role in depression. The present review covers the evidence for this system and includes findings that brain alpha(1)-adrenoceptors are instrumental in behavioral activation, are located near the major monoamine cell groups or target areas, receive EPI as their neurotransmitter, are impaired or inhibited in depressed patients or after stress in animal models, and are restored by a number of antidepressants. This "EPI-alpha(1) system" may therefore represent a new target system for this disorder.

Actions of group i and group ii metabotropic glutamate receptor ligands on 5-hydroxytryptamine release in the rat cerebral cortex in vivo: differential roles in the regulation of central serotonergic neurotransmission

We have previously shown that the release of central neurotransmitters can be modulated by the activation of Group I and Group II subtypes of G-protein-linked metabotropic glutamate (mGlu) receptors. To date, however, very little is known about the regulation of serotonergic neurotransmission by these receptor subtypes. In the present study, we have utilized in vivo intracerebral microdialysis to elucidate the roles of Group I and Group II mGlu receptors in the regulation of neuronal 5-hydroxytryptamine (5-HT) release in the frontal cortex of conscious, freely moving rats. Dialysate 5-HT was of neuronal origin with basal release showing strong calcium dependency and tetrodotoxin sensitivity and marked elevation following K +-induced depolarization. The broad-spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD; 1–3 mM] did not significantly modify basal cerebrocortical 5-HT release. Similarly, the Group I mGlu receptor-specific agonist (RS)-3,5-dihydroxyphenylglycine [(RS)-3,5-DHPG; 1–3 mM] showed no marked effect on cortical dialysate 5-HT levels. To eliminate the possibility that these findings were the result of receptor desensitization, the effects of lower concentrations of (RS)-DHPG (100–300 μM) and shorter ligand exposure time (15 min) were also evaluated. Dialysate 5-HT levels remained unmodified by these manipulations. In comparison, the Group II mGlu receptor agonist, (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine (L-CCG-1; 500 μM), evoked a marked facilitation of release (approximately 150% of basal) which was fully reversed by the Group I/II antagonist, (S)-α-methyl-4-carboxyphenylglycine [(S)-MCPG; 3 mM]. The modulatory action of L-CCG-1 showed a bell-shaped concentration-response relationship. (S)-MCPG (3 mM) and the potent and selective mGlu 5 receptor antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP; 100 μM), when given alone, did not significantly modify 5-HT levels. The current data provide strong evidence to suggest that while the release of neuronal 5-HT in the rat frontal cortex is not subject to regulation by facilitatory Group I mGlu receptors, it may be positively modulated by activation of Group II mGlu receptors. Taken together with data from other studies, the present investigation lends emphasis to the notion that neuromodulation by mGlu receptors is a region-specific phenomenon and also proposes that the heterogeneous distribution of these receptors is neurone-specific in its complexity. The failure of (S)-MCPG alone to modify cortical 5-HT release suggests that Group II mGlu receptors do not tonically modulate serotonergic neurotransmission in the cerebral cortex but this does not preclude an important functional role for these receptors during pathological conditions when endogenous neurotransmitter levels become excessively elevated. The strategic development of new subtype-specific mGlu receptor ligands may provide novel therapeutic agents for the treatment of a range of neurological and psychiatric disorders.

Evidence for disturbed cortical signal processing and altered serotonergic neurotransmission in generalized anxiety disorder

Background Current pathophysiological concepts of generalized anxiety disorder (GAD) assume a disturbed exteroceptive sensory system. Furthermore, central serotonergic neurotransmission has been shown to play an important role in anxiety disorder. Cortical signal processing as measured by auditory evoked potentials (AEPs) may reflect the integrity of the exteroceptive sensory system. Because a special aspect of AEP, the loudness dependence of the N1/P2-component (LD), has been related to central serotonergic activity, the LD may be useful for investigating serotonergic dysfunctions in GAD. Methods The LD was recorded in 31 medication-free patients with GAD without any psychiatric co-morbidity and in 31 matched control subjects. Dipole source analysis was performed to separate the LD of regions including the primary (LD-tangential dipole) and regions including the secondary auditory cortex (LD-radial dipole). Results A shallower LD-tangential was observed in patients with GAD as compared to healthy control subjects [ F(1,60) = 6.727, p = .012; one-way analysis of variance]. The LD-radial showed no differences between groups. Severity of the anxiety symptoms was not related to the LDs. Conclusions The results indicate an altered exteroceptive sensory system in GAD occurring at the level of the primary but not secondary auditory cortex. Because a shallow LD of the primary auditory cortex was related to a high firing rate of neurons in the dorsal raphe nucleus, the results may support evidence for an enhanced serotonergic activity in GAD.

The neurobiological approach to premature ejaculation.

Data showing the neurobiological background of rapid ejaculation was reviewed. In addition, new hypotheses to integrate clinical symptomatology, psychopharmacotherapy and psychotherapy of rapid ejaculation with brain function are provided. A computerized MEDLINE search, and manual bibliographic review of cross-references and neurobiological animal studies were performed. These reports were analyzed, summarized and compared with the studies performed by the author. The literature on premature ejaculation published between 1887 and 2001 was reviewed. It appeared that the various psychological hypotheses and psychotherapies have not adequately been investigated. In contrast, psychopharmacological treatment studies, animal research data and stopwatch assessments in men with rapid (premature) ejaculation indicate that lifelong rapid ejaculation is a neurobiological phenomenon related to central serotonergic neurotransmission and likely influenced by hereditary factors. Basic and clinical psychopharmacological studies suggest that premature ejaculation is a not a psychological disturbance but a neurobiological phenomenon.

Relationship between cortisol and serotonin metabolites and transporters in alcoholism [correction of alcolholism

Stress hormone activation may induce clinical depression via an interference with central serotonergic neurotransmission. In alcoholics, a reduction in serotonin transporters was associated with clinical depression, and an activation of cortisol secretion is frequently found during detoxification. We assessed the interaction between stress hormone activation, serotonin transporters, monoamine metabolites in the cerebrospinal fluid (CSF), and mood states in male and female alcoholics and healthy control subjects. The availability of serotonin transporters was measured with [I-123]beta-CIT and SPECT in the raphe area of the brainstem in 31 alcoholics after four weeks of abstinence and in 25 age-matched healthy volunteers. Concentrations of plasma cortisol were measured on the day of the SPECT scan. Within one week after the SPECT scan, we assessed monoamine metabolites and corticotropin-releasing factor (CRF) in the CSF. Clinical depression was associated with a reduction in serotonin transporter availability among male alcoholics. Among male alcoholics and healthy volunteers, CSF 5-HIAA and plasma cortisol concentrations were inversely correlated with the availability of raphe serotonin transporters and positively correlated with the severity of clinical depression. No significant correlations were observed between raphe serotonin transporters and HVA, MHPG and CRF concentrations in the CSF. Our findings support the hypothesis of an interaction between reduced serotonin transporters, stress hormone activation and clinical depression. They confirm the hypothesis that serotonergic neurotransmission dysfunction in alcoholism is limited to male alcoholics. The observed interactions between high cortisol concentrations and reduced serotonin transporter availability warrant further studies in major depression and other neuropsychiatric diseases with implied cortisol activation and serotonergic dysfunction.

Changes in central serotonergic function as a correlate of duration of illness in paranoid schizophrenia

There is evidence that the duration of untreated psychosis may affect both the course and outcome of treatment in schizophrenic patients. In the present study, we used neuroendocrine probes to test the hypothesis that untreated psychosis may induce time-dependent changes in central serotonergic and dopaminergic neurotransmission. Prolactin responses to the administration of clomipramine (i.v.) and haloperidol (i.m.) were measured in healthy control subjects and in 16 never-treated male patients with DSM-IV diagnoses of schizophreniform or schizophrenic disorders of paranoid subtype, both before and after 5 weeks of treatment with haloperidol. In the drug-free state, schizophrenic patients exhibited significantly increased prolactin responses to clomipramine administration compared with both the healthy control subjects and the schizophreniform patients. Maximum prolactin responses to clomipramine in the total group of patients were positively correlated with the duration of psychotic illness and negatively correlated with changes in Positive and Negative Syndrome Scale (PANSS) total, negative symptoms and general psychopathology scores after 5 weeks of treatment with haloperidol. Prolactin responses to haloperidol challenge in the drug-free state were lower in the schizophreniform group than in the control and the schizophrenic groups, but the differences did not reach statistical significance. The results provide evidence that the persistence of psychotic psychopathology induces secondary neuroadaptive effects, which seem to involve changes in central serotonergic function.

Is long-term heavy alcohol consumption toxic for brain serotonergic neurons? Relationship between years of excessive alcohol consumption and serotonergic neurotransmission

The relationship between years of excessive alcohol consumption and central serotonergic neurotransmission, as assessed by the prolactin (PRL) response to d-fenfluramine, was investigated in 22 male alcohol-dependent subjects. A negative correlation was obtained, that is, the longer duration of excessive alcohol consumption the lower PRL response to d-fenfluramine. It is therefore suggested that long duration of excessive alcohol consumption in alcohol-dependent subjects causes a reduction in central serotonergic neurotransmission, possibly by a toxic effect of alcohol on serotonin neurons. The relationship between depressive and anxiety symptoms during on-going drinking and the PRL response to d-fenfluramine was also investigated. No such correlations were obtained, suggesting that reduction in central serotonergic neurotransmission does not pre-dispose to the development of depressive and anxiety symptoms, at least in relation to on-going drinking in alcohol-dependent subjects.

Electrophysiological indication for a link between serotonergic neurotransmission and personality in alcoholism

The serotonergic neurotransmission seems to be involved in the neuropsychobiology of alcoholism. The intensity dependence of the N1/P2 component of auditory-evoked potentials is discussed as an indicator of the central serotonergic neurotransmission in healthy subjects. The aim of this study was to verify this correlation between intensity dependence and serotonergic neurotransmission, as indicated by the personality trait “harm avoidance” (HA) within the Temperament and Character Inventory (TCI) in alcohol-dependent patients. The intensity dependence was measured in 25 alcohol-dependent patients, 10 and 40 days after detoxification. The personality trait HA was assessed, which is supposed to reflect the serotonergic neurotransmission. The intensity dependence was negatively correlated with the temperament trait HA of the TCI ( r=−.55, P<.01) at Day 40, but neither on Day 10 nor with the other personality dimensions. We conclude, that the intensity dependence reflects the serotonergic neurotransmission in withdrawn alcohol-dependent patients.

Relationship between central serotonergic neurotransmission and reduction in alcohol intake by citalopram

The relationship between the effect of citalopram on alcohol intake and central serotonergic neurotransmission, as assessed by prolactin (PRL) response to fenfluramine, was investigated in 17 male heavy drinkers. A positive correlation was obtained, suggesting that the status of central serotonergic neurotransmission in individuals is associated with the treatment response to citalopram. When the group of subjects were divided into those with high and low PRL response (above and below median, respectively) to fenfluramine, those with high PRL response had a significant reduction in alcohol intake during citalopram treatment, whereas those with low PRL response had no such effect. Thus, in subjects with evidence of unimpaired or only slightly impaired central serotonergic neurotransmission (high PRL response) citalopram may have beneficial effect on alcohol consumption, whereas in those with more evidently impaired serotonergic neurotransmission (low PRL response) citalopram treatment may have no effect on or may even increase the alcohol consumption.

Serotonergic Dysfunction, Negative Mood States, and Response to Alcohol

Dysfunction of central serotonergic neurotransmission has been implicated in the pathogenesis and maintenance of alcoholism. Serotonergic dysfunction may be associated with three behavior patterns relevant for alcoholism: impulsive aggression, negative mood states, and a low response to alcohol intake. We reviewed the literature on the psychopathological correlates of serotonergic dysfunction and focused on studies that assess the interaction between negative mood states and alcohol response. Prospective studies in nonhuman primates that underwent early separation stress found an association between a low serotonin turnover rate and the disposition to excessive alcohol intake and impulsive aggression. These findings seem to be relevant for a subgroup of alcoholics with a low serotonin turnover rate and antisocial personality traits. Cross-sectional data in humans also support a relationship between reduced serotonergic neurotransmission and aggressive behavior and indicate that the association of serotonergic dysfunction and aggression may be mediated by negative mood states. This hypothesis is in accordance with a large body of data linking anxiety and depression to serotonergic dysfunction. In human alcoholics, brain imaging has detected a reduction in serotonin transporter availability in association with depression. Serotonin transporter availability seems to be related to reduced GABA-ergic sedation and the acute response to alcohol intake, an important predictor of subsequent development of alcohol dependence. Several lines of evidence point to a relationship between serotonergic dysfunction, negative mood states, and excessive alcohol intake, which may be mediated in part by reduced alcohol-induced sedation.

Electrophysiological assessment of impulsive behavior in healthy subjects

The different concepts of impulsivity cover a wide range of divergent behaviors. In clinical terms, aspects of impulsivity are both an important feature in several psychiatric conditions related to a low central serotonergic neurotransmission like aggressive behavior and suicidality, and a core symptom of frontal lobe syndromes of various etiologies. Assessment of the different forms of impulsivity so far relies on clinical observations and self-rating questionnaires. Measurements of a distinct brain function associated with impulsive behavior are not available yet, however, electrophysiological parameters of cognitive response control elicited with the execution (Go-condition) and the inhibition (NoGo-condition) of a prepared motor response within the Continuous Performance Test (CPT) might be suitable candidates. By means of a spatial analysis method the centers of gravity (centroids) of the brain electrical fields evoked with Go- and NoGo-responses can be localized and quantified. In the present study, the Go- and NoGo-centroids and the impulsivity score in Eysenck's I 7-scale were determined in 22 healthy subjects (10 women, 12 men, mean age 42.0±10.1 years). Impulsivity was correlated with both, a more anterior location of the Go- ( r=0.58, P<0.01) and the NoGo-centroid ( r=0.53, P=0.01). These results indicate, that in healthy subjects the amount of I 7 -impulsivity is associated with differences in the prefrontal brain activation pattern during cognitive response control. However, a replication study with a larger sample and an investigation of psychiatric patients with pathological levels of impulsivity are necessary to qualify these topographical ERP-parameters of cognitive response control as valid measures of the brain electrical basis of impulsive behavior.

Clinical and Physiological Consequences of Rapid Tryptophan Depletion

We review here the rapid tryptophan depletion (RTD) methodology and its controversial association with depressive relapse. RTD has been used over the past decade to deplete serotonin (5-hydroxy-tryptamine, or 5-HT) in humans and to probe the role of the central serotonin system in a variety of psychiatric conditions. Its current popularity was stimulated by reports that RTD reversed the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) in remitted patients with a history of depression but not in patients treated with antidepressants which promote catecholaminergic rather than serotonergic neurotransmission (such as tricyclic antidepressants or buproprion). However, RTD has inconsistent effects in terms of full clinical relapse in depressed patients. Pooling the data from all published reports, patients who are either unmedicated and/or fully remitted are much less likely to experience relapse (7 of 61, or ∼9%) than patients who are recently medicated and partially remitted (63 of 133, or ∼47%; although, the numbers here may reflect patient overlap between reports). Recently remitted patients who have been treated with non-pharmacological therapies such as total sleep deprivation, electroconvulsive therapy, or bright light therapy also do not commonly show full clinical relapse with RTD. We briefly review RTD effects in other psychiatric disorders, many of which are treated with SSRIs. There is accumulating evidence to suggest that RTD affects central serotonergic neurotransmission. Nevertheless, many questions remain about the ability of RTD to reverse the beneficial effects of SSRIs or MAOIs, or to induce symptoms in unmedicated symptomatic or asymptomatic patients.

Identifying psychiatric patients with serotonergic dysfunctions by event-related potentials

Summary: The increasing knowledge concerning anatomical structures and cellular processes underlying event-related potentials (ERP) as well as methodological advances in ERP data analysis (e.g. dipole source analysis) is beginning to bridge the gap between ERP and neurochemkal aspects. Reliable indicators of the serotonin system are urgently needed because of its role in pathophysiology and as target of pharma-cotherapeutic interventions in psychiatric disorders. Converging arguments from preclinical and clinical studies support the hypothesis that the loudness dependence of the auditory evoked Nl/P2-response (LDAEP) is regulated by the level of central serotonergic neurotransmission. Dipole source analysis represents an important methodological advance in this context, because the two Nl/P2-subcomponents, generated by the primary and secondary auditory cortex known to be differentially innervated by serotonergic fibres, can be separated. A pronounced LDAEP of primary auditory cortices is supposed to reflect low central serotonergic neurotransmission, and vice versa. LDAEP is a parameter with potential clinical value since subgroups of patients with a serotonergic dysfunction can be identified and can be treated more specifically. In depressed patients, a significant relationship between strong LDAEP, indicating low serotonergic function, and a favourable response to SSRI has been found. Additionally, there is evidence from several studies with patients with affective disorders that a strong LDAEP predicts favourable response to a preventive lithium treatment.