Decreased lymphocyte dopamine transporter in romantic lovers.

OBJECTIVE: The role of dopamine (DA) in romantic love is suggested by different evidence and is supported by the findings of some brain imaging studies. The DA transporter (DAT) is a key structure in regulating the concentration of the neurotransmitter in the synaptic cleft. Given the presence of DAT in blood cells, the present study aimed to explore it in resting lymphocytes of 30 healthy subjects of both sexes in the early stage of romantic love (no longer than 6 months), as compared with 30 subjects involved in a long-lasting relationship. METHODS: All subjects had no physical or psychiatric illness. The DAT was measured by means of the [3H]-WIN 35,428 binding and the [3H]-DA reuptake to resting lymphocytes membranes. Romantic love was assessed by a specific questionnaire developed by us. RESULTS: The results showed that the subjects in the early phase of romantic love had a global alteration of the lymphocyte DAT involving both a decreased number of proteins (Bmax) and a reduced functionality (Vmax). CONCLUSIONS: Taken together, these findings would indicate the presence of increased levels of DA in romantic love that, if paralleled by similar concentrations in the brain, would explain some peculiar features of this human feeling.

Plasma Oxytocin Levels in Untreated Adult Obsessive-Compulsive Disorder Patients.

BACKGROUND AND AIM: Given the paucity of information on the possible role of oxytocin (OT) in the pathophysiology of obsessive-compulsive disorder (OCD), our study aimed at evaluating plasma OT levels in a group of 44 OCD outpatients, as compared with a similar group of healthy control subjects. At the same time, the relationships between OT and clinical features and romantic attachment characteristics were examined as well. METHODS: Diagnosis was assessed according to DSM-IV-TR criteria, while the OCD severity was measured by means of the Y-BOCS rating scale. All patients were drug free and not depressed. The romantic attachment was assessed by means of the Italian version of the 'Experiences in Close Relationships' questionnaire. Plasma OT levels were evaluated by means of a standard RIA kit. RESULTS: The main findings of our study showed that OT levels were increased in OCD patients, as compared with healthy subjects, and negatively related to symptom severity. Positive relationships were detected between OT levels and the fearful-avoidant and dismissing styles of romantic attachments, but only in male OCD patients. CONCLUSION: Taken together, these findings suggest that OT may play a role in OCD pathophysiology and also in the romantic attachment of patients with gender specificity.

Plasma amyloid-ß levels in drug-resistant bipolar depressed patients receiving electroconvulsive therapy.

AIMS: Alterations of plasma amyloid-ß (Aß) peptides have been related to a high risk for cognitive impairment and dementia. The present study aimed to measure plasma Aß peptides (Aß40, Aß42) and the Aß40/Aß42 ratio in a sample of drug-resistant bipolar depressed patients, as well as to explore the possible correlation between biological parameters and clinical changes along an electroconvulsive therapy (ECT) course. METHODS: Aß40 and Aß42 were measured by means of an ELISA assay in 25 drug-resistant bipolar depressed patients before (T0) and 1 week after (T1) the end of ECT. The patients were clinically evaluated by means of the Hamilton Rating Scale for Depression, 21-item (HRSD-21), the Mini-Mental State Examination, and the Clinical Global Impressions-Severity of Illness Scale. RESULTS: Plasma Aß levels and the Aß40/Aß42 ratio were similar at T0 and T1. The Aß40/Aß42 ratio correlated positively with the HRSD total score at both T0 and T1. At T0, a negative correlation was found between the Aß40/Aß42 ratio and the improvement of depressive and cognitive symptoms. Moreover, remitters (n = 9; HRSD ≤10) showed a significantly lower Aß40/Aß42 ratio at T0 than nonremitters. CONCLUSION: The present data suggest that a low Aß40/Aß42 ratio might characterize a subgroup of depressed patients who respond to ECT, while higher values of this parameter seem to be typical of more severe cases of patients with cognitive impairment.

Glutamate system as target for development of novel antidepressants.

Depression is a common psychiatric condition characterized by affective, cognitive, psychomotor, and neurovegetative symptoms that interfere with a person's ability to work, study, deal with interpersonal relationships, and enjoy once-pleasurable activities. After the serendipitous discovery of the first antidepressants, for years the only pharmacodynamic mechanisms explored in the search of novel antidepressants were those related to the 3 main monoamines: serotonin, norepinephrine, and dopamine. New-generation monoaminergic antidepressants, such as selective-serotonin and dual-acting serotonin/norepinephrine reuptake inhibitors, improved treatment and quality of life of depressed patients. Nevertheless, there are still important clinical limitations: the long latency of onset of the antidepressant action; side effects, which can lead to early discontinuation; low rate of response; and high rate of relapse/recurrence. Therefore, in the last several years, the focus of research has moved from monoamines toward other molecular mechanisms, including glutamatergic (Glu) neurotransmission. This review provides a comprehensive overview of the current knowledge on the Glu system and on its relationships with mood disorders. Up to now, N-methyl-D-aspartate (NMDA) receptor antagonists, in particular ketamine, provided the most promising results in preclinical studies and produced a consistent and rapid, although transient, antidepressant effect with a good tolerability profile in humans. Although data are encouraging, more double-blind, randomized, placebo-controlled trials are needed to clarify the real potentiality of ketamine, and of the other Glu modulators, in the treatment of unipolar and bipolar depression.

Distribution of serotonin receptor of type 6 (5-HT6) in human brain post-mortem. A pharmacology, autoradiography and immunohistochemistry study.

The aim of this study was to investigate the distribution of serotonin (5-HT) receptors of type 6 (5-HT(6)) in postmortem human prefrontal cortex, striatum and hippocampus. The brain samples were obtained from 6 subjects who had died for causes not involving primarily or secondarily the CNS. The 5-HT(6) receptor distribution was explored by the [(125)I]SB-258585 binding to brain membranes followed by the pharmacological characterization, where possible, and by autoradiographic, immunohistochemical and immunofluorescence evaluations. A specific and saturable [(125)I]SB-258585 binding was detected in striatum only, with a pharmacological characterization consistent with that of a 5-HT(6) receptor. The autoradiography showed the presence of a specific [(125)I]SB-258585 binding distributed homogeneously in caudate, putamen and accumbens. The immunohistochemistry, carried out in the striatum only, coupled with the immunofluorescence with glial fibrillary acidic protein (GFAP) and parvalbumin (PV) showed the co-localization of 5-HT(6) receptor with PV, while indicating that this receptor subtype was expressed in neurons and not in astrocytes. Taken together, the present findings showed the presence of a higher density of 5-HT(6) receptors, as labeled by [(125)I]SB-258585, in striatum than in hippocampus and prefrontal cortex, and specifically within the neuronal body. In addition, they would suggest that striatum is one of the major potential CNS targets linked to 5-HT(6) receptor modulation.

The safety of escitalopram during pregnancy and breastfeeding: a comprehensive review.

OBJECTIVE: Escitalopram (ESC) is considered one of the most effective selective serotonin reuptake inhibitors for the treatment of major depression. However, little is known on its potential risk of inducing major malformations (MMs) and perinatal complications (PCs). Hence, aim of the present study is to provide a comprehensive review of the available literature on the safety profile of ESC during pregnancy and breastfeeding. METHODS: MEDLINE and PubMed databases were searched for English language articles by using the following keywords: escitalopram, selective serotonin reuptake inhibitors, major malformations, perinatal complications, pregnancy, and breastfeeding. RESULTS: Although some cases of MMs have been reported after maternal exposure to ESC during early pregnancy, the rate of these adverse events is substantially in the range of those reported in unexposed women. On the contrary, exposure to ESC seems to be significantly associated with some PCs. No adverse effects have been reported in the few studies evaluating its safety during breastfeeding. CONCLUSIONS: The available data seem to support the notion that ESC might be considered safe during pregnancy, in particular as far as MMs is concerned. However, similar to other selective serotonin reuptake inhibitors, it could be associated with an increased risk of PCs. Given the paucity of the studies published so far, no definitive conclusions can be drawn on its safety profile during breastfeeding.

Plasma fluvoxamine levels and OCD symptoms/response in adult patients.

OBJECTIVE: In this study, we explored the possible relationships between plasma fluvoxamine levels and clinical features and/or response in adult obsessive-compulsive disorder (OCD) patients treated with this drug for 6 months. METHODS: Twenty OCD outpatients of both sexes who were already taking fluvoxamine (mean dose ± SD: 216.7 ± 86.2) for at least 4 weeks were included in the study. The severity of OCD was assessed by means of the Yale-Brown obsessive-compulsive scale (Y-BOCS). The fluvoxamine plasma levels were measured by high-performance liquid chromatography analysis. All evaluations were performed after 4 weeks (t1) and 6 months (t2) of fluvoxamine intake. RESULTS: The plasma levels of fluvoxamine remained stable at the two assessment times, with no sex-related differences. Sixteen (80%) patients responded to treatment as shown by the significant (>35%) decrease of the Y-BOCS total score. Men's compulsions improved more than those of women. Significant and positive correlations were detected between fluvoxamine plasma levels at t1 and t2 and the difference (delta) of the Y-BOCS total and compulsion subscale scores between t1 and t2. Another significant, albeit negative, correlation was measured between the difference of the compulsion subscale score and the difference of fluvoxamine levels at t1 and t2. CONCLUSIONS: These findings underline the potential importance of evaluating fluvoxamine plasma levels in OCD and their relationships with the clinical response that may be gender-related on specific symptoms.

Receptor crosstalk: haloperidol treatment enhances A(2A) adenosine receptor functioning in a transfected cell model.

UNLABELLED: A(2A) adenosine receptors are considered an excellent target for drug development in several neurological and psychiatric disorders. It is noteworthy that the responses evoked by A(2A) adenosine receptors are regulated by D(2) dopamine receptor ligands. These two receptors are co-expressed at the level of the basal ganglia and interact to form functional heterodimers. In this context, possible changes in A(2A) adenosine receptor functional responses caused by the chronic blockade/activation of D(2) dopamine receptors should be considered to optimise the therapeutic effectiveness of dopaminergic agents and to reduce any possible side effects. In the present paper, we investigated the regulation of A(2A) adenosine receptors induced by antipsychotic drugs, commonly acting as D(2) dopamine receptor antagonists, in a cellular model co-expressing both A(2A) and D(2) receptors. Our data suggest that the treatment of cells with the classical antipsychotic haloperidol increased both the affinity and responsiveness of the A(2A) receptor and also affected the degree of A(2A)-D(2) receptor heterodimerisation. In contrast, an atypical antipsychotic, clozapine, had no effect on A(2A) adenosine receptor parameters, suggesting that the two classes of drugs have different effects on adenosine-dopamine receptor interaction. Modifications to A(2A) adenosine receptors may play a significant role in determining cerebral adenosine effects during the chronic administration of antipsychotics in psychiatric diseases and may account for the efficacy of A(2A) adenosine receptor ligands in pathologies associated with dopaminergic system dysfunction. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11302-010-9201-z) contains supplementary material, which is available to authorized users.

Associations between brain-derived neurotrophic factor plasma levels and severity of the illness, recurrence and symptoms in depressed patients.

BACKGROUND: There is increasing evidence that the brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of mood disorders and that its peripheral levels represent a reliable mirror of its concentration in the brain. The aim of the present study was to measure BDNF plasma levels in patients affected by major depression and to explore the possible relationship between the biological parameter and characteristics of the illness. METHOD: BDNF plasma levels were evaluated in 30 inpatients suffering from major depression, according to DSM-IV criteria, by means of a commonly employed ELISA method. The clinical characteristics were assessed by the Hamilton Rating Scale for Depression (HRSD) and the Clinical Global Impression Scale. RESULTS: BDNF plasma levels were significantly lower in the patients with the severest illness compared with the others, and the same was true for patients with dissociative symptoms, severe sleep disturbance and recurrent depression. A significant and negative correlation was observed between the biological parameter and the retardation factor score of the HRSD. CONCLUSION: These findings suggest that low BDNF levels are related to both recurrence and severity of depression, as well as to symptoms typical of dysfunctions of the hypothalamic-pituitary-adrenal axis.

Alterations of the dopamine transporter in resting lymphocytes of patients with different psychotic disorders.

The aim of our study was to investigate and compare the dopamine (DA) transporter (DAT) in resting lymphocytes of 20 psychotic patients and 20 healthy control subjects, by means of both the binding parameters (Bmax and Kd) of 3H-WIN 35,428, and the reuptake parameters (Vmax and Km) of 3H-DA. The results showed that both the Bmax of 3H-WIN 35,428 binding and the Vmax of 3H-DA reuptake of the patients were significantly lower than those of healthy subjects, while the Kd or Km did not show any change. These findings, while indicating a reduced density of the lymphocyte DAT proteins, provide further support of the role of DA in psychoses and suggest that DA alterations may not be limited to brain structures.

Heterogeneity of the jealousy phenomenon in the general population: an Italian study.

INTRODUCTION: Despite the general agreement that normal jealousy is heterogenous, little is known about this specific topic. METHODS: In the present study, we explored the possibility of distinguishing between four subtypes of "normal" jealousy (depressive, anxious, obsessive, and paranoid) amongst a cohort of 500 healthy university students by means of a specifically designed questionnaire, "Ouestionario della gelosia" (QUEGE). QUEGE is a self-report instrument of 30 items which explores the presence, frequency, and duration of feelings and behaviors related to jealousy. It was devised to investigate four hypothetical psychopathological profiles: depressive, paranoid, obsessive, and anxious. RESULTS: The factor analysis identified five rather than four clear-cut factors: self-esteem, paranoia, interpersonal Sensitivity, fear of being abandoned, and obsessionality. Women showed statistically significant lower levels of self-esteem and higher levels of obsessionality than men. Younger age (<25 years) was associated with lower self-esteem and higher levels of paranoia and obsessionality, while being single was associated with lower self-esteem and higher levels of obsessionality. CONCLUSION: The present study provides evidence of the reliability and validity of the QUEGE instrument, which seems to identify the presence of five psychopathological dimensions within the jealousy phenomenon in the general population.

Romantic attachment and subtypes/dimensions of jealousy.

The present study explored the possible relationship between romantic attachment and jealousy in 100 healthy subjects. The romantic attachment and jealousy were evaluated by means of, respectively, the "Experiences in Close Relationships" questionnaire (ECR), and the "Questionario della Gelosia" (QUEGE). The ECR anxiety scale was related to all QUEGE dimensions, while the ECR avoidance scale to three. Individuals with the preoccupied attachment style showed higher scores than secure subjects on the obsessionality, interpersonal sensitivity and fear of loss dimensions. Fearful-avoidant individuals had higher score than secure subjects on the fear of loss dimension only, while dismissing individuals had lower scores on the self-esteem dimension.These findings suggest that romantic attachment and jealousy are intertwined.

Decreased density of the platelet serotonin transporter in pathological gamblers.

BACKGROUND/AIMS: The aim of this study was to investigate the serotonin transporter (SERT), by means of the 3H-paroxetine ([3H]-Par) binding to platelet membranes, in patients affected by pathological gambling (PG), as compared with a similar group of healthy control subjects. METHODS: Seventeen PG patients were selected amongst those who were drug-free and at the first psychiatric interview in a Department of Addiction. The diagnosis was assessed according to DSM-IV criteria and PG severity was measured by means of the South Oaks Gambling Screen. The platelet [3H]-Par binding was carried out according to a standardized method. The binding parameters, the maximum binding capacity (B(max)) and the dissociation constant (K(d)), were obtained by means of the Scatchard analysis. RESULTS: The B(max) values of PG patients were significantly lower than that of healthy subjects, while the K(d) values were not different in the two groups. No significant effect of age, sex or psychiatric comorbidity on B(max) or K(d) was observed; there were also no correlations between clinical and biological variables. CONCLUSIONS: PG patients showed a dysfunction at the level of the platelet SERT that would suggest the involvement of the 5-HT system in this condition.

Effectiveness of long-term augmentation with citalopram to clomipramine in treatment-resistant OCD patients.

INTRODUCTION: The high percentage (between 40% and 60%) of resistance to first-line drugs, such as clomipramine or selective serotonin reuptake inhibitors, is a major problem in the pharmacologic management of obsessive-compulsive disorder (OCD). In these cases, different strategies have been employed with controversial outcomes. The meager information available on the association of two serotonergic drugs prompted us to explore the possible effectiveness and tolerability of citalopram+clomipramine in resistant OCD patients. METHODS: Twenty outpatients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of OCD, who had failed to respond to at least two trials with a selective serotonin reuptake inhibitor and were currently taking clomipramine at different doses, were administered citalopram at a maximum dose of 60 mg/day. The clinical assessment was carried out at baseline (t0) and at the 4th (t1), 12th (t2), 24th (t3), 36th (t4), and 48th (t5) week by means of the Yale-Brown Obsessive Compulsive Scale, Hamilton Rating Scale for Depression, Clinical Global Impression scale, and the Dosage Record and Treatment Emergent Symptom Scale. The response was defined as a 35% decrease of the Yale-Brown Obsessive-Compulsive Scale total score. RESULTS: The results showed that approximately 50% of the patients improved significantly after 1 month of this regimen and after 1 year of treatment. CONCLUSION: This study, although carried out in a small sample and in an open fashion, represents one of the few experiences with the association of two serotonergic compounds in resistant OCD and confirms its potential usefulness and good tolerability profile. Controlled research on this association in OCD is recommended.

Executive function abnormalities in pathological gamblers.

BACKGROUND: Pathological gambling (PG) is an impulse control disorder characterized by persistent and maladaptive gambling behaviors with disruptive consequences for familial, occupational and social functions. The pathophysiology of PG is still unclear, but it is hypothesized that it might include environmental factors coupled with a genetic vulnerability and dysfunctions of different neurotransmitters and selected brain areas. Our study aimed to evaluate a group of patients suffering from PG by means of some neuropsychological tests in order to explore the brain areas related to the disorder. METHODS: Twenty outpatients (15 men, 5 women), with a diagnosis of PG according to DSM-IV criteria, were included in the study and evaluated with a battery of neuropsychological tests: the Wisconsin Card Sorting Test (WCST), the Wechsler Memory Scale revised (WMS-R) and the Verbal Associative Fluency Test (FAS). The results obtained in the patients were compared with normative values of matched healthy control subjects. RESULTS: The PG patients showed alterations at the WCST only, in particular they had a great difficulty in finding alternative methods of problem-solving and showed a decrease, rather than an increase, in efficiency, as they progressed through the consecutive phases of the test. The mean scores of the other tests were within the normal range. CONCLUSION: Our findings showed that patients affected by PG, in spite of normal intellectual, linguistic and visual-spatial abilities, had abnormalities emerging from the WCST, in particular they could not learn from their mistakes and look for alternative solutions. Our results would seem to confirm an altered functioning of the prefrontal areas which might provoke a sort of cognitive "rigidity" that might predispose to the development of impulsive and/or compulsive behaviors, such as those typical of PG.

Thermal balneotherapy induces changes of the platelet serotonin transporter in healthy subjects.

Although the beneficial effects of balneotherapy have been recognized since a long time, a few information is available on the biological mechanisms underlying them and the subjective feelings of increased well-being and mood. The links between the serotonin (5-HT) system and mood prompted us to investigate the 5-HT platelet transporter (SERT), which is considered a reliable, peripheral marker of the same structure present in presynaptic neurons, in 20 healthy volunteers before (t0) and 30 min after (t1) thermal balneotherapy with ozonized water of Montecatini spa, as compared with a similar group who underwent a bath in non-mineral water. The SERT was evaluated by means of the specific binding of (3)H-paroxetine ((3)H-Par) to platelet membranes. Equilibrium-saturation binding data, the maximal binding capacity (Bmax) and the dissociation constant (Kd), were obtained by means of the Scatchard analysis. The results showed that, while Bmax values did not change in both groups, the Kd values decreased significantly at t1 only in those subjects who bathed in ozonized water. The results of this study, while showing a decrease of the dissociation constant (Kd) which is the inverse of affinity constant, of (3)H-Par binding to SERT in all subjects after balneotherapy and not in those bathing in normal water, suggest that SERT modifications may be related to a specific effect of ozonized water and, perhaps, also to the increased sense of well-being.

Newer antipsychotics and the rabbit syndrome.

BACKGROUND: Rabbit syndrome is a movement disorder that is associated with long-term exposure to neuroleptic medications. Of particular interest and importance is the risk of rabbit syndrome with exposure to the newer atypical antipsychotics. Our recent experience with such a case brought to light the importance of exploring this risk. METHODS: MEDLINE and PubMed (1972-2006) databases were searched for English language articles using the keywords rabbit syndrome, tardive dyskinesia, antipsychotic, extrapyramidal symptoms and side effects. A recent case study is used to expand upon the literature available on newer antipsychotics and rabbit syndrome. RESULTS: We reviewed papers that addressed the following aspects of rabbit syndrome 1) the clinical manifestations 2) prevalence and risk factors, 3) etiopathogenesis 4) older antipsychotics and rabbit syndrome 5) newer antipsychotics, 6) treatment options. Moreover, we report a case of RS in a 50 year old white female, diagnosed with bipolar I disorder, that, after the discontinuation of risperidone, developed involuntary movements of the mouth that were fine, rhythmic and rapid, along the vertical axis, and without involvement of the tongue. After the re-introduction of risperidone, the symptoms decreased in a few hours and disappeared after 3 days. CONCLUSION: Eleven cases of rabbit syndrome have been documented since the implementation of newer antipsychotics. Future research is needed to better understand the etiopathogenesis of rabbit syndrome in psychiatric populations treated with the atypical antipsychotics. Understanding the differences and similarities of rabbit syndrome and tardive dyskinesia is crucial to the creation of a successful treatment paradigm.

Pathological gambling and impulsivity: an Italian study.

AIM: Although the precise nature of pathological gambling (PG) is still elusive, currently it is considered an impulse-control disorder that shares several features with substance dependence, such as deficit in self-regulation and impaired impulsivity. The aim of this study was to evaluate the impulsivity of PG patients by means of the Barratt Impulsivity Scale, version 11 (BIS-11), as compared with healthy control subjects, and to explore the possible correlations with gambling severity. METHODS: Thirty-five outpatients (all men) with a diagnosis of PG were recruited at their first psychiatric interview in a psychiatric outpatient ward, and compared with a similar group of healthy control subjects. The severity of PG was assessed by means of the South Oaks Gambling Screen (SOGS). RESULTS: The results showed that the BIS-11 total score, as well as the scores of different factors (motor impulsity and cognitive complexity) and subscales (motor and non-planning impulsivity) were significantly higher in PG patients than in control subjects. In addition, positive correlations were detected between the SOGS and the BIS-11 total scores, and the attention and cognitive instability factor scores, or the attentional and motor impulsivity (rs=0.459, p=.021) subscale scores. CONCLUSIONS: These findings support the notion that impulsivity represents a core element of PG linked to the severity of the clinical picture.

Clozapine effects on adenylyl cyclase activity and serotonin type 1A receptors in human brain post-mortem.

Although the pharmacological profile of the atypical antipsychotic clozapine has been extensively studied in animal models, little information is available on its effects in the human brain. In particular, much interest is focused on the understanding of clozapine activity on serotonin (5-HT) neurotransmission, particularly on 5-HT receptor of type 1A (5-HT(1A)) that seems to play a pivotal role in the control of the 5-HT system. The present work, therefore, aimed at evaluating the effects of clozapine and its major metabolite, norclozapine, on the modulation of adenylyl cyclase (AC) velocity via 5-HT(1A) receptors in human post-mortem brain regions, in particular the prefrontal cortex, hippocampus and raphe nuclei. Concomitantly, the ability of the two compounds to displace the specific binding of the 5-HT(1A) receptor agonist [³H]-8-hydroxy-(2-di-N-propylamino) tetralin ([³H]-8-OH-DPAT) was evaluated in the same brain areas. The results showed that both clozapine and norclozapine, although with a 20-fold lower affinity, displaced [³H]8-OH-DPAT binding in all of the brain regions analysed, suggesting their interaction with 5-HT(1A) receptors. At the same time, clozapine and, to a lesser extent, norclozapine were found to inhibit the forskolin (FK)-stimulated AC system, while decreasing cyclic adenosine monophosphate (cAMP) concentrations in the hippocampus only. The receptor characterisation of the clozapine effect on AC observed in the hippocampus by the use of antagonists showed a mixed profile, involving not only the 5-HT(1A) receptor but also a muscarinic (M) receptor subtype, most likely the M4 one. These findings, while considering all the limitations due to the use of post-mortem tissues, are strongly suggestive of a region-dependent pharmacological action of clozapine in the human brain that may explain its peculiar clinical effects and open up research towards novel targets for future antipsychotic drugs.

Inflammation, serotonin and major depression.

The understanding of the neurobiological processes leading to major depressive disorder (MDD) is an active field of research in the scientific community. For years, the alteration of monoamine neurotransmission, in particular serotonin (5-HT), has been considered the most significant pathophysiological mechanism of the disorder. However, biological data supporting the postulated MDD-related monoamine alterations have been inconclusive, and the use of monoaminergic antidepressants has not yielded the expected results. In the last few years, it has been demonstrated that inflammatory pathways have a significant role in the pathophysiology of MDD. According to the cytokine hypothesis, the disorder would be due to a stress-related increased production of cytokines, including interleukins, tumor necrosis factor- α and interferon- α and γ . These, in turns, would cause the activation of the indoleamine 2,3 dioxygenase (IDO), with subsequent production of tryptophan (TRP) catabolites along the IDO pathway (TRYCATs) and decreased availability of TRP and 5-HT. Besides monoamines, other molecular mechanisms, as those within the inflammatory pathways, should be taken into account in the attempt to clarify the pathophysiology of MDD and to improve its treatment.