Federico Mucci

Depression, Serotonin and Tryptophan.

Depression is a major cause of worldwide disability. Although its etiology is unclear, for over sixty years the study of its pathophysiology has focused mainly on serotonin (5-HT) and serotonergic neurotransmission. Generally, the study of the pathophysiological processes underpinning depression have led to the appreciation of its complexity, although such study continues to support the role of 5-HT in this disorder. The aim of this review is to briefly summarize the available findings on 5-HT and depression, with a special focus on alterations in tryptophan (TRP) metabolism that can shift from 5-HT synthesis towards other, potentially neurotoxic, compounds, such as the tryptophan catabolite, quinolinic acid. The evidence that the TRP shunt may be promoted by stress hormones and proinflammatory cytokines strongly supports the notion that depression should now be considered a systemic disorder that can be triggered by different factors that ultimately target the 5-HT system in vulnerable individuals. In addition, such intriguing findings suggest biochemical targets for novel treatment options in depression.

Anxiety, Stress-Related Factors, and Blood Pressure in Young Adults

Hypertension (HT) is a long-term medical condition characterized by persistently elevated blood pressure (BP) in the arterial vessels. Although HT initially is an asymptomatic condition, it chronically evolves into a major risk factor for cardiovascular, cerebrovascular, and renal diseases that, in turn, represent crucial causes of morbidity and mortality in industrialized countries. HT is a complex disorder that is estimated to affect more than a quarter of the world’s adult population. It is classified on the basis of both its pathophysiology (primary and secondary HT) and on the resting BP values (elevated systolic, diastolic, and pulse pressure). It originates from a complicated interaction of genes and several environmental risk factors including aging, smoking, lack of exercise, overweight and obesity, elevated salt intake, stress, depression, and anxiety. Anxiety and depressive disorders are the most commonly diagnosed mental disorders, affecting millions of people each year and impairing every aspect of everyday life, both of them characterized by affective, cognitive, psychomotor, and neurovegetative symptoms. Moreover, work-related stress has been considered as an important risk factor for HT and cardiovascular diseases (CVDs). Although different authors have investigated and suggested possible relations between HT, stress, anxiety, and depression during the last decades, a full understanding of the underlying pathophysiological mechanisms has not been satisfactorily achieved, especially in young adults. The aim of this study was to investigate the impact of anxiety and work-related stress in the development of HT amongst young health care profession students and the possible related consequences of early CVDs.

Current Trends on Antipsychotics: Focus on Asenapine.

Over the years, both first- (FGAs) and second-generation antipsychotics (SGAs), continue to gain increasing evidence of being effective in the treatment of psychotic symptoms. Currently, they represent the first-line treatment of schizophrenia and bipolar disorder, although they are widely used in psychotic depression and other clinical conditions, such as agitation and/or behavioural disturbances. Despite representing an indispensable tool for the treatment of severe psychotic disorders, they are widely known to have a number of unwanted side effects that the clinician must be aware of, and handle carefully to provide the patient the best available treatment in the short and long-term. However, even with respect to the long-term use of some of the most effective SGAs, it is imperative for clinicians not to overlook the risk linked to the onset of potentially severe metabolic side effects such as weight gain, dyslipidaemia, insulinresistance and type II diabetes. Asenapine is one of the newest SGAs licenced in Europe for the treatment of manic episodes and in the US for schizophrenia. It belongs to the same class of clozapine, olanzapine and quetiapine, sharing with them a rather complex pharmacological binding profile. In fact, asenapine shows a high affinity for the serotonin (5HT) receptor of the type 2A (5HT2A) and to a lesser extent for the dopamine receptor of the type 2 (D2), similar to other SGAs. Asenapine behaves also as an antagonist at the level of 5HT2C, H1 and α2-receptors. Asenapine has been reported to be effective either in monotherapy or in combination with mood stabilers (lithium and valproate) in the treatment of manic or mixed episodes, with a lower propensity to induce, or being followed by, depressive symptoms, when compared to other SGAs. These unique properties may explain the increasing interest towards the use of this drug in mixed states, besides schizophrenia and acute mania. The aim of this paper was at reviewing current data on pharmacological properties and clinical use of asenapine, as well as on possible future indication of this SGA.

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.

Nalmefene: A Novel Drug for an Old Disorder

Alcoholism is an increasing problem all over the world, and nowadays especially amongst teenagers. Although several drug treatments have been proposed for this condition, only a few have demonstrated a significant efficacy. Nalmefene, a novel compound that combines opioids mu-receptors antagonism and kappa-receptors partial agonism, was recently approved by the European Medicine Agency for the treatment of alcoholism. This drug can be very helpful in reducing the alcohol intake, and, as such, it can be considered one of the first and fundamental steps towards alcohol abstinence. The aim of this review is to discuss and comment on the available literature on nalmefene, as well as on novel treatment strategies of this condition (and perhaps of other addictions) opened by this latest pharmacological approach.

Obsessive-compulsive disorder with comorbid bipolar disorders: clinical features and treatment implications

BACKGROUND Obsessive-compulsive disorder (OCD) symptoms within the context of a bipolar disorder (BD) have been described since the 19th century. Interestingly, the existence of a relevant overlap between the aforementioned psychiatric syndromes has been confirmed by a number of recent epidemiological and family studies. AIMS The aim of the present paper is to review the clinical features and the therapeutic implications of the OCD-BD comorbidity. DISCUSSION In the last two decades, the frequent association between OCD and BD has been earning a growing interest given its relevant nosological and therapeutic implications. Usually patients suffering from OCD-BD comorbidity show a peculiar clinical course, characterized by a larger number of concomitant depressive episodes and episodic course. In these cases, the treatment with antidepressants is more likely to elicit hypomanic or manic switches, while mood stabilizers significantly improve the overall clinical picture. Moreover, OCD-BD patients are frequently comorbid with a number of other psychiatric disorders, in particular anxiety disorders, social phobia, and different substance abuses, such as alcohol, nicotine, caffeine and sedatives. CONCLUSIONS BD-OCD comorbidity needs further investigations in order to provide more solid evidences to give patients a more precise clinical diagnosis and a more targeted therapeutic approach.

A SYSTEMATIC EXPLORATION OF CLINICAL FEATURES AND TREATMENT OUTCOME OF OBSESSIVE-COMPULSIVE-BIPOLAR COMORBIDITY

Introduction Notwithstanding the emerging literature on co-morbidity between obsessive compulsive disorder (OCD) and bipolar disorder, relatively little systematic data exists on the clinical characteristics of this interface and its treatment. The aim of the present study is to address this challenge as it appears in a setting of routine clinical practice Methods The sample comprised 68 patients with comorbid DSM-IV diagnoses of OCD and Major Depression, admitted and treated at the day-hospital in the Department of Psychiatry at the University of Pisa during a 3-year period (January 1995 - December 1998). Thirty-eight (55.8%) patients showed lifetime comorbid bipolar disorder (BD) (12, 31.6% Bipolar I and 26, 68.4% Bipolar II). Diagnoses and clinical features were collected by means of structured (SCID) and semi-structured interviews (OCD-Interview). Assessment of drug treatments, clinical outcome and adverse effects were made prospectively as part of routine clinical care, throughout the course of their day-hospitalization Results In contrast with non-bipolar patients, OCD-bipolar patients showed a more episodic course with a greater number of concurrent major depressive episodes. They reported a significantly higher rate of sexual obsessions and significantly lower rate of ordering rituals. Furthermore, they reported more frequent current comorbidity with Panic Disorder-Agoraphobia and abuse of different substances (alcohol, sedatives, nicotine and coffee). Drug treatment with Clomipramine and, to a lesser extent, with SSRIs was associated with hypomanic switches in OCD bipolars, expecially in patients not concomitantly treated with mood stabilizers Discussion A combination of multiple mood stabilizers was necessary in 22 (57.9%) OCD-bipolars and combination with atypical antipsychotics was required in 4 (10.5%) cases. OCD-bipolars tended to show a less positive outcome for mood symptomatology and general functioning. Three patients required hospitalization for severe mixed episode. Conclusions In a tertiary care center, comorbidity between OCD and bipolar disorder is a significant clinical problem affecting a large number of patients, with a substantial impact on the clinical characteristics and treatment outcome of both disorders.

THE ROLE OF ADENYLATE-CYCLASE ACTIVITY IN PLATELETS OF PATIENTS WITH OBSESSIVE-COMPULSIVE DISORDER

Introduction Blood platelets can be considered a reliable peripheral model of presynaptic serotonergic neurons, as they are endowed with a 5-HT reuptake transporter similar to that present in the brain cells (Marazziti et al., 2004). The biological basis of the patophysiology of obsessive-compulsive disorder (OCD) is centered on serotonergic system, although evidences of both dopaminergic and adrenergic systems involvement are consistent (Westenberg et al., 2007). A possible role of second messengers, such as cyclic adenosine monophosphate (cAMP) signaling, in the development of OCD has been recently postulated, although evidences are meager and, in some cases, contradictory (McDougle et al., 1999). The aim of the present study was to explore and to compare the adenylate cyclase (AC) activity either in basal conditions, either after the stimulation by isoprenaline (ISO) in platelets of OCD patients and healthy control subjects. Also, AC activity was measured both in the absence and in the presence of α- and β- adrenoreceptor antagonists. Materials and methods Forty patients (20 men and 20 women, aged between 23 and 34 years; mean±SD: 26.5 ± 4.8) were included in the study. All of them met Diagnostic and Statistic Manual of Mental Disorders 5th edition (DSM-5) criteria for OCD, were not currently depressed, nor had any history of mood disorders or any other comorbid conditions. This group was compared to a similar one, composed by 40 healthy volunteers patients (20 men and 20 women, aged between 21 and 32 years; mean±SD: 24.6 ± 6.3), all of them without familiar or personal history of major psychiatric disorders. The severity of OC symptoms was evaluated by means of the Yale Brown Obsessive-Compulsive Scale (Y-BOCS). Thirty (30) ml of blood were collected from fasting subjects between 8.00-10.00 a.m. to avoid circadian rhythm interference. Results The platelet basal AC activity was similar in OCD patients and healthy subjects. The addition of 10 μM ISO enhanced significantly (p Discussion No difference in the basal AC activity in platelet membranes of healthy subjects and OCD patients was found. The addition of 10 µM ISO to platelet membranes provoked a significant stimulation of the enzyme activity of the same magnitude in the two groups. Our findings suggests that, at our experimental conditions, there is an inhibitory component of ISO effect on platelet AC, due to the agonist interaction with α2 receptors, at its higher concentrations (> 1 μM). These data suggest the presence of a condition of supersensitive β-receptors in platelets of OCD patients that, perhaps, could reflect (or provoke) alterations of the intracellular signaling system mediated by the cAMP and of the related kinases. In conclusion, the results of the present study suggest that abnormal second messenger pathways in OCD may be also related to cathecolamine system disturbances, which might open new therapeutic strategies especially in resistant patients who do not respond to serotonergic medications.

EFFECTIVENESS OF A CLOZAPINE–ARIPIPRAZOLE COMBINATION IN TOURETTE SYNDROME AND BIPOLAR SPECTRUM DISORDER

Introduction Antipsychotic combination is a common strategy used in both bipolar disorder and schizophrenia, although just a few trials are available exploring its effectiveness. We report herein the case of a patient suffering from severe Tourette syndrome (TS) and bipolar spectrum disorder who benefited from a combination of clozapine and aripiprazole. Case report “Mr. FS,”a 39-year-old art-craft worker, had been suffering from TS since his early childhood. During the adolescence, TS was character-ized by mouth opening and shoulder rotation, complex motor tics, such as trunk-bending or gyrating, screaming, and complex phonic tics. He was treated with pimozide 8 mg/day, which led to a complete remission of tics for about 20 years, although the clinical picture was complicated by the onset of mood shifts associated with impulsive behaviors and obsessions (numerical obsessions, rituals of order and symmetry, disproportionate aggressiveness). In 2007, when he was 35, he visited us for a major depressive episode with suicidal thoughts, panic attacks, and agoraphobic avoidance. Paroxetine (20 mg/day) led to a fast improvement of mood and anxiety symptoms, albeit being ineffective on tics. Only transient responses were obtained with the association of various drugs (haloperidol, risperidone, olanzapine, amisulpiride) to paroxetine and mood stabilizers (valproic acid, 600 mg/day). After about 2 years of different combinations, a significant improvement was obtained with tetrabenazine 75 mg/day1 clozapine 25mg/day1valproic acid 600 mg/day and fluvoxamine 150 mg/day. This strategy had a good impact only on the affective and obsessive symptoms, while tics remained stable. Therefore, tetra-benazine, fluvoxamine, and valproic acid were tapered down. At the same time, aripiprazole (15 mg/day) was introduced, and, after about 1month, we observed a dramatic improve-ment of TS symptoms. The improvement is still maintained at 2-year follow-up, so that currently the patient, who is regularly taking clozapine 25 mg/day and aripiprazole 15 mg/day with no significant side effects, shows a good affective balance, with no impulsive behavior, obsessions, or tics. Discussion Clozapine is considered a standard treatment for schizophrenia and bipolar disorder, whereas it has been reported to exacerbate obsessions and tics, although this topic is controversial. The effectiveness of aripiprazole in bipolar disorder is well documented, and preliminary data do exist for its possible use in obsessive-compulsive (OCD) and related disorders. Conclusions Our case report highlights the possible usefulness of combining clozapine and aripiprazole in TS comorbid with bipolar spectrum disorders, perhaps due to the different and not overlapping pharmacological profile of these two antipsychotics. Aripiprazole has much higher affinity for D2 receptors than clozapine and, since it behaves as a 5-HT2A antagonist and 5-HT2C partial agonist, may have a robust anti-obsessional (and perhaps anti-tic) activity. Further controlled studies are necessary to investigate the benefits of antipsychotic polypharmacy in patients suffering from both bipolar and OCD spectrum disorders.

THE ROLE OF GUILT SENSITIVITY IN OCD SYMPTOM DIMENSIONS

Introduction Although some studies have found that guilt may precede, motivate, or be a consequence of obsessive–compulsive disorder (OCD), the relationship between guilt and OCD has been under-investigated. Since it has been suggested that OCD patients perceive guilt in a more threatening manner, it might also be relevant to test to what extent they negatively evaluate the experience of guilt (i.e., guilt sensitivity; GS). Methods Study 1 investigated the psychometric properties of a new 10‐item Italian measure developed to assess GS—named Guilt Sensitivity Questionnaire—in a nonclinical sample (N= 473). Study 2 investigated the role of GS in OCD symptoms, in particular with regard to responsibility for harm obsessions and checking compulsions, using a heterogeneous OCD sample (N= 61) and a control group of patients with anxiety disorders (N= 47). Results Results from exploratory factor analyses supported the unidimensionality of the scale. It also showed excellent internal consistency and good discriminant validity. GS was the unique significant predictor of checking related OCD symptoms independent of negative mood states and obsessive beliefs. Discussion Guilt Sensitivity Questionnaire scores of patients with responsibility for harm concerns were significantly higher than those of patients with other kinds of obsessive concerns and with anxiety disorders. Conclusions Findings supported the hypothesis that GS plays a relevant role inOCD symptoms when checking rituals are primarily involved. Implications for current cognitive behavioral models are discussed.