G. Consoli

Cognitive impairment in major depression

In the past decade, a growing bulk of evidence has accumulated to suggest that patients suffering from major depression (MD) present some cognitive disturbances, such as impairment in attention, working memory, and executive function, including cognitive inhibition, problem- and task-planning. If the results of short-term memory assessment in depressed patients are equivocal, a general consensus exists that memory problems are secondary to attentional dysfunctions, and reflect the inability to concentrate. Moreover, both unipolar and bipolar patients show evidence of impaired verbal learning that has been commonly interpreted as reflecting an inability to transfer information from short-term to long-term storage. According to some authors, there would be a gender-related as well age-related specificity of some disturbances. Depressed patients also show impairments of executive functions and their recent exploration through brain imaging techniques has recently permitted to formulate some general hypotheses on the possible involvement of different brain areas in MD.

Inflammatory and Neurodegenerative Pathways in Depression: A New Avenue for Antidepressant Development?

The latest advancement in neurobiological research provided an increasing evidence that inflammatory and neurodegenerative pathways play a relevant role in depression. Preclinical and clinical studies on depression highlighted an increased production of inflammatory markers, such as interleukin (IL)-1, IL-6, tumor necrosis factor-α and interferon- α and γ. On the other hand, acute and chronic administration of cytokines or cytokine inducers were found to trigger depressive symptoms. According to the cytokine hypothesis, depression would be due to a stress-related increased production of pro-inflammatory cytokines that, in turn, would lead to increased oxidative and nitrosative brain damage and to indoleamine 2,3 dioxygenase (IDO) induction, with production of tryptophan (TRP) catabolites along the IDO pathway (TRYCATs) and consequent reduced availability of TRP and serotonin (5-HT). Cytokines would also play a role in the onset of the glucocorticoid resistance, underlying the overdrive of the hypothalamic-pituitary-adrenal axis. Therefore, the activation of the inflammatory and neurodegenerative pathways would lead to the brain damage observed in depression through both reduced neurogenesis and increased neurodegeneration. Besides the 5-HT system, other targets, possibly within the I&ND pathways, should be considered for the future treatment of depression: cytokines and their receptors, intracellular inflammatory mediators, IDO, TRYCATs, glucocorticoid receptors, neurotrophic factors may all represent possible therapeutic targets for novel antidepressants. In addition, it should be also clarified the role of the existing anti-inflammatory drugs in the treatment of depression, and those compounds with the anti-inflammatory and anti-oxidative properties should be examined either as monotherapy or adjunctive therapy. In conclusion, the molecular inflammatory and neurodegenerative pathways might provide new targets for antidepressant development and might be crucial to establish a rational treatment of depression aimed, hopefully, to its causal factors.

Association between thyroid autoimmunity and fibromyalgic disease severity

Our objectives were to investigate thyroid abnormalities and autoimmunity in 120 patients affected by fibromyalgia (FM) and to study their relationships with clinical data and symptoms. Thyroid assessment by means of antithyroglobulin antibodies, antithyroid peroxidase antibodies, free triiodo–thyronine, free thyroxine, and thyroid stimulating hormone analyses was carried out. The clinical parameters “Fibromyalgia Impact Questionnaire”, pain, tender points, fatigue, and other symptoms, and the presence of depression or anxiety disorders were evaluated. The basal thyroid hormone levels of FM patients were in the normal range, while 41% of the patients had at least one thyroid antibody. Patients with thyroid autoimmunity showed a higher percentage of dry eyes, burning, or pain with urination, allodynia, blurred vision, and sore throat. Correlations found between thyroid autoimmunity and age or with the presence of depression or anxiety disorders were not significant. However, in the cohort of post-menopausal patients, the frequency of thyroid autoimmunity was higher with respect to pre-menopausal patients. In conclusion, autoimmune thyroiditis is present in an elevated percentage of FM patients, and it has been associated with the presence of typical symptoms of the disease.

The impact of mood, anxiety, and sleep disorders on fibromyalgia

INTRODUCTION Several studies carried out mainly in North America revealed high rates of mood, anxiety and sleep disorders in patients with fibromyalgia (FM), while the information in other countries is scant. Therefore, we aimed at investigating the prevalence and the impact of such conditions on the health-related quality of life (HRQoL) and the severity of pain in a sample of Italian FM patients. METHODS One-hundred and sixty-seven women suffering from primary FM were consecutively enrolled. Psychiatric diagnoses were made by means of DSM-IV criteria. The HRQoL and the severity of pain were measured through the Medical Outcomes Study 36-item Short-Form Health Survey (MOS-SF-36) and the FM Impact Questionnaire (FIQ). RESULTS Fibromyalgia patients showed a high rate (80.8%) of lifetime and/or current comorbidity with mood and anxiety disorders. Patients with psychiatric comorbidity resulted significantly more impaired on the Mental Component Summary score of the MOS-SF-36 and showed a higher FIQ total score than those suffering from FM only. The severity of pain was associated with current psychiatric comorbidity. Patients with current mood disorders showed significantly lower Mental and Physical Component Summary scores of the MOS-SF-36 and higher FIQ total scores than those with current anxiety disorders or those without psychiatric comorbidity. Finally, patients with sleep disorders reported a lower HRQoL than those with a normal sleep, and specifically those with difficulty in falling in sleep had higher severity of pain. CONCLUSION Psychiatric comorbidity, in particular with mood disorders, provokes a significant impairment of the HRQoL and, when current, a higher severity of pain in FM patients.

Comorbidity with axis I anxiety disorders in remitted psychotic patients 1 year after hospitalization

INTRODUCTION Comorbid anxiety disorders are frequently encountered in psychoses and mainly assessed during the hospitalization. METHODS Comorbidity was investigated in 98 patients with schizophrenia, schizoaffective, or bipolar disorder, previously hospitalized for psychotic symptoms. Assessments, including Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Brief Psychiatric Rating Scale, and Clinical Global Impressions Scale, were performed during hospitalization (t0) and subsequently in a phase of remission (t1). Comorbidity was assessed at t1 only. RESULTS One or more comorbid anxiety diagnoses were made in 46 (46.9%) patients. Of these, 15 (32.6%) received multiple anxiety diagnoses, while 31 (67.4%) single anxiety diagnoses. Schizophrenic patients had a rate of social anxiety disorder (SAD) higher (P<.05) than the others. Patients assessed with panic disorder or with obsessive-compulsive disorder at t1 showed significantly greater severity of illness at t0; patients with SAD demonstrated greater severity at t1. No significant differences in the rates of individual anxiety disorders were found in patients treated with typical or atypical antipsychotics or with both. CONCLUSION Anxiety disorders, particularly obsessive-compulsive disorder, panic disorder and SAD, seem to be frequently comorbid in remitted psychotic patients; SAD would be more prevalent in schizophrenia and might negatively impact the course of the illness.

ABCB1 polymorphisms are associated with clozapine plasma levels in psychotic patients.

AIMS ABCB1 is a transmembrane transporter that is expressed in excretory organs (kidneys and liver), in intestine mucosa and on the blood-brain barrier. Because of the particular distribution of the protein, the activity of ABCB1 may significantly affect drug pharmacokinetics during absorption and distribution. Of note, several SNPs of ABCB1 are known and many of them affect transporter activity and/or expression. In this view, changes in the pharmacokinetics of drugs that are ABCB1 substrates could be clinically relevant and the evaluation of ABCB1 SNPs should deserve particular attention. Therefore, the aim of the present study was to investigate the possible association between ABCB1 polymorphisms and clozapine plasma levels in psychotic patients. MATERIALS & METHODS c.1236C>T (exon 12), c.2677G>T (exon 21) and c.3435C>T (exon 26) SNPs of ABCB1 were evaluated by PCR techniques, while plasma levels of clozapine and norclozapine were measured by HPLC in 40 men (aged, 47.6 +/- 16.6 years, median: 42 years) and 20 women (aged 40.7 +/- 11.4 years, median: 38 years) 1 month after the start of clozapine administration. RESULTS A total of three SNPs were in Hardy-Weinberg equilibrium, with a calculated frequency of the wild-type alleles of 0.54, 0.55 and 0.45 for SNPs on exons 12, 21 and 26, respectively. Patients with c.3435CC or c.2677GG genotypes had significantly lower dose-normalized clozapine levels than those who were heterozygous or TT carriers. More interestingly, c.3435CC patients (15 subjects) needed significantly higher daily doses of clozapine (246 +/- 142 mg/day) compared with the remaining 24 CT and 21 TT patients (140 +/- 90 mg/day) in order to achieve the same clinical benefit. CONCLUSION c.3435CC patients require higher clozapine doses to achieve the same plasma concentrations as CT or TT patients, and ABCB1 genotyping should be considered as a novel strategy that should improve drug use.

Latest advancements on serotonin and dopamine transporters in lymphocytes.

Different data show that circulating lymphocytes possess functional serotonin and dopamine transporters (SERT and DAT, respectively). This papers aims to review most of the available literature on this topic, while highlighting the possible role of SERT and DAT, as well as that of their substrates including antidepressants on the immune system.

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.

Childhood traumata, Dexamethasone Suppression Test and psychiatric symptoms: a trans-diagnostic approach.

BACKGROUND Childhood traumatic events and functional abnormalities of the hypothalamus-pituitary-adrenal (HPA) axis have been widely reported in psychiatric patients, although neither is specific for any diagnosis. Among the limited number of studies that have evaluated these topics, none has adopted a trans-diagnostic approach. The aim of the present research is to explore the relationship between childhood stressors, HPA axis function and psychiatric symptoms, independent of the diagnosis. METHOD A total of 93 moderate to severely ill psychiatric out-patients of Florence and Pisa University Psychiatric Units and 33 healthy control subjects were recruited. The assessment consisted of salivary cortisol pre- and post-low dose (0.5 mg) Dexamethasone, early and recent life events, 121 psychiatric symptoms independent of diagnosis, SCID, BPRS. RESULTS In total, 33.5% of patients were Dexamethasone Suppression Test (DST) non-suppressors, compared with 6.1% of controls (p=0.001). Among patients, non-suppression was associated with particular symptoms (i.e. depressive and psychotic), but not to any specific diagnosis. Early stressful life events were significantly associated with higher salivary cortisol levels, with DST non-suppression and with approximately the same subset of symptoms. A recent stressful event seemed to be associated to the HPA response only in those subjects who were exposed to early traumata. CONCLUSIONS Our report suggests a relationship between life stress, HPA axis and psychopathology. A cluster of specific psychiatric symptoms seems to be stress related. Moreover, it seems that an abnormal HPA response is possibly triggered by an excessive pressure in vulnerable individuals.

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 (Bmax) and the dissociation constant (Kd), were obtained by means of the Scatchard analysis. Results: The Bmax values of PG patients were significantly lower than that of healthy subjects, while the Kd values were not different in the two groups. No significant effect of age, sex or psychiatric comorbidity on Bmax or Kd 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.