Safety of SSRIs during pregnancy: a controlled study.

OBJECTIVE: The objective of our study was to analyze the efficacy and the safety of SSRIs during pregnancy. METHODS: A group of 30 pregnant women affected by Major Depressive Disorder by SCID I interview (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision criteria) and treated with selective serotonin reuptake inhibitor (SSRI) were included in the study. They were matched to a comparison group of 26 pregnant women. RESULTS: There were no statistically significant differences in any of the pregnancy outcomes of interest between the treated women and comparison group. There was no statistically significant association in newborns of women treated with an SSRI and the control group in the first and fifth minute Apgar score, and no newborns were admitted to neonatal Intensive Care Units. CONCLUSIONS: No definitive association between use of SSRIs during pregnancy and an increased risk of birth defects or other adverse outcomes could be found.

Psychiatric diagnosis and aggression before acute hospitalisation.

OBJECTIVE: To examine the predictors of aggressive behaviours occurring before acute hospitalisation. METHODS: We analysed 350 acute admissions to a psychiatric ward during a 12-month period. The diagnoses were formulated according to the DSM IV axis I and II criteria. Aggressive behaviours occurring in the week before admission were retrospectively assessed using the modified overt aggression scale. The patients' clinical and sociodemographic variables, concurrent drug or alcohol abuse, and admission status were recorded at the time of admission. RESULTS: Aggressive and violent behaviours were highly prevalent, respectively, in 45% and 33% of the cases. Violence before admission was independently associated with drug abuse, involuntary admission status, and severe psychopathology. A diagnosis of a psychotic disorder did not increase the risk of aggression or violence, compared to the other psychiatric diagnoses. Personality disorders were significantly more associated to aggressive behaviours than psychotic disorders. CONCLUSION: The diagnosis of psychotic disorder is a poor predictor of aggression in a sample of psychiatric patients. Other clinical and non-clinical variables are associated to aggression before hospitalisation: they include drug abuse, involuntary admission status, general severity of symptoms, and diagnosis of personality disorder.

Primary psychosis with comorbid drug abuse and drug-induced psychosis: Diagnostic and clinical evolution at follow up.

The study reports a follow-up assessment of 48 patients with concomitant drug abuse at the first admission for psychosis. We focused on the diagnostic distinction between primary psychosis with concomitant drug abuse and drug induced psychosis, to observe whether the diagnoses are stable over time and whether the clinical course significantly differs. The study examined 25 primary psychotic disorder with comorbid drug abuse and 23 drug-induced psychotic disorder patients. Diagnostic and psychopathological assessments were made at baseline and at follow-up. Mean follow-up period was 4.96 years. Patients with comorbid Drug Abuse exhibited higher scores in the item Unusual Content of Thought at baseline than drug-induced psychotic disorder patients: 5.48 vs 4.39 while the two patients groups did not differ in any of the BPRS items evaluated at follow-up. The primary psychosis with comorbid drug abuse and the substance induced psychosis groups were similar regarding diagnostic stability, and a diagnosis of schizophrenia at follow-up occurred similarly. There was no evidence that Drug Induced psychotic patients' symptoms tend to improve more after cessation of drug abuse. An earlier age of onset was found in primary psychotic patients, particularly for patients diagnosed as affected by schizophrenia at follow up. These results might reflect the uncertainty of the distinction between Primary and Drug Induced Psychosis and the difficulties in applying the DSM IV-TR criteria for diagnosing comorbid drug use disorders and psychotic disorders.

Paliperidone for the treatment of schizophrenia and schizoaffective disorders - a drug safety evaluation.

INTRODUCTION: Paliperidone, the major active metabolite of risperidone, is a second-generation antipsychotic that has been developed as an extended-release (ER) oral formulation and a long-acting injectable paliperidone palmitate (PP) formulation. Paliperidone has demonstrated efficacy in the reduction of acute schizophrenia symptoms and clinical benefits were maintained also in the long-term treatments. Paliperidone ER and PP are generally well tolerated with a predictable adverse event profile. Areas covered: Data from studies evaluating safety and tolerability in the acute and maintenance treatment of schizophrenia with paliperidone are reviewed. The reported treatment-emergent adverse events of these formulations are discussed. Expert opinion: In the treatment of schizophrenia and schizoaffective disorders the safety profile has a central role because it can enhance patient compliance. In fact treatment-emergent adverse events are one of the main causes of discontinuation in these patients. In particular the main limitation in the administration of paliperidone could be represented by the onset of hyperprolactinemia (especially in women) and of mild parkinsonism. Paliperidone has a high impact on current long-term drug strategies, especially given the new 3 month long-acting injectable formulation of PP.

Substance abuse in first-episode schizophrenic patients: a retrospective study.

Several studies suggest a high comorbidity of substance abuse and schizophrenia, associated with higher frequency of relapse, more positive symptoms and depression, cognitive impairment, poorer outcome and treatment response. A high incidence of substance abuse is also observed in first-episode patients. Among patients with substance abuse, the onset precedes the onset of psychosis of several years in most cases. All the patients with a first episode of schizophrenia, at first admission to the Psychiatric Service of Diagnosis and Treatment of Ospedale Maggiore of Milan during the years 1990 to 2004, have been included in our study.The clinical evaluation has been obtained considering the following items of Brief Psychiatric Rating Scale (BPRS): conceptual disorganization, depressed mood, hostility, hallucinations, unusual content of thought.The results showed that 34.7% of first-episode schizophrenic patients had a lifetime history of substance abuse. The age of onset of schizophrenia is significantly lower for drug abusers than for patients without any type of abuse and for alcohol abusers (p < 0.005). In multi drug abusers, cannabis resulted the most frequently used (49%), followed by alcohol (13%), and cocaine (4%). Substance abusers have obtained a significant higher score in "thought disturbance" item (p < 0.005) and in "hostility" item (p < 0.005) compared to non substance abusers. Non drug abusers showed lower mean scores of "hostility" item compared to cocaine abusers and multi drug abusers (p < 0.005). Our findings seem to indicate that substance abuse in the early course of illness determines an earlier onset of schizophrenia and increases severity of some psychotic symptoms like "hallucination" and "unusual content of thought". Therefore persons incurring a risk of schizophrenia may be warned of the possible relation between substances and psychosis and have to be counselled against the use of them.

Clinical outcome and olanzapine plasma levels in acute schizophrenia.

PURPOSE: This open label study was performed to evaluate the relationship between the plasma concentration of olanzapine and the response in acute schizophrenic inpatients. MATERIAL AND METHODS: A total of 54 inpatients, 38 males and 16 females, age ranging from 18 to 75 years, affected by Schizophrenia (DSM IV criteria) during an exacerbation phase were included in the study. Olanzapine (OLZ) was started at a dose of 5-20 mg/day and was increased to a mean dose of 15.27 mg +/-5.53 S.D. Patients were evaluated at baseline, and after 2 weeks, by using BPRS, PANNS, HRS-D, EPSE, and ACS. RESULTS: BPRS and total PANSS showed a statistically significant improvement at the end of the study. Olanzapine plasma levels (PL) ranged from 5 to 120 ng/ml (mean 33.15 ng/ml +/- 28.28 S.D.) and showed a positive correlation with OLZ dosage. A significant curvilinear correlation between OLZ PL and clinical improvement (BPRS, PANSS and HRS-D percent of amelioration) was observed. CONCLUSION: Olanzapine plasma level determination seems to be a useful tool in optimizing acute treatment particularly for more problematic cases.

Plasma and platelet excitatory amino acids in psychiatric disorders.

Plasma and platelet levels of excitatory amino acids were measured in 38 psychiatric out-patients and in 19 comparison subjects; the patients had DSM-III-R diagnoses of organic mental disorders (N = 3), mood disorders (N = 15), schizophrenia (N = 13), and anxiety disorders (N = 7). The glutamate plasma levels were significantly higher in the patients with mood disorders than in the comparison group.

Trazodone in late life depressive states: a double-blind multicenter study versus amitriptyline and mianserin.

Seventy five elderly depressed in-patients, ages ranging from 60 to 83 years, diagnosed as Major Depression according to DSM III were treated, under double-blind conditions, with 75 mg Amitriptyline (AMI) (26 patients), 60 mg Mianserin (MIA) (24 patients) or 150 mg Trazodone (TRZ) (25 patients) p.o. for 5 weeks. There were no differences in the clinical outcome between the three groups of patients at the end of the trial, with a significant amelioration (P less than 0.01) at the Hamilton Rating Scale for Depression and Geriatric Depression Scale. TRZ showed a significantly lower incidence of side effects compared to MIA and AMI. Atypical antidepressants, including TRZ, seem more suitable for treating elderly depression than the first generation antidepressants on the basis of risk/benefit ratio considerations.

Clozapine metabolism rate as a possible index of drug-induced granulocytopenia.

A possible relationship between haematological adverse reactions and clozapine (CLZ) metabolism rate was studied. Sixteen chronic schizophrenic outpatients (mean age 34.62 years +/- 7.56 SD) were treated with CLZ, 75-600 mg/daily for 9 weeks. CLZ and norclozapine (NCLZ) plasma levels were determined weekly, contemporarily with blood cell counts. CLZ plasma levels ranged from 25 to 1270 ng/ml (mean 266.27 ng/ml +/- 197.44 SD), while NCLZ plasma levels ranged from 25 to 1280 ng/ml (mean 169.0 ng/ml +/- 127.94 SD). NCLZ/CLZ ratio ranged from 0.13 to 1.72 (mean 0.72 +/- 0.28 SD). Leukocyte count ranged from 5.2 to 18.8 10(9)/l (mean 9.37 10(9)/l +/- 2.94 SD) and neutrophil count ranged from 1.8 to 13.4 10(9)/l (mean 5.73 +/- 2.57 SD). No correlation was found between CLZ dosage and NCLZ plasma levels. Both CLZ and NCLZ plasma levels correlated positively with neutrophil count (CLZ: P = 0.001, r = 0.26; NCLZ: P = 0.01, r = 0.20). The correlation between NCLZ/CLZ plasma level ratio and neutrophil count was significantly negative (P = 0.002, r = 0.25). These preliminary data suggest that the NCLZ/CLZ ratio, as an index of CLZ metabolism, might be a possible risk factor associated with CLZ treatment.

A risk-benefit assessment of sulpiride in the treatment of schizophrenia.

Sulpiride is a substituted benzamide with a selective action on receptors of the dopamine D2-like family, and clinical and pharmacological data suggest that it could be considered to be an atypical antipsychotic. Sulpiride penetrates the blood-brain barrier poorly because of its low lipid solubility. It is mainly excreted unchanged in the urine, and accumulation of the drug could occur in patients with renal dysfunction and possibly in elderly patients with declining glomerular filtration rate. At low dosages (50 to 150 mg/day), sulpiride produces a disinhibiting and antidepressant effect, which is probably related to its action on D2 presynaptic autoreceptors, thus facilitating dopaminergic neurotransmission. Data have confirmed the efficacy of sulpiride in patients with acute or chronic schizophrenia during both short and long term treatment, but long term, placebo-controlled trials are still lacking. It is still doubtful whether sulpiride is more effective than typical antipsychotics for the treatment of negative symptoms. Data from clinical studies are controversial; the majority of authors indicate that sulpiride produces a better recovery rate from negative than from positive symptoms at low doses, but it shows a similar efficacy either on negative and positive symptoms at higher doses. The safety profile of sulpiride is similar to that of typical antipsychotics, although the frequency of adverse effects seems to be globally lower. Extrapyramidal reactions appear generally to be mild. Autonomic effects occur less frequently with sulpiride than with typical antipsychotics, showing no clinically relevant influence on cardiovascular parameters and, on the whole, good tolerability in elderly patients. Sulpiride is known to induce prolactin elevation in both serum and CSF, which may be associated with impotence in men and diminished gonadal function in women; these effects appear to be dosage-dependent. Sulpiride can be considered to be an atypical antipsychotic, considering its action on negative, defective symptoms, its partial activity against positive symptoms, and its low incidence of extrapyramidal adverse effects. Sulpiride could find its specific therapeutic role in elderly patients with schizophrenia, as it shows a good margin of safety between therapeutic dosages and toxic concentrations.

Age, therapeutic "milieu" and clinical outcome in depressive patients treated with viloxazine: a study with plasma levels.

Authors studied 42 depressed patients of both sexes suffering from Major Depression and Dysthimic Disorder, treated with viloxazine for 4 weeks. All patients were divided into two groups on the basis of their age (Group 1 mean age 45 +/- 2.2 and Group 2 mean age 68.3 +/- 1.12). Viloxazine was effective in different depressive situations, regardless of the age of the patient or the therapeutic context, even if in Group 2 the out-patients did significantly better (p less than 0.01) than the hospitalized ones. Mean steady-state plasma levels and level/dose ratios were significantly higher (p less than 0.05) in elderly patients than in younger ones. No correlation between viloxazine plasma levels-clinical efficacy and side-effects was found even though patients suffering from Major Depression showed a trend to a better response with plasma levels below 5 gamma/ml. The satisfactory antidepressant activity and the good tolerability of viloxazine in elderly depressed patients make this drug particularly suitable for using in ambulant geriatric depressed patients.

L-sulpiride in young and elderly negative schizophrenics: clinical and pharmacokinetic variables.

1. Clinical activity, tolerability and kinetic profile of L-sulpiride (200-300 mg/die p.o.) in relation to age, in 14 chronic schizophrenic in patients diagnosed according to DSM III-R, typed as negative forms, were studied. 2. The drug showed its efficacy in negative forms of schizophrenia, without any significant difference between negative and positive symptoms even if productive symptom scores were quite low already in pre-treatment condition. 3. No more side effects (anticholinergic and extrapyramidal) in elderly patients compared to young/adult ones were reported. 4. No significant differences between young/adult and elderly patients for the various pharmacokinetic parameters (t1/2, AUC, Cmax, Tmax, Vd and Cl), after acute and multiple dosing, were observed.

Fluphenazine decanoate in acute and maintenance therapy of schizophrenia.

1. The knowledge of the pharmacokinetic profile of fluphenazine decanoate (FPZ-D) suggested it was suitable for treatment of schizophrenic patients not just during the maintenance phase of the disease but also during acute relapses. 2. 27 acute schizophrenic in-patients (diagnosed according to the DSM III) were treated with FPZ-D, 25 mg i.m. with repeated administrations (after 2, 4, 30 days). 3. FPZ-D proved effective in all cases, already after the second day and particularly on Brief Psychiatric Rating Scale items such as delusion, hallucinations, hostility. 4. Extrapyramidal side-effects, appeared in about 40% of the patients. 5. The use of the drug both in the acute phase and maintenance schizophrenia therapy is envisaged, overcoming the problems deriving from the rejection by patients of any therapeutic tool and consequently the therapeutic "milieu".

Plasma and brain pharmacokinetics of mianserin after single and multiple dosing in mice.

Pharmacokinetics parameters describing the time course of concentrations of mianserin (MIA) in plasma and brain and the relationship between plasma and brain concentrations were studied after acute and chronic administration of increasing doses of MIA in adult mice. There was a linear relationship between the area under the curve (AUC), the maximum concentration (Cmax) and doses, in plasma and brain, both during acute and chronic experiments (p less than 0.05). A five-fold variation in plasma and brain terminal half-life (t 1/2) after chronic administration of the drug was observed, possibly due to a reduction in plasma drug clearance (CL). The values of Cmax and AUC in plasma and brain showed an increase of respectively about three and twelve times after chronic treatment. A very good correlation was observed between plasma and brain Cmax in both acute and chronic experiments; brain Cmax was 10.2 (+/- 0.16) times higher than plasma Cmax after acute administration and 12.08 (+/- 1.33) times higher after chronic administration.

Haloperidol decanoate in chronic schizophrenia: a study of 12 months with plasma levels.

1. Clinical activity, extrapyramidal side-effects were evaluated in 22 schizophrenic out patients diagnosed according to DSM III and treated with haloperidol decanoate (50-300 mg i.m. monthly dose) for 12 months. 2. BPRS total scores did not show significant fluctuations showing a clinical stability of the patient population. 3. Patients with a duration of illness greater than 10 yrs (Group 2) showed significant (p less than 0.01) higher EPSE total scores compared to those with a duration of illness less than 10 yrs (Group 1). 4. A positive correlation was found between the administered dose and haloperidol plasma levels. 5. Patients from Group 2 reached the steady-state more slowly and showed a lower total L/D ratio compared to those from Group 1. 6. The pharmacokinetic approach seems desirable in order to adjust the dose and avoid schizophrenic relapses.

Psychopathological and cognitive features in subclinical hypothyroidism.

1. To evaluate effective and cognitive dysfunctions in subjects with a marginal form of thyroid hypofunction the authors studied a population of female goiter patients, divided in two groups on the basis of thyroid function: euthyroidism and subclinical hypothyroidism (SCH). 2. The SCH patients were treated with levothyroxine (LT4) in order to obtain euthyroidism, as demonstrated by normalization of the hormonal pattern. 3. Both groups were evaluated with a wide range of psychometric tests (Wechsler memory test, scribble test, reaction times) and psychopathological rating scales (Hamilton rating scales for depression and anxiety, brief psychiatric rating scale) at admission and after 3 months. 4. At admission, a significant decrease in logical memory was found in SCH patients; no differences in affectivity ratings were found between the groups. 5. After LT4 treatment, SCH patients showed a significant improvement in some items of memory performance. 6. In conclusion, when interfering factors relating to the perception of disease were excluded by employing euthyroid goiter patients as a comparison group, SCH appeared associated only with memory impairment, while the impairment of affective functions described in previous studies comparing SCH patients with normal controls was not confirmed. A significant improvement of memory skills was induced by LT4 treatment in SCH patients.

Depressive symptoms and schizophrenic relapses: the effect of four neuroleptic drugs.

1. A prevalence of depressive symptomatology, ranging from 25% to 80% has been reported during the course of schizophrenia. 2. Depressive symptoms were assessed in 144 schizophrenic patients (DSM IV) during an acute exacerbation phase. 3. Depressive symptoms showed a prevalence ranging from 5.5% (severe clinical pictures) to 54.8 (mild clinical pictures). 4. The authors did not find a correlation between depressive symptoms per se and the presence of negative psychotic symptoms. Depression may be linked not so much to negative symptoms but to the psychotic state itself. 5. Depressive symptomatology concurrently occurred with schizophrenic relapses and improved together with the psychotic clinical picture, independently of the neuroleptic drug employed. Haloperidol, haloperidol decanoate and fluphenazine decanoate all showed a similar improvement of depressive symptoms. 6. L-sulpiride showed a trend to be most effective on depressive symptomatology in comparison to the other neuroleptics.

Neurobiological and psychopharmacological basis in the therapy of bulimia and anorexia.

1. Eating disorders can be found in several psychiatric pathologies: schizophrenia, delusional disorder (somatic type), bipolar disorders, major depressive disorder, borderline personality disorder, generalized anxiety disorder, body dysmorphic disorder, somatization disorder and conversion disorder. 2. Although their clinical features have been defined, relatively little is known about the role of neurobiological patterns in the pathogenesis of these disorders. Several CNS neurotransmitters and neuromodulators are involved in the regulation of eating behavior in animals and have been implicated in symptoms such as depression and anxiety often observed in patients with eating disorders. The authors will review some studies on NA, DA, 5-HT, beta-endorphins, CRH, VP, OT, CCK, NPY and PYY involved in eating disorders. Furthermore, we will highlight some of the studies on drug therapy of eating disorders taking into account the effects of these agents on neurotransmitters and neuromodulators. 3. Antidepressant drugs have long been used for anorexia nervosa and bulimia, these disorders been claimed to be affective equivalent. Antidepressant agents seem to be effective in reducing the frequency of binge-eating episodes, purging behavior and depressive symptomatology. It is notable that antidepressant agents have been proved to be effective in patients with chronic bulimic symptoms, even in cases persisting for many years and in patients who had repeatedly failed courses of alternative therapeutic approaches. In all of the positive studies, antidepressant agents appeared effective even in bulimic subjects who did not display concomitant depression. 4. Few controlled studies on use of medications for anorexia nervosa have been published. Central serotonergic receptor-blocking compounds such as cyproheptadine cause marked increase in appetite and body weight. Zinc supplementation or cisapride could be a therapeutic option in addition to psychological and other approaches in anorexia nervosa. 5. There is no therapy as yet which is fully effective in alimentary disorders. Psychotropic drugs give some relief from symptoms, but they cannot cure the disorders. An integrated approach, either pharmacological or psychological, is still recommendable.

A single blind comparison of amisulpride, fluoxetine and clomipramine in the treatment of restricting anorectics.

1. The study evaluated the efficacy of amisulpride, fluoxetine and clomipramine at the beginning of the re-feeding phase of the treatment of restricting anorexia nervosa according to DSM-IV criteria. 2. 13 patients, mean weight 37.61 kg +/- 9.80 SD, were treated with clomipramine at a mean dosage of 57.69 mg +/- 25.79 SD; 10 patients, mean weight 40.90 kg +/- 6.98 SD, were treated with fluoxetine at a mean dosage of 28.00 mg +/- 10.32 SD; 12 patients, mean weight 38.41 kg +/- 8.33 SD, were treated with amisulpride at a mean dosage of 50.00 mg +/- 0.00 SD. 3. Clinical evaluation was carried out under single-blind condition at basal time and after three months by a structured clinical interview, the Eating Disorder Interview based on Long Interval Follow-up Evaluation (LIFE II BEI). 4. Patients treated with amisulpride showed a more significant increase (p=0.016) of mean weight. Concerning weight phobia, body image disturbance and amenorrhoea, no significant difference resulted.

Antidepressant efficacy in the treatment of dysthymia.

Although the existence of chronic depression has been recognized for a long time, their definition was too inaccurate to enable reliable studies concerning their treatment. Among the numerous diagnostic classes that patients with chronic depression were assigned to, neurotic depression was the most common one, and was often considered to be unresponsive to antidepressant medication. Since DSM-III introduced 'Dysthymic Disorder', a new research was developed on the efficacy of tricyclic antidepressants, MAOIs or new antidepressants, whose results reversed previous opinion on its unresponsiveness. However the interpretation of those studies are hampered by methodological problems, yet unresolved, pertaining to the difficulty to differentiate dysthymia and major depression, to the frequency of 'double-depression', the usual mildness of symptoms in dysthymia, and the need of long-term trials.