Juan José López-Ibor

Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial

BACKGROUND Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia; however, their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated. We aimed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol, in first-episode schizophrenia. METHODS We did an open randomised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites, in 14 countries. Eligible patients were aged 18-40 years, and met diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. 498 patients were randomly assigned by a web-based online system to haloperidol (1-4 mg per day; n=103), amisulpride (200-800 mg per day; n=104), olanzapine (5-20 mg per day; n=105), quetiapine (200-750 mg per day; n=104), or ziprasidone (40-160 mg per day; n=82); follow-up was at 1 year. The primary outcome measure was all-cause treatment discontinuation. Patients and their treating physicians were not blinded to the assigned treatment. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN68736636. FINDINGS The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone. Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio [HR] 0.37, [95% CI 0.24-0.57]), olanzapine (HR 0.28 [0.18-0.43]), quetiapine (HR 0.52 [0.35-0.76]), and ziprasidone (HR 0.51 [0.32-0.81]). However, symptom reductions were virtually the same in all the groups, at around 60%. INTERPRETATION This pragmatic trial suggests that clinically meaningful antipsychotic treatment of first-episode of schizophrenia is achievable, for at least 1 year. However, we cannot conclude that second-generation drugs are more efficacious than is haloperidol, since discontinuation rates are not necessarily consistent with symptomatic improvement.

World Psychiatric Association Pharmacopsychiatry Section statement on comparative effectiveness of antipsychotics in the treatment of schizophrenia

Data from two major government-funded studies of comparative antipsychotic effectiveness in schizophrenia contradict the widely prevalent belief that the newer second-generation medications are vastly superior to the older first-generation drugs. This has caused uncertainty among patients, clinicians and policy-makers about the relative utility of first- and second- generation antipsychotic agents in its treatment. To reduce confusion and provide a contextual understanding of the new data, the World Psychiatry Association Section on Pharmacopsychiatry comprehensively reviewed the literature on the comparative effectiveness of different antipsychotic treatments for schizophrenia and developed this update. Utilizing data from the approximately 1,600 randomized controlled trials of antipsychotic treatment in schizophrenia, we applied the two indirect and one direct method to comparing the effectiveness of 62 currently-available antipsychotic agents. The subclasses of 51 first-generation and 11 second-generation antipsychotics were both found to be very heterogeneous, with substantial differences in side-effect profiles among members. Second-generation antipsychotic agents were found to be inconsistently more effective than first-generation agents in alleviating negative, cognitive, and depressive symptoms and had a lower liability to cause tardive dyskinesia; these modest benefits were principally driven by the ability of second-generation antipsychotics to provide equivalent improvement in positive symptoms along with a lower risk of causing extrapyramidal side-effects. Clozapine was found to be more efficacious than other agents in treatment-refractory schizophrenia. There were no consistent differences in efficacy among other second-generation antipsychotic agents; if such differences exist, they are likely small in magnitude. Dosing was found to be a key variable in optimizing effectiveness of both first- and second- generation antipsychotic agents. There was enormous individual variability in antipsychotic response and vulnerability to various adverse effects. In contrast to their relatively similar efficacy in treating positive symptoms, there were substantial differences among both first- and second- generation antipsychotic agents with regard to their propensity to cause extrapyramidal, metabolic and other adverse effects; second-generation agents have a lower liability to cause acute extrapyramidal symptoms and tardive dyskinesia along with a tendency to cause greater metabolic side-effects than first-generation agents. Based on these data about the comparative effectiveness of different antipsychotic treatment options, we summarize elements of current best antipsychotic practice for the treatment of schizophrenia and discuss the role of government and the pharmaceutical industry in obtaining and disseminating information which can facilitate best practice.

Global pattern of experienced and anticipated discrimination reported by people with major depressive disorder: a cross-sectional survey

BACKGROUND Depression is the third leading contributor to the worldwide burden of disease. We assessed the nature and severity of experienced and anticipated discrimination reported by adults with major depressive disorder worldwide. Moreover, we investigated whether experienced discrimination is related to clinical history, provision of health care, and disclosure of diagnosis and whether anticipated discrimination is associated with disclosure and previous experiences of discrimination. METHODS In a cross-sectional survey, people with a diagnosis of major depressive disorder were interviewed in 39 sites (35 countries) worldwide with the discrimination and stigma scale (version 12; DISC-12). Other inclusion criteria were ability to understand and speak the main local language and age 18 years or older. The DISC-12 subscores assessed were reported discrimination and anticipated discrimination. Multivariable regression was used to analyse the data. FINDINGS 1082 people with depression completed the DISC-12. Of these, 855 (79%) reported experiencing discrimination in at least one life domain. 405 (37%) participants had stopped themselves from initiating a close personal relationship, 271 (25%) from applying for work, and 218 (20%) from applying for education or training. We noted that higher levels of experienced discrimination were associated with several lifetime depressive episodes (negative binomial regression coefficient 0·20 [95% CI 0·09-0·32], p=0·001); at least one lifetime psychiatric hospital admission (0·29 [0·15-0·42], p=0·001); poorer levels of social functioning (widowed, separated, or divorced 0·10 [0·01-0·19], p=0·032; unpaid employed 0·34 [0·09-0·60], p=0·007; looking for a job 0·26 [0·09-0·43], p=0·002; and unemployed 0·22 [0·03-0·41], p=0·022). Experienced discrimination was also associated with lower willingness to disclose a diagnosis of depression (mean discrimination score 4·18 [SD 3·68] for concealing depression vs 2·25 [2·65] for disclosing depression; p<0·0001). Anticipated discrimination is not necessarily associated with experienced discrimination because 147 (47%) of 316 participants who anticipated discrimination in finding or keeping a job and 160 (45%) of 353 in their intimate relationships had not experienced discrimination. INTERPRETATION Discrimination related to depression acts as a barrier to social participation and successful vocational integration. Non-disclosure of depression is itself a further barrier to seeking help and to receiving effective treatment. This finding suggests that new and sustained approaches are needed to prevent stigmatisation of people with depression and reduce the effects of stigma when it is already established. FUNDING European Commission, Directorate General for Health and Consumers, Public Health Executive Agency.

Cognitive Effects of Antipsychotic Drugs in First-Episode Schizophrenia and Schizophreniform Disorder: A Randomized, Open-Label Clinical Trial (EUFEST)

OBJECTIVE Cognitive impairment, manifested as mild to moderate deviations from psychometric norms, is present in many but not all schizophrenia patients. The purpose of the present study was to compare the effect of haloperidol with that of second-generation antipsychotic drugs on the cognitive performance of patients with schizophreniform disorder or first-episode schizophrenia. METHODS Subjects were 498 patients with schizophreniform disorder or first-episode schizophrenia who were randomly assigned to open-label haloperidol (1 to 4 mg/day [N=103]), amisulpride (200 to 800 mg/day [N=104]), olanzapine (5 to 20 mg/day [N=105]), quetiapine (200 to 750 mg/day [N=104]), or ziprasidone (40 to 160 mg/day [N=82]). The Rey Auditory Verbal Learning Test, Trail Making Test Part A and Part B, WAIS Digit Symbol Test, and Purdue Pegboard Test were administered at baseline and the 6-month follow-up evaluation. RESULTS Compared with scores at baseline, composite cognitive test scores improved for all five treatment groups at the 6-month follow-up evaluation. However, there were no overall differences among the treatment groups. In addition, there was a weak correlation between the degree of cognitive improvement and changes in Positive and Negative Syndrome Scale scores. CONCLUSION Treatment with antipsychotic medication is associated with moderate improvement in the cognitive test performance of patients who have schizophreniform disorder or who are in their first episode of schizophrenia. The magnitude of improvement does not differ between treatment with haloperidol and treatment with second-generation antipsychotics. Moreover, cognitive improvement is weakly related to symptom change.

Biological correlations of suicide and aggressivity in major depressions (with melancholia): 5-hydroxyindoleacetic acid and cortisol in cerebral spinal fluid, dexamethasone suppression test and therapeutic response to 5-hydroxytryptophan

5-Hydroxyindoleacetic acid (5-HIAA) and cortisol in cerebrospinal fluid (CSF), response of the dexamethasone suppression test (DST) and the clinical response to treatment with 5-hydroxytryptophan (5-HTp) plus carbidopa were studied in a group of 21 depressed inpatients (major depression with melancholia) in order to correlate biological findings with psychopathologicalones. A positive correlation was found between strong suicidal thoughts, suicidal attempts and self-aggressivity and low concentration of 5-HIAA in CSF and a less significant but still positive correlation with abnormal DST response and with clinical response to the treatment.

Correlates of cognitive impairment in first episode schizophrenia: the EUFEST study.

BACKGROUND Profile and correlates of cognitive deficits in first episode (FE) schizophrenia patients are still debated. The present study is aimed to clarify in a large sample of FE patients the extent of impairment in key cognitive domains and its relationships with demographic and clinical variables. METHOD The European First Episode Schizophrenia Trial collected demographic, clinical and neurocognitive baseline data in 498 FE patients with minimal or no prior exposure to antipsychotics. Two-hundred-twenty healthy subjects (HS) were also evaluated. Neurocognitive assessment included the Rey Auditory Verbal Learning Test; Trail Making A and B, Purdue Pegboard and Digit-Symbol Coding. RESULTS Patients performed worse than HS on all tests (effect sizes from -0.88 to -1.73). Correlations with psychopathological dimensions were weak and involved reality distortion and disorganization. The duration of untreated psychosis (DUP) was not associated with cognitive impairment. Subjects living alone had a better neurocognitive performance, while the occupation status did not reveal any association with cognition. CONCLUSIONS A moderate/severe impairment of processing speed, motor dexterity, verbal memory and cognitive flexibility was found in the largest sample of FE patients analyzed so far. The impairment was largely independent from psychopathology and not associated with DUP.

Low platelet monoamine oxidase activity in pathological gambling

Decreased platelet monoamine oxidase (MAO) activity has been reported in association with sensation‐seeking personality type and in some mental disorders associated with a lack of impulse control. Pathological gambling itself has been related with both sensation‐seeking and reduced impulse control. Platelet MAO activity was investigated in 15 DSM‐III‐R pathological gamblers from our outpatient clinic. Gamblers had a significantly lower platelet MAO activity than a group of 25 healthy controls. The range of MAO levels in gamblers was also significantly shorter than in controls. In controls, platelet MAO levels showed the previously described negative correlations with sensation‐seeking scores but not in gamblers. The findings are consistent with previous studies showing an association of low platelet MAO activity with impulse control disorders and raise some interesting therapeutic alternatives for pathological gambling.

Psychiatric diagnosis and classification

List of Contributors.Preface. Criteria for Assessing a Classification in Psychiatry (Assen Jablensky and Robert E. Kendall). International Classifications and the Diagnosis of Mental Disorders: Strengths, Limitations and Future Perspectives (T Bedirhan Ustun, Somnath Chatterji and Gavin Andrews). The American Psychiatric Association (APA) Classification of Mental Disorders: Strengths, Limitations and Future Perspectives (Darrel A. Regier, Michael First, Tina Marshall and William E. Narrow). Implications of Comorbidity for the Classification of Mental Disorders: The Need for a Psychobiology of Coherence (C. Robert Cloninger). Evolutionary Theory, Culture and Psychiatric Diagnosis (Horacia Fabrega Jr). The Role of Phenomenology in Psychiatric Diagnosis and Classification (Josef Parnas and Dan Zahavi). Multiaxial Diagnosis in Psychiatry (Juan E. Mezzich, Aleksandar Janca and Marianne C. Kastrup). Clinical Assessment Instruments in Psychiatry (Charles B. Pull, Jean--Marc Cloos and Marie--Claire Pull--Erpelding). Psychiatric Diagnosis and Classification in Primary Care (David Goldberg, Greg Simon and Gavin Andrews). Psychiatric Diagnosis and Classification in Developing Countries (R. Srinivasa Murthy and Narendra N. Wig). Index.Acknowledgements.

Psychopathological status and interpersonal functioning following weight loss in morbidly obese patients undergoing bariatric surgery.

Background: We questioned whether differences in psychopathological status and interpersonal relations exist in a group of morbidly obese patients 18 months after bariatric surgery,as related to extent of weight loss. Methods: The study group consisted of 100 morbidly obese patients (85 female, 15 male) who had undergone surgical treatment (vertical banded gastroplasty) for weight reduction. Each patient completed the Lancashire Quality of Life Profile - European version, the Eating Disorder Inventory,the Symptom Check List-90-Revised, and the Millon Clinical Multiaxial Inventory-II. The sample was divided into 2 groups according to the percentage of excess weight loss 18 months after surgery: a greater weight loss group (weight loss >30%) and a lesser weight loss group (weight loss <30%). Results: Significant differences were found between the 2 groups in percentage of weight loss (P<0.0001), negative self-esteem (P<0.001), drive for thinness (P<0.001), body dissatisfaction (P<0.001), global EDI (P<0.002), anxiety (P<0.003), GSI (P<0.002), avoidant (P<0.001), borderline (P<0.0001), and passive-aggressive (P<0.002). Conclusion: Greater weight loss strongly correlates with improved quality of life, less disturbed eating behavior, and lower psychopathology. These results justify the clinical use of surgical procedures and demonstrate that weight loss has powerful psychological and psychosocial implications.

Regional cerebral blood flow in obsessive-compulsive patients with and without a chronic tic disorder. A SPECT study.

Abstract The main goal of the present study was to explore whether regional cerebral blood flow (rCBF) differs between obsessive-compulsive disorder (OCD) patients without chronic motor tic disorder and those OCD patients with a comorbid chronic tic disorder. Twenty-seven patients suffering from OCD (DSM-IV criteria), including 7 OCD patients who met DSM-IV criteria for simple chronic motor dic disorder, and 16 healthy volunteers were examined at rest using a high resolution SPECT. Seven regions of interest (ROIs) were manually traced and quantified as a percentage of the mean cerebellar uptake. Severity of obsessive-compulsive symptoms (OCS), anxiety and depressive symptoms and presence of motor tics were assessed with the Y-BOCS, HRS-A, HRS-D, MADRS, and Yale Global Tics Severity Scale, respectively. We found a significant relative decrease in rCBF in OCD patients without motor tics compared to healthy volunteers in the right orbitofrontal cortex (OCD without tics = 0.87; healthy volunteers = 0.94; p = 0.02). No significant differences in rCBF were seen when OCD patients with and without chronic tics were directly compared. A lower severity of OCS in OCD patients with chronic tics was found. These results are consistent with previous functional neuroimaging studies at rest that have widely involved the orbitofrontal cortex in the pathophysiology of the OCD. However, our results do not support the idea that OCD patients with chronic tics may constitute a biological subgroup within the OCD.