Antipsychotic drugs are used in a range of schizophrenic patients from the acutely disturbed to the chronically inert. Acute psychotic breakdowns usually involve secondary phenomena such as anxiety, depression and hostility superimposed on a worsening of the psychotic illness: a threshold of arousal is exceeded. This sets up a vicious circle which requires a major therapeutic effort to interrupt. Unfortunately, patients still relapse despite apparently adequate medication, suggesting only partial protection. Relapse is influenced by drug-related factors such as compliance and substance abuse, psychological factors such as cultural context, family dynamics and life events, and illness features such as poor insight. Treatment strategies, such as low-dose and intermittent medication, have proved disappointing. The most pragmatic model is the classic stressor-vulnerability model, but this does not explain the enhanced efficacy of clozapine.
The use of clozapine (CLZ) for treatment-resistant schizophrenia is well established in adults. However, it is seldom used in youth with early onset schizophrenia (EOS) largely because of lack of clarity about its risk benefit ratio. This review synthesises and evaluates available evidence regarding the efficacy and tolerability of CLZ in EOS with the aim to assist clinical decision-making.
We conducted a systematic review of the primary literature on the clinical efficacy and adverse drug reactions (ADRs) observed during CLZ treatment in EOS. We also identified relevant practice guidelines and summarised current guidance.
CLZ showed superior efficacy than other antipsychotics in treating refractory EOS patients; short-term clinical trials suggest an average improvement of 69% on the Brief Psychiatric Rating Scale that was sustained during long-term follow-up (up to 9 years). No fatalities linked to CLZ treatment were reported. Sedation and hypersalivation were the most common complaints, reported by over 90% of patients. Other common ADRs (reported in 10-60% of patients) were enuresis, constipation, weight gain, and non-specific EEG changes. Less common ADRs (reported in 10-30% of patients) were akathisia, tachycardia and changes in blood pressure. Neutropenia was reported in 6-15% of cases but was usually transient while agranulocytosis was rare (<0.1%). Seizures were also uncommon (<3%). Metabolic changes were relatively common (8-22%) but emergent diabetes was not frequently observed (<6%). Overall the rate of discontinuation was low (3-6%). Current guidelines recommend the use of CLZ in EOS patients who have failed to respond to two adequate trials with different antipsychotics and provide detailed schedules of assessments to evaluate and assess potential ADRs both prior to initiation and throughout CLZ treatment.
Available data although limited in terms of number of studies are consistent in demonstrating that CLZ is effective and generally safe in the treatment of refractory EOS provided patients are regularly monitored.
In a previous study of 15 panic patients, we demonstrated that body-related (somatic) word stimuli elicited an enhanced positive cortical slow wave compared to non-somatic word stimuli. Healthy controls did not show this difference. The present paper reports on psychometric ratings in relation to cortical slow waves in these patients. Patients were clinically reexamined after about 1.5 years. Although no significant correlations between neurophysiology and psychometric measures could be found at the onset of the study, there was a significant correlation between improvement over the follow-up period and neurophysiology. A decline in the Hamilton Anxiety Scale (HAMA), which proved to be the best estimate for improvement, was associated with the relative magnitude of the positive slow wave elicited by somatic stimuli. Our findings support cognitive models of panic disorder, which stress that abnormal processing of bodily symptoms is relevant for the development and/or maintenance of the disorder.
The catechol-O-methyltransferase (COMT) enzyme inactivates catecholamines, and the COMT Val(108/158)Met polymorphism (rs4680) influences the enzyme activity. Recent clinical studies found a significant effect of rs4680 on antidepressant response to fluoxetine and paroxetine, but several other studies were negative. No study considered drug plasma levels as possible nuisance covariate.
We studied the effect of rs4680 on response to fluvoxamine antidepressant monotherapy.
Forty-one consecutively admitted inpatients affected by a major depressive episode in course of major depressive disorder were administered fluvoxamine for 6 weeks. Changes in severity of depression were assessed with weekly Hamilton Depression ratings and analyzed with repeated measures ANOVA in the context of General Linear Model, with rs4680 and fluvoxamine plasma levels as factors.
rs4680 significantly interacted with time in affecting antidepressant response to fluvoxamine, with outcome being inversely proportional to the enzyme activity: better effects in Met-carriers, worse effects in Val/Val homozygotes. The effect became significant at the fourth week of treatment, and influence final response rates. Fluvoxamine plasma levels had marginal effects on outcome.
This is the first study that reports a positive effect of rs4680 on response to fluvoxamine, and the third independent report of its influence on response to selective 5-HT reuptake inhibitors (SSRIs). Our findings support the hypothesis that factors affecting catecholaminergic neurotransmission might contribute to shape the individual response to antidepressants irrespective of their primary molecular target.
To examine the relationship between different intervention approaches and subsequent real-life outcomes in patients changing treatment from escitalopram 10 mg.
This was a retrospective cohort study of patients starting antidepressant treatment between 2002 and 2004. Data were extracted from a US health-insurance reimbursement claims database. Eligible patients started escitalopram 10 mg and changed within 3 months to: escitalopram ≥20 g; another antidepressant; or a combination of escitalopram with another antidepressant. Medication persistence and healthcare costs over 3 months were compared between the treatment groups.
Overall, 37,791 patients started escitalopram 10 mg. Of the 12,830 patients (34%) who changed treatment, 56% increased escitalopram dose, 26% switched antidepressant and 18% combined escitalopram with another antidepressant. Patients in the switch and combination groups had significantly higher rates of non-persistence (56% and 91%, respectively) vs the dose-increase group (39%; both P<0.001). Combination-group patients incurred significantly greater costs vs the dose-increase group ($2805 vs $1767, respectively; P<0.001).
Results suggest that increasing escitalopram dose in patients responding inadequately to 10 mg is associated with higher persistence rates vs the other treatment approaches. Receiving an increased dose of escitalopram was associated with significantly lower costs than combining escitalopram 10 mg with another antidepressant.
We performed an Internet-based questionnaire survey of the opinions of German-speaking psychiatrists regarding the experiences with the 10th revision of the international classification of mental disorders (chapter F of ICD-10). We received 304 completed questionnaires including more than 500 free-text comments. The responding group was characterized by professionally experienced middle-aged psychiatrists. German-speaking psychiatrists were comparatively content with ICD-10. Most diagnostic categories received a "satisfied" or "very satisfied" rating by the majority of respondents. Negative "goodness of fit" ratings--a possible indicator of the need for revision--were not higher than 50% for any category. Based on free-text entries, neurasthenia was the single diagnostic category most often suggested for deletion in ICD-11. Changes were considered necessary mainly for dementias and personality disorders. Adult attention deficit disorder and narcissistic personality disorder were the two diagnostic categories most frequently suggested to be added as new categories. This study provides valuable information related to perceived clinical utility of the classification, though with a narrow sample. Information about clinicians' experiences should be combined with scientific evidence for the revision process of ICD-11.
To determine the change in prevalence of posttraumatic stress disorder (PTSD) symptoms in victims of the March 11 attacks and their relatives, 1 and 6 months after the attacks.
Evaluation of PTSD symptoms using the Davidson Trauma Scale (DTS) and General Health Questionnaire (GHQ) in a sample of 56 patients admitted to an emergency room of a general hospital, and assessment of PTSD symptoms in relatives of the patients.
At Month 1, 41.1% of patients (31.3% of males and 54.2% of females) presented with PTSD. At Month 6, this figure was 40.9% (30.4% of males and 52.4% of females). There was a significant improvement in perception of health among females between Month 1 and Month 6. Relatives presented similar DTS scores at baseline and at 6 months.
We verified that rates of PTSD did not vary substantively between the two evaluations. PTSD symptoms positively correlated with psychological health involvement. This correlation points out that both PTSD symptoms and subjective general health involvement are part of the psychological response to trauma.
The prevalence of PTSD symptoms was high and remained stable between Month 1 and Month 6, while subjective perception of health improved significantly.
In the course of the international development of tianeptine (T), depressed patients were recruited by 18 centres from Belgium, Italy, Mexico, Portugal, Spain and Switzerland in a double-blind parallel group study versus placebo (P) and imipramine (I). Efficacy and safety of tianeptine were evaluated in 187 depressed inpatients (56% female, 44% male), who fulfilled criteria for either major depression, single episode (24.6%) or recurrent (66.8%), or depressed bipolar disorder (8.6%). After a seven-day run-in placebo pre-inclusion period, patients were treated in double-blind conditions with tianeptine (37.5 mg/d) or imipramine (150 mg/d) or placebo for 14 days, including an increasing daily dose period of three days. After the fourteenth day and until the end of the sixth week of treatment, a flexible dosage was introduced in accordance with the therapeutic efficacy and/or the potential adverse events (T: 25-50 mg/d; I: 100-200 mg/d; P; 2-4 capsules). Discontinuation of treatment occurred in 57 patients (30.5%) with more inefficacy on placebo and tianeptine (P: 16/23; T: 11/17; I: 7/17), and more side-effects on imipramine (P: 1/23; T: 1/17; I: 7/17). Final MADRS scores in intention-to-treat analysis were 22.3 +/- 1.5, 17.3 +/- 1.6 and 18.4 +/- 1.5 for placebo, tianeptine and imipramine, respectively. Statistical analysis demonstrated the antidepressive efficacy of tianeptine and imipramine versus placebo (P = 0.012 and P = 0.034, respectively), and no difference between tianeptine and imipramine. In patients treated for 42 days (n = 129) the MADRS scores dropped from 62.3% on tianeptine, 54.2% on imipramine and 48.5% on placebo. These results confirmed the efficacy of tianeptine (37.5 mg/d) in the treatment of major depression and depressed bipolar disorder when compared to placebo. No difference was found between tianeptine and imipramine (150 mg/d) for the efficacy and between tianeptine and placebo for all safety criteria. The following adverse events were significantly more frequent with imipramine than with tianeptine or placebo: dry mouth (P < 0.001), constipation (P = 0.007), and hot flushes (P = 0.011). No difference in adverse events was found between tianeptine and placebo. While the usual cardiovascular signs of tricyclic antidepressants were observed in the imipramine group, no difference between tianeptine and placebo was shown in respect to heart rate or blood pressure (supine or standing). The assessment of haematological, renal, metabolic and hepatic parameters confirmed the safety of tianeptine.
Under-recognitions of somatic illnesses have frequently been suggested to explain the well-known increased risks of mortality in long-stay psychiatric patients. There are, however, no studies, in which register information on realized somatic hospitalisations and mortality from somatic illnesses in psychiatric patients are actually linked and simultaneously evaluated. In this study, 208 long-stay psychiatric patients, suffering from functional psychoses (mainly schizophrenia) in Northern Finland were followed up for 11 years, and screened for all somatic hospitalisations and subsequent causes of death. 86.5% of the patients had undergone hospital treatment due to some physical illness after their first psychiatric admission. During specialized psychiatric care the majority of the deceased patients had received some somatic treatment for illnesses that ultimately caused their deaths: 81% representing circulatory, 71% digestive, 56% neoplastic, and 36% respiratory ailments. We found no evidence for the frequently expressed view that somatic illnesses in psychiatric patients were under-recognized. Thus, the widely-documented poor physical outcome of long-stay psychiatric patients may be not attributable to neglect of care or abandon, but to difficulties in efficaciously addressing medical conditions in a population characterised by unhealthy life-style habits, psychiatric disability and isolation. The health care systems apparently offer a range of services, but the latter do not always reach the patients. Why this is so requires detailed further investigation.
People with Subjective Cognitive Impairment (SCI) may be at increased risk of dementia. In this study we examined amyloid load in 5 SCI subjects and 14 controls using PIB PET scanning. One SCI subject had significantly increased PIB retention in the cortical areas of interest. Larger, longitudinal studies are indicated.
Decreased hippocampal volume reported in neuropsychiatric and endocrine disorders is considered a result of putative neuronal damage mediated by corticosteroids. This is the first prospective study of hippocampal volume and function in patients treated with corticosteroids.
14 subjects treated systemically with prednisone or betamethasone for dermatological or rheumatic disorders underwent prospective neurocognitive testing (Auditory Verbal Learning Test-AVLT, Trail Making Test-TMT, Digit Span-DS) and nine of them also repeated magnetic resonance volumetry.
The mean duration of treatment between the first and the second assessment was 73+/- 38 days with mean daily dose of 37+/- 17 mg prednisone and 193+/- 29 days, with mean daily dose of 24+/- 15 mg prednisone between the first and the third assessment. There was a trend towards decreases in total AVLT scores and an improvement in the TMT and DS, but no significant changes in the volumes of the right or the left hippocampi between the assessments. Prednisone dose did not correlate with the hippocampal volume change.
We observed a trend for decline in verbal memory despite improvement in psychomotor speed, attention/working memory and no macroscopic hippocampal volume changes during 36-238 days of treatment with therapeutic doses of corticosteroids.
Abnormalities in the serotonergic system have been implicated in the pathophysiology of depressive disorders. Human platelets possess serotonin-2A (5-HT(2A)) receptors, and previous research using LSD or ketanserin as ligands have indicated that their number is increased in depressed patients. Compared to other ligands previously used in platelet studies, DOI is highly selective for the 5-HT(2A) receptor and binds to its high-affinity state, therefore labeling only the receptors that are biologically coupled to the G-protein. We determined the density (Bmax) and the affinity (Kd) of 5-HT(2A) receptors labeled by [(125)I]-DOI in platelets from 21 untreated patients with major depression and 21 healthy volunteers. The density of the 5-HT(2A) binding sites was found to be increased in platelets from female depressed patients as compared to controls. No changes were observed in the Kd. We did not find any relationship between the binding parameters and either the severity of the depressive episode or the suicidal tendencies of the patients. Our results show that the number of coupled platelet 5-HT(2A) receptors is increased in depressed patients, indicating that platelet 5-HT(2A) receptor function is enhanced in depression.
We investigated the genotype frequency of methylenetetrahydrofolate reductase (MTHFR) 1298A > C polymorphism in the group of patients with bipolar disorder type I (BDI) ( n = 200) and schizophrenia ( n = 200) and in the control group ( n = 300). Odds ratio (OR) for patients with BD and schizophrenia in 1298CC homozygous state was 3.768 (95% CI = 1.752–8.104); P = 0.0003; ( P = 0.0006 after Bonferroni correction) and 2.694; (95% CI = 1.207–6.013); P = 0.0123 ( P = 0.0246 after Bonferroni correction), respectively. The stratification of patients based on gender revealed significant association of 1298CC genotype with female patients only with BDI (OR = 7.293; 95% CI = 2.017–26.363; P = 0.0005).
Our results confirm association of BD and schizophrenia with the 1p36.3 MTHFR locus and with the methyl group transfer using folate-dependent one-carbon pathway.
Clinical evidence suggests that hallucinogenic drug-induced altered states of consciousness (ASCs) and the incipient, acute stages of endogenous psychoses share many common phenomenological features. The aim of our study was to assess hallucinogen-like phenomena in endogenous psychotic patients using standardised methods. We examined 93 endogenous psychotic patients, 50 healthy controls and a small group of drug induced psychotic patients (n = 7) with two ASC self-assessment scales (questionnaire APZ = Abnormer Psychischer Zustand = Altered State of Consciousness [Dittrich et al, 1985]; and questionnaire OAV = Abbreviation of the three subscales: Oceanic Boundlessness/Angst = Dread of Ego Dissolution/Visionary Restructuralisation [Bodmer 1989]). Patients were examined shortly after remission of their last acute psychotic episode and they answered the questionnaires referring to the early phase of this episode. Differences in the questionnaire scores were significant between psychotic patients and controls. Drug induced patients had numerically higher scores than endogenous psychotic patients, however these differences were only significant for the APZ total score and the undifferentiated items of the APZ, but not for the three APZ subscale and the OAV scores. More than 50% of the endogenous psychotic patients answered 26% of the APZ-and 43% of the OAV-items with "yes". The OAV total score and the OSE (Ozeanische Selbstentgrenzung = oceanic boundlessness) scores of both questionnaires correlated significantly with BPRS Factor 3 (thought disturbance). Our results support the hypothesis that hallucinogen-like experiences represent common phenomena during the acute stages of endogenous psychoses. Remarkably, these phenomena include subjectively pleasant experiences of the OSE dimension. In the routine clinical assessment of endogenous psychotic patients experiences of this dimension may be more easily overlooked than the negative experiences of the AIA dimension (AIA: Angst vor der Ich-Auflösung = dread of ego dissolution).
The objectives of this study were (1) to evaluate the prevalence of relational withdrawal behaviour in infants aged 14-18 months attending a public health centre in Paris, (2) to check some identified risk factors for relational withdrawal behaviour in this population.
A cross-sectional study was conducted in infants aged 14-18 months attending a child health screening centre during the year 2005.
A total of 640 children were included in the study. Thirteen percent of the 640 infants (n=83, 95% CI [10.4%; 15.6%]) had an ADBB score at 5 and over 5 on the ADBB. There was a clear relationship between withdrawal behavior and having psychological difficulties as reported by parents, and between withdrawal and developmental delay. Withdrawal was also significantly associated with being a boy, with living in risk conditions (e.g. child being in joint custody, or with living in a foster family), with being adopted, or with being a twin. More withdrawn infants were taken care of at home.
Sustained relational withdrawal behaviour was linked with developmental disorders and psychopathology and not with SES, ethnical origin or rank of birth. The scale could be used in screening early psychopathology in infants aged 2-24 months of age.
We performed an association study between three SNPs in the genes of 14-3-3 family and paranoid schizophrenia. SNP rs983583 G/A in the YWHAZ gene showed significant association with paranoid schizophrenia. Our study indicated that the YWHAZ gene was a potential susceptibility gene for paranoid schizophrenia in the population studied.
This study aimed to investigate the possible association between T102C and -1438 G/A polymorphism in the 5-HT2A receptor gene and susceptibility to and clinical features of obsessive-compulsive disorder (OCD).
Fifty-eight patients with OCD and 83 healthy controls were included in the study. All patients were interviewed and rated by Yale-Brown Obsessive-Compulsive Scale. T102C and -1438 G/A polymorphisms of 5-HT2A receptor gene were determined by PCR technique in DNAs of peripheral leucocytes.
OCD patients and healthy controls did not show significant differences in genotype distribution for both polymorphisms investigated. We found that frequencies of the TT genotype for T102C polymorphism and the AA genotype for -1438 G/A polymorphism were significantly higher in patients with severe OCD compared to those with moderate or moderate-severe OCD.
The -1438 G/A and T102C polymorphisms of the 5-HT2A receptor gene are not associated with an increased risk of OCD. Our data suggest that the TT genotype of T102C and the AA genotype of -1438 G/A polymorphism might be a factor in clinical severity of OCD.
Investigation into the family burden (FB) of schizophrenic patients has recently risen sharply. Nevertheless, to date there has been little consensus as to what factors influence the FB. The purpose of this study is to acquire a greater insight into the variables that influence the FB.
The FB was measured with the interview for the family burden (Kluiter H, Kramer JJAM, Wiersma D, et al. Interview voor de belasting van de familie 1997 [Interview for the burden on the family]. Department Sociale Psychiatrie. Groningen: Rijksuniversiteit). One hundred and fifty family members (parents/partners) of schizophrenic patients participated in the study.
The results of our study show (1) that family members experience burden both on a practical and an emotional level, (2) a highly significant correlation between the amount of symptomatic behaviour of the patient and FB, (3) that parents had taken on more tasks, had contributed more financially and had experienced a tenser atmosphere at home than partners did and (4) that family members of patients who have been treated for less than 1 year worry more about the other members of their family than family members of patients who have been receiving treatment for more than 1 year.
Family members of schizophrenic patients experience burden on a practical, financial and emotional level and the extent of the burden is closely linked to the amount of symptomatic behaviour of the patient.
Six chronic neuroleptic-resistant schizophrenic patients, partial responders to clozapine, were co-administered 600 mg/day of sulpiride (a selective D(2) dopaminergic antagonist) as an augmentation to clozapine (a relatively weak D(2) blocker), for 10 weeks, open-labeled. A remarkable reduction in positive and negative symptoms was observed in four of the six patients.
The gene encoding catechol- O -methyltransferase (COMT), an enzyme which regulates prefrontal cortex dopamine, contains a common functional single nucleotide polymorphism (val ¹⁵⁸ met, rs4680 G/A), which accounts for part of the interindividual variance in performance during working memory tasks and also predicts personality traits.
We examined the relationship between the val ¹⁵⁸ met polymorphism and cognitive function as well as personality traits in 522 healthy individuals (mean age: 24.75 years, SD = 5.84, mean years of education: 15.59, SD = 2.65).
COMT val ¹⁵⁸ met genotype was related in allele dosage fashion to performance in an executive function test, with the met/met carriers scoring highest. Subjects carrying the met/met genotype also scored higher in the disorganization domain of the SPQ-B personality inventory.
Consistent with evidence from previous studies, higher dopamine availability of the met/met genotype enhances prefrontally mediated executive function in healthy individuals.
Furthermore, we replicated findings from a recent study whereby the COMT genotype also predicts disorganized personality features.
The authors investigated the historical and clinical variables of 159 inpatients affected by mood disorders in order to identify variables which might differentiate psychotic from non-psychotic forms. The results showed that 32% of the patients had psychotic symptoms. Although no significant difference was detected with regard to the severity of depression, psychotic depressives were younger and had a lower age at onset, as well as a shorter episode length. These features suggest that depression may express itself with or without psychotic symptoms, according to the different individual and, perhaps, biological substrate. Taken together, our findings seem to indicate that psychotic depression should not be considered a separate clinical entity, but a subtype of mood disorders.
We have followed up a patient with 8q24.2 --> qter and 15q14 --> pter duplication due to a maternal reciprocal translocation, a condition related to Prader-Willi Syndrome. Apart from dysmorphic features, the patient suffered from recurring episodes of bipolar psychosis. Interestingly, PET scanning revealed revealed prominent bilateral hypometabolism in the frontal, temporal, and parietal lobes as well as in the cerebellum. Possible implications of this rare chromosomal abnormality with regards to psychiatric disorders are discussed, with emphasis on recent evidence suggesting chromosome 15q13-15 as a susceptibility locus for psychosis.
To compare the clinical management of typical scenarios by using three case vignettes in a substantial number of European countries.
Three case vignettes and an associated questionnaire, filled in and finalised by at least two experts from each country.
Legislation and clinical practice varies widely across the 16 included countries. No specific pattern emerged. Certain practices (intravenous medication, mechanical restraint, net beds and forensic transfers, respectively) only exist in few countries. Legislation for involuntary medication is most restrictive in the Netherlands.
There is little harmonisation and a lack of consistent standards within and across European countries regarding treatment and management of violent patients.
From 20,000 households regularly surveyed by a national survey institute (Sofres), two groups were selected and questioned (using a 23-item questionnaire) about sleep vigilance and quality of life. The first group was composed of insomniacs using zopiclone for the last 12 months and no other CNS treatments (167 subjects). The second group was composed of 381 "good sleepers" selected as having no or occasionally one sleep disturbance in the last 12 months. No difference was found between the two groups in average total sleep time. Sleep disturbances were statistically equal in the two groups except for difficulties in initiating sleep which is more present for zopiclone users (13% vs 3%). Vigilance was mostly comparable in both groups.Five aspects of quality of life explored by the questionnaires (the professional, relational and sentimental, domestic, leisure and safety aspects) appeared to be comparable in the two groups.