Joint Crisis Plans and Crisis Cards in Inpatient Psychiatric Treatment­a Multicenter Randomized Controlled Trial

BACKGROUND: Joint Crisis Plans (JCP) and crisis cards (CC) are both instruments designed to improve the management of future psychiatric crisis situations, but they differ, for example, in terms of resource use, legal validity, and aims. International research findings for JCP are inconsistent. METHODS: From January 2018 to December 2020, a single-blinded, two-armed multicenter RCT was carried out, with assessments at T0 (baseline) and T1 (18 months later). The patients included had schizophrenia or schizoaffective disorder and were aged between 18 and 62 years. The primary outcome was the cumulative duration of inpatient treatment (voluntary/involuntary), and coercive measures comprised the secondary outcome. Trial registration: DRKS00013985. RESULTS: Of the 266 study participants, 157 completed the study. In the CC group 57.8% and in the JCP group 64.9% were admitted to psychiatric hospitals between the index treatment and T1 (p = 0.367); 8.4% of the CC group and 12.2% of the JPC group were admitted against their will (p = 0.441). The cumulative treatment duration was not significantly shorter (p = 0.631) in the JPC group (mean 42.43 days, SD = 48.60) than in the CC group (50.16 days, SD = 74.16). Thus, JPCs did not achieve the expected improvement with regard to the primary endpoint. There were also no relevant differences regarding the secondary endpoint. Major effects in favor of the JCP were observed, however, in patients' development of conficence in the treatment teams and in their active participation in the treatment procedure. CONCLUSION: Although the study showed no superiority of JCP over CC with regard to the primary and secondary outcomes, JCP should be used more frequently in routine practice as an intervention to support a participative approach to treatment.

Psychosocial functioning as a personal resource promoting a milder course of schizophrenia.

Schizophrenia has been shown repeatedly to be associated with a low level of psychosocial functioning. It is assumable that psychosocial functioning is related not only to current, but also to future symptom severity. To test this assumption, a follow-up study with two measurement time points with an interval of 18 months was conducted. In total, 154 inpatients from five psychiatric hospitals with a diagnosis of a schizophrenic disorder took part at both visits. Psychosocial functioning was measured with the Personal and Social Performance Scale (PSP scale) at baseline, and schizophrenic symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS) at baseline and at follow-up. Two PSP subscales, i.e. socially useful activities and control over disturbing and aggressive behavior, turned out to be significant predictors of symptom severity 18 months later. The findings reveal that personal resources in the occupational domain and in adequate interpersonal behavior can have a positive impact on the long-term course of schizophrenia.

[Weighing the benefits and harms of psychotropic and analgesic substances - A perspective of German addiction medicine experts]. / Abwägung von Nutzen und Schädlichkeit von berauschenden und schmerzlindernden Substanzen aus der Perspektive von deutschen Suchtmedizinern.

BACKGROUND: In Europe, there have been several addiction-expert rankings of harms related to the use of psychotropic substances in the last 15 years. Among them, only one expert ranking took into account the potential benefits of these drugs. Non-Opioidergic Analgesics (NOAs), such as gabapentinoids and NSAIDs, which have been increasingly the subject of abuse / misuse reports, have not been considered in such expert rankings. Likewise, there is currently no multi-substance comparison as to whether the valuation rank of the harmfulness of an illegal drug may change along with an imagined change in legal status in Germany. OBJECTIVES AND METHODS: Using a questionnaire, 101 experienced addiction physicians (first cohort) evaluated 33 psychoactive substances including analgesics with regard to their health and social harms as well as potential usefulness for the consumer and their environment / society ('others'). In addition, this cohort investigated whether the harmfulness assessment of an illegal substance changes if it would be legalized. In order to obtain the average overall harmfulness (overall risk) of a substance, the percentage contribution of each dimension to the overall harmfulness was determined in a second survey (second cohort, 36 experienced addiction medicine experts). Finally, the average benefit and overall risk ratings of each substance were related to each other. RESULTS: Prescription psychoactive substances such as analgesics, NOAs (including gabapentinoids) and opioidergic maintenance medications to treat opiate dependence were judged to have a favorable benefit-harm profile. Cannabis and ketamine were placed in the midfield of both, the harm and benefit rankings. Together with most illicit narcotic drugs, alcohol and nicotine, have been ranked among the most harmful and least useful substances, whereby alcohol was judged on average to be more harmful but also more useful than nicotine. In the event of potential legalization, the overall harm of the traditional illegal drugs methamphetamine, heroin, cocaine and cannabis was estimated to be reduced. This was mainly due to a more favorable valuation of the harm to others under these virtual conditions. CONCLUSION: Prescription substances including opioidergic and non-opioidergic analgesics as well as opioid maintenance therapy medications (methadone and buprenorphine) were assigned a favorable benefit-harm profile. Alcohol, nicotine and traditional illicit drugs (with the exception of cannabis and ketamine) were determined to have an unfavorable profile. The overall harm of traditional illicit drugs was assessed to decrease along with legalization, mainly by decreasing the harm to others in this virtual event.

Availability of Illegal Drugs During the COVID-19 Pandemic in Western Germany.

Background: In response to the COVID-19-pandemic, a lockdown was established in the middle of March 2020 by the German Federal Government resulting in drastic reduction of private and professional traveling in and out of Germany with a reduction of social contacts in public areas. Research Questions: We seek evidence on whether the lockdown has led to a reduced availability of illegal drugs and whether subjects with substance-related problems tried to cope with possible drug availability issues by increasingly obtaining drugs via the internet, replacing their preferred illegal drug with novel psychoactive substances, including new synthetic opioids (NSO), and/or by seeking drug treatment. Methods: A questionnaire was anonymously filled in by subjects with substance-related disorders, typically attending low-threshold settings, drug consumption facilities, and inpatient detoxification wards from a range of locations in the Western part of Germany. Participants had to both identify their main drug of abuse and to answer questions regarding its availability, price, quality, and routes of acquisition. Results: Data were obtained from 362 participants. The most frequent main substances of abuse were cannabis (n = 109), heroin (n = 103), and cocaine (n = 75). A minority of participants reported decreased availability (8.4%), increased price (14.4%), or decreased quality (28.3%) of their main drug. About 81% reported no change in their drug consumption due to the COVID-19 pandemic and the lockdown. A shift to the use of novel psychoactive substances including NSO were reported only by single subjects. Only 1-2% of the participants obtained their main drug via the web. Discussion: Present findings may suggest that recent pandemic-related imposed restrictions may have not been able to substantially influence either acquisition or consumption of drugs within the context of polydrug users (including opiates) attending a range of addiction services in Germany.

High lifetime, but low current, prevalence of new psychotropic substances (NPS) use in German drug detoxification treatment young inpatients.

BACKGROUND: Over the last 15 years, a large number of new psychoactive substances (NPS) has been identified, with their use being associated with a range of acute medical and psychopathological complications. Conversely, NPS addictive liability levels have not been systematically assessed in clinical populations. AIMS OF THE STUDY: Investigating the lifetime and current prevalence of NPS use in a sample of substance use disorder (SUD) patients admitted to an inpatient detoxification treatment centre. METHODS: Assessment of previous/current NPS intake carried out with the means of standardised questionnaire based on the European version of Addiction Severity Index. RESULTS: Some 206 patients (males 77.1%; average age: 30.7 years-old; most typical diagnosis: opioid/polydrug dependence) participated to the survey. Roughly half (e.g. 111/206; 53.9%) of them reported a lifetime use of NPS, most typically synthetic cannabinoids. Conversely, the current prevalence of NPS use was 2.9%; no NPS dependence condition was diagnosed. Among NPS users, 56.3% reported severe side-effects such as heavy anxiety or psychotic experience, and 64% reported an aversion of ever using the respective NPS again, whilst 84.3% of those reporting a single NPS intake reported an aversion. DISCUSSION: The sharp contrast between lifetime prevalence of NPS use and prevalence of current use might be explained by the high frequency of severe side effects reported by NPS users.

Ranking the Harm of Psychoactive Drugs Including Prescription Analgesics to Users and Others-A Perspective of German Addiction Medicine Experts.

Background: Over the past 15 years, comparative assessments of psychoactive substance harms to both users and others have been compiled by addiction experts. None of these rankings however have included synthetic cannabinoids or non-opioid prescription analgesics (NOAs, e.g., gabapentinoids) despite evidence of increasing recreational use. We present here an updated assessment by German addiction medicine experts, considering changing Western consumption trends-including those of NOAs. Methods: In an initial survey, 101 German addiction medicine physicians evaluated both physical and psychosocial harms (in 5 dimensions) of 33 psychoactive substances including opioids and NOAs, to both users and others. In a second survey, 36 addiction medicine physicians estimated the relative weight of each health and social harm dimension to determine the overall harm rank of an individual substance. We compared our ranking with the most recent European assessment from 2014. Results: Illicit drugs such as methamphetamine, heroin, cocaine and also alcohol were judged particularly harmful, and new psychoactive drugs (cathinones, synthetic cannabinoids) were ranked among the most harmful substances. Cannabis was ranked in the midrange, on par with benzodiazepines and ketamine-somewhat more favorable compared to the last European survey. Prescribed drugs including opioids (in contrast to the USA, Canada, and Australia) were judged less harmful. NOAs were at the bottom end of the ranking. Conclusion: In Germany, alcohol and illicit drugs (including new psychoactive substances) continue to rank among the most harmful addictive substances in contrast to prescribed agents including opioid analgesics and NOAs. Current laws are incongruent with these harm rankings. This study is the first of its kind to include comparative harm rankings of several novel abused substances, both licit/prescribed and illicit.

Joint versus separate inpatient rehabilitation treatment for patients with alcohol use disorder or drug use disorder: an observational study.

BACKGROUND: In many national treatment systems, patients with alcohol use disorders (AUD) and those with drug use disorders (DUD) are treated separately, while other systems provide joint treatment for both kinds of substance use disorders (SUDs). Regarding long-term rehabilitation treatment of DUD and AUD patients, there is however a lack of empirical studies on the comparison between a separate versus joint treatment modality. METHODS: Data were gathered from 2 rehabilitation units located in small towns from the same German region. One unit provided treatment to a mixed group of AUD and DUD patients, while the other unit treated the 2 groups separately. Staffing, funding, and treatment programs were otherwise similar between facilities. Data were gathered from standardized routine documentation and standardized interviews. In order to understand correlates of premature treatment termination, a logistic regression analysis was performed, with treatment modality and type of SUD as main predictors, and a range of patient characteristics as covariates. RESULTS: Patients (N=319) were diagnosed with AUD (48%), DUD (34%), or AUD plus DUD (18%). Patients in joint treatment showed a higher prevalence of lapses during treatment than those in separate treatment (26% versus 12%; p=0.009), but there was no significant difference in the prevalence of premature terminations (38% versus 44%, p=0.26). Treatment modality and interaction between modality and type of SUD was not significantly associated with premature termination. Joint treatment completers showed higher satisfaction with treatment than separate treatment completers (p<0.001). CONCLUSION: We found no evidence here for a difference between treatment modalities in terms of premature termination rate. Satisfaction level was higher in those who completed joint treatment compared to separate treatment.

"This Treatment Can Really Help Me"-A Longitudinal Analysis of Treatment Readiness and Its Predictors in Patients Undergoing Alcohol and Drug Rehabilitation Treatment.

BACKGROUND: There is evidence that patients entering alcohol or drug treatment have different levels of treatment readiness and change their motivation differently over time. Nonetheless, existing studies mainly use single measures of motivation and do not consider individual differences. This study addresses 2 questions: (i) How does treatment readiness change in patients with alcohol and drug use dependence over the course of an inpatient rehabilitation treatment?; and (ii) Can changes in treatment readiness be explained by sociodemographic and substance use-related characteristics? METHODS: Data from 177 alcohol-dependent patients and 152 drug-dependent patients were collected in 2 inpatient rehabilitation centers in Germany. Three single-item indicators of treatment readiness were assessed weekly over the course of the treatment. Sociodemographic and substance use-related characteristics were assessed at baseline. To model developments of treatment readiness that may be different for each patient, multilevel analyses for longitudinal data were used. RESULTS: The overall effect of time on treatment readiness was not significant, indicating that average motivation across all patients did not change over the course of the treatment. However, individuals showed different initial states and different rates of change. School education, employment status, earlier substance use treatments, and craving predicted treatment readiness. Interactions with time were found for craving and marital status. CONCLUSIONS: The results suggest that it is necessary to consider individual differences when evaluating treatment motivation in alcohol- and drug-dependent patients. The identification of variables predicting motivation may help to improve substance abuse treatment contents and outcomes.

[Research with big data: the European perspective]. / Forschung mit Big Data - die europäische Perspektive.

The article examines the impact that legislative developments in the European Union have had, still have and are continuing to have on cross-border access to microdata for research purposes. Therefore, we describe two competing aims: the tension between the ambitions of the EU to create a European Research Area within which research communities gain access to and share data across national boundaries; and the desire within the EU to establish a harmonious legislative framework that provides protection from the misuse of personal information. We attempt to examine which new developments at the EU level will have an impact upon research plans and the challenges researchers face when analysing big data.

Cohort profile: the lidA Cohort Study-a German Cohort Study on Work, Age, Health and Work Participation.

The lidA Cohort Study (German Cohort Study on Work, Age, Health and Work Participation) was set up to investigate and follow the effects of work and work context on the physical and psychological health of the ageing workforce in Germany and subsequently on work participation. Cohort participants are initially employed people subject to social security contributions and born in either 1959 (n = 2909) or 1965 (n = 3676). They were personally interviewed in their homes in 2011 and will be visited every 3 years. Data collection comprises socio-demographic data, work and private exposures, work ability, work and work participation attitudes, health, health-related behaviour, personality and attitudinal indicators. Employment biographies are assessed using register data. Subjective health reports and physical strength measures are complemented by health insurance claims data, where permission was given. A conceptual framework has been developed for the lidA Cohort Study within which three confirmatory sub-models assess the interdependencies of work and health considering age, gender and socioeconomic status. The first set of the data will be available to the scientific community by 2015. Access will be given by the Research Data Centre of the German Federal Employment Agency at the Institute for Employment Research (http://fdz.iab.de/en.aspx).

The lunar cycle, sunspots and the frequency of births in Germany, 1920-1989.

Based on multivariate linear regression models, we analyze the effect of the lunar cycle and the number of sunspots occurring on a particular day on the number of births using social security data and controlling for a number of other potential confounders. The daily numbers of births between 1920 and 1989 have been calculated from the full sample of individuals who have been registered at least once in the German social security system. While the lunar cycle does not affect the number of births, the number of sunspots is positively correlated to the number of births. The empirical results may be explained by medical technological progress making natural influences on births less important over time. This interpretation is supported by the results on the intertemporal influence of weekends and holidays on the frequency of daily births.

Internal capsule size associated with outcome in first-episode schizophrenia.

Subtle structural brain abnormalities are an established finding in first-episode psychosis. Nevertheless their relationship to the clinical course of schizophrenia is controversially discussed. In a multicentre study 45 first-episode schizophrenia patients (FE-SZ) underwent standardized MRI scanning and were followed up to 1 year. In 32 FE-SZ volumetric measurement of three regions of interests (ROIs) potentially associated with disease course, hippocampus, lateral ventricle and the anterior limb of the internal capsule (ALIC) could be performed. The subgroups of FE-SZ with good (12 patients) and poor outcome (11 patients), defined by a clinically relevant change of the PANSS score, were compared with regard to these volumetric measures. Multivariate analysis of covariance revealed a significant reduced maximal cross sectional area of the left ALIC in FE-SZ with clinically relevant deterioration compared to those with stable psychopathology. There were no differences in the other selected ROIs between the two subgroups. In conclusion, reduced maximal area of ALIC, which can be interpreted as a disturbance of fronto-thalamic connectivity, is associated with poor outcome during the 1 year course of first-episode schizophrenia.

Maintenance treatment with risperidone or low-dose haloperidol in first-episode schizophrenia: 1-year results of a randomized controlled trial within the German Research Network on Schizophrenia.

OBJECTIVE: Second-generation antipsychotics (SGAs) have proven superior to first-generation antipsychotics regarding relapse prevention, mainly in multiple-episode patients. Practice guidelines recommend SGAs as first-line treatment particularly in first-episode patients, although evidence for this group is still limited. Accordingly, the hypothesis of whether 1-year relapse rate in first-episode schizophrenia under maintenance treatment with risperidone is lower compared to haloperidol in low dose was tested. METHOD: Between November 2000 and May 2004, 1372 patients had been screened for eligibility in the inpatient facilities of 13 German psychiatric university hospitals. 159 remitted patients were enrolled after treatment of an acute first episode of schizophrenia according to ICD-10 F20 criteria. In the randomized controlled trial, double-blind antipsychotic treatment with risperidone or haloperidol was maintained in a targeted dose of 2 to 4 mg/day for 1 year. 151 patients were eligible for analysis. For 127 patients, this was a continuation trial after 8 weeks of randomized, double-blind, acute treatment with the same drugs; 24 patients were additionally randomly assigned after open acute treatment. RESULTS: With both antipsychotics (risperidone, N = 77; haloperidol, N = 74), no relapse evolved. Additionally, according to 2 post hoc defined measures of "marked clinical deterioration," significant differences occurred neither in the 2 respective deterioration rates (risperidone = 9%/23%; haloperidol = 8%/22%) nor in time until deterioration. Both antipsychotics were equally effective regarding significant symptom reduction and improvement in quality of life. Extrapyramidal symptoms were slightly higher with haloperidol. The overall dropout rate of 68%, however, was not significantly different between the 2 drug groups. CONCLUSION: Against the background of an overall favorable outcome, the hypothesized difference between risperidone and low-dose haloperidol regarding relapse prevention could not be supported for this sample of patients with first-episode schizophrenia. Possible design-related reasons for this finding are discussed. With regard to the high dropout rate, special programs are needed to keep schizophrenia patients who are in their early acute and postacute illness course in effective and safe treatment. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT00159081.

The intensity dependence of auditory ERP components in unmedicated patients with major depression and healthy controls. An analysis of group differences.

BACKGROUND: The intensity dependent amplitude change (IDAP) of auditory evoked Event Related Potential (ERP) components has been found to correlate with the level of central serotonergic neurotransmission and to be associated with response to certain antidepressants. However, it is currently unknown whether there is a general abnormality of the IDAP in patients with major depression. Therefore, the purpose of the present study was to compare the IDAP in unmedicated depressed patients with that of healthy control subjects. METHODS: We report the results of a study evaluating the change of auditory evoked P1, N1, P2 as well as P1/N1 and N1/P2 peak to peak amplitudes in 34 in-patients with major depressive episode prior to antidepressant treatment, and 44 healthy control subjects. Clinical symptoms of depression were assessed by means of standardized psychiatric rating scales (CGI, HDRS, HAMA and BDI). RESULTS: In multivariate analyses of variance we found no group differences in the intensity dependent increase neither of the P1, N1, and P2 nor of the P1/N1 and N1/P2 peak to peak amplitudes between patients and controls. CONCLUSIONS: Our data revealed no general abnormality of the IDAP in patients with major depression in comparison to healthy control subjects. This result suggests that specific alterations of the IDAP are not to be expected in major depression in general, these may be confined to subgroups of depressed patients.

The efficacy of the dopamine D2/D3 antagonist tiapride in maintaining abstinence: a randomized, double-blind, placebo-controlled trial in 299 alcohol-dependent patients.

In this investigation, the hypothesis was tested whether the selective dopamine D2/D3 receptor antagonist tiapride is effective in maintaining abstinence after detoxification in alcohol-dependent patients. The rationale of the study was based on the relevance of the dopaminergic system for addictive behaviour as well as some preliminary studies. A multi-centre, randomized, double-blind, placebo-controlled, parallel-group study was conducted. A total of 299 detoxified alcohol-dependent patients (ICD-10: F10.2) received either tiapride (300 mg/d) or placebo over a 24-wk study period. Subjects with severe comorbid psychiatric disorder such as schizophrenia or Wernicke-Korsakoff syndrome were excluded. Primary outcome variable was the time to first relapse with relapse defined as any alcohol consumption after detoxification. Data analysis was done with Kaplan-Meier estimates with log-rank test (one-sided, p<0.05). Tiapride was not superior to placebo in maintaining abstinence. The time to first relapse was 71 d in the tiapride group and 92 d in the placebo group (log-rank test, p=0.9895). Relapse rate was higher in the intervention group (54.4%) than in the control group (40.7%). Like the dopamine antagonist flupenthixol, tiapride was not effective in maintaining alcohol abstinence. Regarding the high success rate in the placebo group the influence of psychosocial treatment in studies investigating drug effects on the course of alcohol dependence has to be considered.

Influence of atypical neuroleptics on executive functioning in patients with schizophrenia: a randomized, double-blind comparison of olanzapine vs. clozapine.

Accepted clinical evidence suggests superior efficacy of novel antipsychotics in the treatment of cognitive symptoms in schizophrenia. Whether this constitutes a primary drug effect or a secondary effect due to easing extrapyramidal side-effects or improving positive symptoms when converting from a first- to a second-generation neuroleptic is still open to debate. Long-term efficacy as well as differential drug effects on cognitive performance are also poorly documented. We therefore compared cognitive performance of olanzapine vs. clozapine treatment in a controlled, randomized, double-blind trial. Fifty-four patients were assessed following a 2- to 9-day washout and again after 4 and 26 wk of neuroleptic treatment. Patients were rated on the PANSS for psychopathological changes, extrapyramidal side-effects were assessed on the Simpson-Angus Scale, and cognitive performance was assessed with the Stroop, Wisconsin Card Sorting and the Tower of London tests. Schizophrenia symptoms, extrapyramidal side-effects and cognitive performance improved significantly in the course of either drug treatment. Stroop test performance and Tower of London planning time improved significantly over 26 wk compared to baseline and 4-wk follow-up assessment while Wisconsin Card Sorting and Tower of London execution time improved significantly after 4 wk with no further improvement after 26 wk. Improved executive function was not related to improving positive symptoms and easing extrapyramidal side-effects, thus indicative of a primary treatment effect of either antipsychotic. However, Stroop reaction time improved with olanzapine while clozapine had a stronger effect on improving negative symptoms, thus suggestive of a differential drug effect.

Functional MRI BOLD response to Tower of London performance of first-episode schizophrenia patients using cortical pattern matching.

Due to its three-dimensional folding pattern, the human neocortex poses a challenge for accurate co-registration of grouped functional brain imaging data. The present study addressed this problem by employing three-dimensional continuum-mechanical image-warping techniques to derive average anatomical representations for co-registration of functional magnetic resonance brain imaging data obtained from 10 male first-episode schizophrenia patients and 10 age-matched male healthy volunteers while they performed a version of the Tower of London task. This novel technique produced an equivalent representation of blood oxygenation level dependent (BOLD) response across hemispheres, cortical regions, and groups, respectively, when compared to intensity average co-registration, using a deformable Brodmann area atlas as anatomical reference. Somewhat closer association of Brodmann area boundaries with primary visual and auditory areas was evident using the gyral pattern average model. Statistically-thresholded BOLD cluster data confirmed predominantly bilateral prefrontal and parietal, right frontal and dorsolateral prefrontal, and left occipital activation in healthy subjects, while patients' hemispheric dominance pattern was diminished or reversed, particularly decreasing cortical BOLD response with increasing task difficulty in the right superior temporal gyrus. Reduced regional gray matter thickness correlated with reduced left-hemispheric prefrontal/frontal and bilateral parietal BOLD activation in patients. This is the first study demonstrating that reduction of regional gray matter in first-episode schizophrenia patients is associated with impaired brain function when performing the Tower of London task, and supports previous findings of impaired executive attention and working memory in schizophrenia.

The intensity dependence of the auditory evoked N1 component as a predictor of response to Citalopram treatment in patients with major depression.

The intensity dependence of the auditory evoked N1 ERP component (IDAP) has been suggested as an indicator of central serotonergic neurotransmission with relevance to pharmacological treatment. We report the results of a study evaluating the IDAP in 16 in-patients fulfilling DSM-IV criteria for major depressive episode in the course of treatment with the SSRI Citalopram. Our data revealed a significant correlation between the intensity slopes of the N1 amplitude prior to Citalopram treatment and treatment response: patients with higher intensity slopes of N1 amplitude showed a significantly stronger decrease of HDRS-Score after Citalopram treatment than patients within the lower intensity slope ranges. Our results indicate an association of N1 amplitude intensity dependence with response to antidepressant treatment with Citalopram.

Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene.

Clozapine (CLO), an atypical antipsychotic, depends mainly on cytochrome P450 1A2 (CYP1A2) for its metabolic clearance. Four patients treated with CLO, who were smokers, were nonresponders and had low plasma levels while receiving usual doses. Their plasma levels to dose ratios of CLO (median; range, 0.34; 0.22 to 0.40 ng x day/mL x mg) were significantly lower than ratios calculated from another study with 29 patients (0.75; 0.22 to 2.83 ng x day/mL x mg; P < 0.01). These patients were confirmed as being CYP1A2 ultrarapid metabolizers by the caffeine phenotyping test (median systemic caffeine plasma clearance; range, 3.85; 3.33 to 4.17 mL/min/kg) when compared with previous studies (0.3 to 3.33 mL/min/kg). The sequencing of the entire CYP1A2 gene from genomic DNA of these patients suggests that the -164C > A mutation (CYP1A2*1F) in intron 1, which confers a high inducibility of CYP1A2 in smokers, is the most likely explanation for their ultrarapid CYP1A2 activity. A marked (2 patients) or a moderate (2 patients) improvement of the clinical state of the patients occurred after the increase of CLO blood levels above the therapeutic threshold by the increase of CLO doses to very high values (ie, up to 1400 mg/d) or by the introduction of fluvoxamine, a potent CYP1A2 inhibitor, at low dosage (50 to 100 mg/d). Due to the high frequency of smokers among patients with schizophrenia and to the high frequency of the -164C > A polymorphism, CYP1A2 genotyping could have important clinical implications for the treatment of patients with CLO.