A Systematic Review of Clozapine Concentration-Dose Ratio from Therapeutic Drug Monitoring Studies in Children and Adolescents Treated with Clozapine for Mental Disorders.

BACKGROUND: Therapeutic drug monitoring of clozapine in children and adolescents has received insufficient attention. Calculation of concentration-to-dose (C/D) ratios from trough steady-state concentrations estimate drug clearance. METHODS: A systematic electronic literature search was conducted in 3 article databases from inception until January 10, 2023, and articles reporting clozapine concentrations in children and adolescents were retrieved. The pharmacokinetic quality of the studies was assessed, and clozapine C/D ratios were calculated using the sample mean clozapine dose and concentration. RESULTS: Of the 37 articles of potential interest, only 7 reported clozapine trough and steady-state concentrations. After excluding case reports and a study confounded by fluvoxamine, 4 studies on psychosis from Europe and the United States were included. The clozapine C/D ratios were similar to published adult values and ranged from 0.82 to 1.24 with a weighted mean of 1.08 ng/mL per mg/d. The weighted means were 334 mg/d for the dose and 380 ng/mL for the concentration. The stratified analysis of the weighted mean clozapine C/D ratios from 2 studies showed lower values in 52 male (1.05 ng/mL per mg/d) than in 46 female (1.46 ng/mL per mg/d) children and adolescents, with values similar to those reported for European adult nonsmokers. Two female adolescents had high clozapine C/D ratios (2.54 ng/mL per mg/d), an Asian American patient with borderline obesity and a patient with intellectual disability with low dosage (mean = 102 mg/d) and concentration (mean = 55 ng/mL). CONCLUSIONS: Reports on clozapine therapeutic drug monitoring in children and adolescents are limited in number and quality. Future studies should focus on basic pharmacokinetic issues, such as stratification by sex, smoking, and relevant comedications with inductive or inhibitory properties.

Illness Insight and Medication Adherence Among Patients With Bipolar Disorder.

The aim of this study was to investigate the factors associated with illness insight and medication adherence in bipolar disorder (BD). This is a cross-sectional study (with a retrospective evaluation of longitudinal variables) and a secondary analysis of a BD database. The insight of 108 outpatients (age, 48.2 ± 14.1 years, 69% women, 33% euthymic) was measured with three items of the Association of Methodology and Documentation in Psychiatry scale. Their adherence was assessed through patients' and caregivers' reports, plus serum levels. We performed multivariate logistic regression analyses. Full insight was independently and directly associated with adherence, a social support score, and depressive symptoms and inversely associated with intensity of manic symptoms, problems ever with alcohol, and age at onset of the first symptoms. Medication adherence was independently and directly associated with insight, being married, and having had a psychiatric hospitalization and inversely with having suffered a high number of depressive episodes, intensity of manic symptoms, and heavy tobacco smoking.

Temperament traits and remission of depression: A naturalistic six-month longitudinal study.

BACKGROUND: The aim of this naturalistic longitudinal study was to add evidence regarding the potential of Cloninger's temperament traits (novelty seeking, harm avoidance, reward dependence and persistence) for predicting the effect of pharmacological treatment on the rates of therapeutic response and remission. METHODS: The study was based on 200 outpatients with unipolar depressive disorders of different severity and course of illness, and extended up to 6 months of follow-up. Patients were assessed in their temperament with the Tridimensional Personality Questionnaire (TPQ) and their condition was classified (in course and severity) according to the International Classification of Diseases, Tenth revision (ICD-10) diagnostic criteria for research. Patients were blindly rated (concerning other predicting variables) on the improved Clinical Global Impression-Severity scale for depression (iCGI-S) at baseline, 6 weeks, 3 months and 6 months. Outcome measures at the last observation carried forward were therapeutic response (reduction of ≥50% in the last iCGI-S) and remission (last iCGI-S = 0), which were available for 187 patients. RESULTS: Remission was independently and directly associated with length of follow-up, and inversely with the baseline iCGI-S score and harm avoidance (patients in the high tertile had a 2.7 likelihood of non-remission in comparison with those in the low tertile); persistence was found to have a complex, V-shape relationship with remission. Within a sub-sample of more severe cases (n = 118), having higher harm avoidance scores, a more favorable outcome was associated with higher reward dependence and the non-smoking condition. LIMITATIONS: With a naturalistic, non-experimental design, the sample may not be representative of the general population. CONCLUSIONS: Temperament traits may help predict outcome in patients treated for depression.

Temporal sequencing of nicotine dependence and major depressive disorder: A U.S. national study.

Major Depressive Disorder (MDD) and Nicotine dependence (ND) often co-occur. However, little attention has been given to the temporal order between the two disorders. We compared the sociodemographic and clinical characteristics of individuals whose onset of ND preceded (ND-prior) or followed the onset of MDD (MDD-prior). Binary logistic regression models were computed to compare ND-prior (n=546) and MDD-prior (n=801) individuals from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC, n=43,093). We found that MDD-prior were more likely to have a history of suicide attempts and a family history of both depression and antisocial behavior, to have had psychiatric hospitalization, and to have an earlier age of onset of the first depressive episode; but a later age of onset for both daily smoking and ND. On average, MDD-prior individuals showed a significantly longer transition time from daily smoking to ND (15.6±0.6 vs. 6.9±0.4 years, P<0.001). In contrast, ND-prior subjects had a significantly greater proportion of withdrawal symptoms, and of lifetime alcohol use or alcohol use disorder. We conclude that the phenomenology and course of ND and MDD vary significantly, depending on which disorder had earlier onset.

Caffeine consumption in a long-term psychiatric hospital: Tobacco smoking may explain in large part the apparent association between schizophrenia and caffeine use.

This study further explores the association between schizophrenia and caffeine use by combining two prior published Spanish samples (250 schizophrenia outpatients and 290 controls from the general population) with two Spanish long-term inpatient samples from the same hospital (145 with schizophrenia and 64 with other severe mental illnesses). The specific aims were to establish whether or not, after controlling for confounders including tobacco smoking, the association between schizophrenia and caffeine is consistent across schizophrenia samples and across different definitions of caffeine use. The frequency of caffeine use in schizophrenia inpatients was not significantly higher than that in non-schizophrenia inpatients (77%, 111/145 vs. 75%, 48/64) or controls but was significantly higher than in schizophrenia outpatients. The frequency of high caffeine users among caffeine users in schizophrenia inpatients was not significantly higher than in non-schizophrenia inpatients (45%, 50/111 vs. 52%, 25/48) or controls, but was significantly lower than in schizophrenia outpatients. Smoking was significantly associated with caffeine use across all samples and definitions. Between 2 and 3% of schizophrenia inpatients, schizophrenia outpatients and non-schizophrenia inpatients showed caffeinism (>700 mg/day in smokers). Several of these smoking patients with caffeinism were also taking other inducers, particularly omeprazole. The lack of consistent association between schizophrenia and caffeine use is surprising when compared with the very consistent association between tobacco smoking and caffeine use across all of our analyses (use and high use in users) and all our samples. The confounding effects of tobacco smoking may explain in large part the apparent association between schizophrenia and caffeine use.

Dose-response effect between cannabis use and psychosis liability in a non-clinical population: evidence from a snowball sample.

This study aimed to explore the associations between daily cannabis use and the specific profiles of subclinical symptoms in a non-clinical population obtained through snowball sampling, taking into account alcohol use, other drug use, social exclusion and age at onset of cannabis use. We included 85 daily cannabis users and 100 non-daily cannabis users. Both the case and the control populations were identified by snowball sampling. Daily cannabis use was associated with more alcohol intake and other drug use, as well as with early onset in the use of cannabis. Daily cannabis use appeared to exert a dose-response effect on first-rank symptoms, mania symptoms and auditory hallucinations, even after adjusting for sex, age, other drug use, social exclusion and age at onset of cannabis use. The paranoid dimension was only associated with the heaviest consumption of cannabis. Initial age of cannabis use modified the effects of daily cannabis use on the first-rank and voices experiences. Daily cannabis use was associated with significantly more first-rank and voices experiences among those subjects who started to use cannabis before 17 years of age. Our study supports the association of psychotic experiences with cannabis use even among non-psychotic subjects.

Adherence to the Mediterranean dietary pattern and personality in patients attending a primary health center.

Personality influences lifestyle behaviors, and particularly dietary behavior. The possible association of personality with adherence to the Mediterranean diet pattern (MDP) has not been reported. The objective of this study was to analyze the possible association of personality traits with adherence to the MDP, controlling for sociodemographic variables, presence of chronic illnesses, minor psychiatric morbidity, body mass index (BMI), daily smoking, and physical activity. This cross-sectional study included 206 patients, age 18 to 65 years, recruited at a primary health service in Granada, Spain, during 2007 to 2008. The participants answered a questionnaire, including sociodemographic characteristics, data on personality, and MDP. Personality was measured by the Temperament and Character Inventory (TCI-125). Adherence to MDP was measured using the validated 14-point Mediterranean Diet Adherence Screener (MEDAS). MEDAS score was directly associated with the character dimension of self-directedness, age, and minor psychiatric morbidity score; and inversely with marital status (widowed, separated, or divorced) and BMI. Because highly self-directed individuals may respond better to diet advice, consideration of personality may prove helpful in the design of interventions to enhance the adherence to MDP. To improve the adherence to MDP in interventions with patients with low self-directedness, more intensive professional support and counseling with tailored messages about the health benefits of MDP may be indicated.

Temporal relationship of first-episode non-affective psychosis with cannabis use: a clinical verification of an epidemiological hypothesis.

BACKGROUND: We analyzed the association of age at onset of psychosis treatment (AOPT) with having a history of cannabis use in patients with a first episode of non-affective psychosis. We also investigated the impact on the AOPT of exposure to cannabis in adolescence, compared with young adulthood, and of the additional exposure to cocaine. METHOD: We recruited 112 consecutive patients (66 men and 46 women; age range, 18-57years) with a first psychotic episode. The composite international diagnostic interview (CIDI) was used to assess drug use and to define the age at onset of heaviest use (AOHU) of a drug, defined as the age when drug was used the most for each patient. The effect of cannabis and cocaine AOHU on AOPT was explored through Kruskal-Wallis and Mann-Whitney tests, and logistic regression. Sex-adjusted cumulative hazard curves and Cox regression models were used to compare the AOPT of patients with and without a history of cannabis use, or associated cocaine use. RESULTS: We found that the AOPT was significantly associated with the use of cannabis, independently of sex, use of cocaine, tobacco smoking or excessive alcohol consumption. There was a dose-response relationship between cannabis AOHU and AOPT: the earlier the AOHU the earlier the AOPT. Hazard curves showed that patients with a history of cannabis use had a higher hazard of having a first-episode psychosis than the rest of the patients (sex-adjusted log-rank chi(2)=23.43, df=1, p<0.001). Their respective median AOPT (25th, 75th percentiles) were 23.5 (21, 28) and 33.5years (27, 45) (for log-transformed AOPT, t=5.6, df=110, p<0.001). The sex-adjusted hazard ratio of psychosis onset comparing both groups was 2.66 (95% CI, 1.74-4.05). CONCLUSIONS: Our results are in favor of a catalytic role for cannabis use in the onset of psychosis.

Nicotine dependence vs. daily smoking as a meaningful variable: implications for clinical and epidemiological psychiatric studies.

OBJECTIVE: As an indication of potential psychopathology, our aim was to compare, in a non-psychiatric sample, the variables associated to daily smoking with those associated to nicotine dependence. We also compared dependent and non-dependent smokers on these variables and on the age of onset of daily smoking (AODS). METHOD: A sample of 290 persons aged 18 or older, recruited in a family medical clinic, were interviewed to inquire about their tobacco, caffeine, alcohol, and illegal drugs consumption, and on their practice of physical exercise. Psychiatric morbidity was assessed with the General Health Questionnaire (GHQ-28) and defined by a score>6. They also were questioned on their use of psychotropic medication and previous suicide attempt. The smokers answered the Fagerström Test for Nicotine Dependence (FTND) and the question on their age of onset of daily smoking (AODS). RESULTS: In comparison with non-dependent smoking, nicotine dependence was associated with current use of psychotropic medication, psychiatric morbidity, previous suicide attempt, and earlier AODS. Logistic regression analyses showed that nicotine dependence was associated with antecedents of suicide attempt and primary or lower education as well as with high caffeine use and the regular use of illegal drugs; in contrast, daily smoking showed a significant association with high caffeine use, the regular use of illegal drugs and lack of physical exercise. CONCLUSIONS: In terms of psychopathology or behavioral disturbance-particularly attempting suicide-nicotine dependence adds significant information as opposed to the simple daily smoking, with important implications in clinical and epidemiological psychiatric studies.

Personality traits associated with caffeine intake and smoking.

OBJECTIVES: Some studies find a relationship between certain personality traits, as impulsivity or sensation seeking, and caffeine consumption, but these studies do not consider the potential confounding effect of smoking on caffeine intake, a co-occurrence that has been well demonstrated in epidemiological and clinical studies. The main objective of this cross-sectional study was to analyze the association of personality with caffeine intake controlling for the effects of smoking; a secondary objective was to explore the effect of caffeine intake on the previously known relationship between personality and smoking. METHODS: A sample of 498 adults answered a self-questionnaire including socio-demographic variables, and items regarding consumption of tobacco and caffeine. Personality was measured by the Temperament and Character Inventory (TCI-125). We analyzed the association of personality traits with both caffeine intake and smoking, controlling the possible confounding effects of sex, age and each substance with the other one. RESULTS: Logistic regression analyses showed that the temperamental dimension of novelty seeking was associated with heavy caffeine consumption (>200 mg/day) (adjusted OR=2.0; 95% CI: 1.1-3.9), controlling for the effect of smoking. Moreover, novelty seeking was associated with both smoking (adjusted OR=1.8; 95% CI: 1.1-2.9) and heavy smoking (>20 cigarettes/day) (adjusted OR=1.8; 95% CI: 1.0-3.7), after controlling for the effect of caffeine intake. CONCLUSION: Our study offers an epidemiological evidence of the relationship of novelty seeking, considered to be associated with low basal dopaminergic activity, with both nicotine consumption and heavy caffeine intake, two substances that enhance dopaminergic neurotransmission.

Subjective effects and the main reason for smoking in outpatients with schizophrenia: a case-control study.

This study examines in daily smokers (1) subjective effects and main reason for smoking after controlling for nicotine dependence level in 100 controls and 173 patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, schizophrenia and (2) the association of specific subjective effects and schizophrenia symptoms. The subjective effects and the main reason for smoking were studied using a questionnaire and the schizophrenia symptoms with the Positive and Negative Syndrome Scale. Proportions were compared by odds ratios controlling for the effects of sex, age, education, and level of nicotine dependence by logistic regression. Schizophrenia was strongly associated with subjective effects of cheerfulness, agility, alertness, concentration, and calmness. In patients with schizophrenia, a cheerfulness effect was associated with higher depressive symptoms; a calming effect, with higher anxiety symptoms; and a sociability effect, with lower negative symptoms. Compared with controls, desire for calmness as the main reason for smoking was more frequent in patients with schizophrenia. These survey data call for confirmation through experimental studies and may help in the design of more focused smoking cessation programs for these patients.

Does smoking reduce akathisia? Testing a narrow version of the self-medication hypothesis.

BACKGROUND: The self-medication hypothesis proposes that schizophrenia patients smoke to decrease their schizophrenia symptoms or antipsychotic side effects, but they usually start smoking before their illness and heavy smoking is not consistently associated with fewer symptoms or side effects. A narrow version of the self-medication hypothesis, heavy smoking reduces akathisia, is explored. METHOD: The sample included 250 outpatients with DSM-IV schizophrenia assessed with the Positive and Negative Syndrome Scale (PANSS) and the Barnes Akathisia Scale. Prevalences were 69% (173/250) for smoking, 39% (98/250) for heavy smoking (> or =30 cigarettes/day), 7% (17/250) for akathisia (Barnes Global score>1), 14% (35/250) for a broader akathisia definition (Barnes Global score>0) and 20% for excited symptoms (>1 on the PANSS factor score). RESULTS: Heavy smoking was not associated with akathisia (41% of patients with akathisia were heavy smokers versus 39% of patients without akathisia; chi2=0.3, df=1, p=0.86), even after correcting for confounding factors and/or using a broader akathisia definition. Heavy smoking was associated with excited schizophrenia symptoms (possibly reflecting agitation). Particularly in patients taking lower doses of typical antipsychotics, excited symptoms, with or without akathisia, were strongly associated with heavy smoking and appear to interact with patients' reports of smoking's calming effect as the main reason for smoking. CONCLUSION: The self-medication hypothesis does not explain increased smoking and heavy smoking in schizophrenia. Moreover, heavy smoking may be associated with more disturbed brain homeostatic mechanisms. Prospective studies need to explore whether temporary increases in cigarette smoking may be associated with periods of higher agitation, with or without akathisia.

Fewer but heavier caffeine consumers in schizophrenia: a case-control study.

According to the literature, there is an association between schizophrenia and caffeine consumption, but it is not clear whether schizophrenia is associated with either higher prevalence of daily caffeine intake or the amount consumed. In this study we compared our previously published schizophrenia patients (n=250) with a control sample (n=290) after controlling for demographic variables and tobacco and alcohol consumption. Current caffeine intake was less frequent in schizophrenia patients (59%, 147/250) than in controls (70%, 204/290). In the multivariate analyses, caffeine intake was less frequent at an older age and in schizophrenia patients, and more frequent in smokers and alcohol users. Among caffeine consumers, heavy caffeine intake (> or =200 mg/day) was significantly associated with schizophrenia (64%, 94/147 in schizophrenia versus 36%, 73/204 in controls), as well as older age and smoking. Daily amount of caffeine intake and smoked cigarettes correlated significantly in the schizophrenia group but not in the control group; the correlation of caffeine intake with nicotine dependence was low and non-significant in both groups. The association between current smoking and heavy caffeine intake may be partly explained by a pharmacokinetic effect: tobacco smoke compounds induce caffeine metabolism by the cytochrome P450 1A2. Although schizophrenia by itself may be associated with heavy caffeine intake in caffeine users, part of this association was explained by the association between schizophrenia and smoking. The relationship between caffeine and alcohol intake appeared to be more complex; alcohol and caffeine use were significantly associated, but within caffeine users alcohol was associated with less frequent heavy caffeine consumption among smokers. In future studies, the measurement of plasma caffeine levels will help both to better define heavy caffeine intake and to control for smoking pharmacokinetic effects.

Nicotine dependence, use of illegal drugs and psychiatric morbidity.

The purpose of this study was to examine the association of smoking and nicotine dependence with psychiatric morbidity, controlling for the potential confounding effect of smoking on the relationship between the use of other substances and psychiatric morbidity. A sample of 290 adults were interviewed at a primary health centre (patients, 58%; patients' relatives, 34%; staff, 8%) to inquire about their tobacco, caffeine, alcohol, and illegal drug consumption. Psychiatric morbidity, defined by a score >6 on the General Health Questionnaire (GHQ-28), showed a strong direct association with nicotine dependence. The use of illegal drugs, but not of alcohol, was also strongly associated with psychiatric morbidity, after controlling for smoking. Both smoking and high nicotine dependence were also associated with use of caffeine, alcohol, cannabis and cocaine. High nicotine dependence may be considered as an expression of individual psychopathologic vulnerability. Tobacco may have a central facilitating role in the use of caffeine, alcohol, and illegal drug.

Smoking initiation and schizophrenia: a replication study in a Spanish sample.

In a prior US study, schizophrenia vulnerability was associated with higher risk of initiating daily smoking after 20 years of age. A survival analysis of onset age of daily smoking compared 290 controls with 250 consecutive DSM-IV schizophrenia patients from outpatient facilities at an urban catchment area in Spain. After controlling for gender and education, the cumulative hazard curves for smoking initiation age of controls and schizophrenia patients were significantly different. After age 20, smoking initiation rates were higher in all schizophrenia patients (and in 107 schizophrenia patients who started daily smoking at least 5 years before illness onset).

Nicotine dependence and symptoms in schizophrenia: naturalistic study of complex interactions.

BACKGROUND: Smoking may have a beneficial effect on either schizophrenic symptoms or antipsychotic side-effects, but studies are hampered by the lack of control of confounding factors. AIMS: To explore the self-medication hypothesis in a large sample of stable out-patients with schizophrenia. METHOD: Symptoms, assessed with the Positive and Negative Syndrome Scale (PANSS), and number of hospitalisations were compared in 250 out-patients with DSM-IV schizophrenia classified into three categories: highly dependent smokers, mildly dependent smokers and non-smokers. Log-linear analysis was used to control for potential confounding and interacting variables. RESULTS: High PANSS total scores and positive symptoms were less frequent in mildly dependent smokers than in non-smokers or highly dependent smokers. The highly dependent smokers had the worst outcome. CONCLUSIONS: The data do not generally support the self-medication hypothesis but rather suggest a complex interaction between nicotine dependence and nicotine dependence and schizophrenic symptoms.

Caffeine intake in outpatients with schizophrenia.

Several studies suggest that caffeine intake is high in patients with schizophrenia and a few of them suggest that caffeine may contribute to schizophrenia symptomatology. None of these studies control for the effect of tobacco smoking, which is associated with induction of caffeine metabolism. Therefore, the high amount of caffeine intake among patients with schizophrenia may be due to their high prevalence of smoking. This is the first large study to explore whether caffeine intake in patients with schizophrenia is related to tobacco (or alcohol) use or to the severity of schizophrenia symptomatology. The sample included 250 consecutive consenting outpatients with a diagnosis of DSM-IV schizophrenia from Granada, Spain. Fifty-nine percent (147/250) of patients consumed caffeine. Current caffeine intake was associated with current smoking and alcohol use. As none of the females used alcohol, the association with alcohol was only present in males with schizophrenia. Among caffeine consumers, smoking was associated with the amount of caffeine intake. Cross-sectional schizophrenia symptomatology was not associated with caffeine intake.

Exploring brief measures of nicotine dependence for epidemiological surveys.

A score > or = 6 in the Fagerström Test for Nicotine Dependence (FTND), identifying high nicotine dependence, was compared with three briefer classifications: (1) Item 4: heavy smoking (more than 30 cigarettes per day); (2) Item 1: high early smoking (smoking within 30 min of waking up); and (3) a score > or = 4 by combining Items 1 and 4. The FTND scores from 1642 smokers from five samples in the US and Spain were analyzed. Heavy smoking had low sensitivity. High early smoking had low specificity. A score > or = 4 by combining Items 1 and 4 had relatively good sensitivity (94%) and specificity (88%). Researchers needing definition of nicotine dependence briefer than FTND may want to only use Items 1 and 4 of FTND with a cutting score > or = 4.

The association between high nicotine dependence and severe mental illness may be consistent across countries.

BACKGROUND: Studies all over the world suggest that severe mental illness, including schizophrenia and mood disorders, is associated with tobacco smoking. This study, combining samples from the United States and Spain, had 3 objectives: (1) to test the hypothesis that severely mentally ill patients who smoke are more likely to have a high nicotine dependence when compared with control smokers, (2) to compare frequencies of high nicotine dependence in controls in both countries, and (3) to compare frequencies of high nicotine dependence in severely mentally ill patients in both countries. METHOD: Scores on the Fagerström Test for Nicotine Dependence (FTND) for 4 samples of current daily smokers were analyzed. The sample sizes of the U.S. and Spanish control groups were 129 and 646 subjects, respectively. The diagnoses for the U.S. patients were DSM-IV schizophrenia, 74% (89/120), and DSM-IV mood disorders, 26% (31/120). The diagnoses for the Spanish patients were DSM-IV schizophrenia, 87% (173/199), and DSM-III-R mood disorders, 13% (26/199). High nicotine dependence (FTND score > or = 6) was the dependent variable in 5 logistic regression analyses. RESULTS: The main findings were that (1) severely mentally ill patients had significantly higher frequencies of high nicotine dependence than controls (odds ratio [OR] = 10.59, 95% CI = 7.31 to 15.34) even after controlling for gender, country, interaction between country and mental illness, and age; (2) U.S. controls had significantly higher frequencies of high nicotine dependence than Spanish controls (OR = 3.18, 95% CI = 2.02 to 5.00); and (3) U.S. and Spanish patients did not have significantly different frequencies of high nicotine dependence. CONCLUSION: New studies, specially designed to test for transcultural differences in nicotine dependence, are needed to verify that nicotine dependence in severely mentally ill patients is consistently high and similar in different countries.