Antidepressive Effectiveness of Amisulpride, Aripiprazole, and Olanzapine in Patients With Schizophrenia Spectrum Disorders: A Secondary Outcome Analysis of a Pragmatic, Randomized Trial (BeSt InTro).

BACKGROUND: Depressive symptoms are frequent in schizophrenia and associated with a poorer outcome. Currently, the optimal treatment for depressive symptoms in schizophrenia remains undetermined. Amisulpride, aripiprazole, and olanzapine all have antidepressive pharmacodynamic properties, ranging from serotonergic affinities to limbic dopaminergic selectivity. Consequently, in a 12-month pragmatic, randomized clinical trial, we aimed to investigate differences in antidepressive effectiveness among amisulpride, aripiprazole, and olanzapine as a secondary outcome, measured by change in the Calgary Depression Scale for Schizophrenia sum score in patients within the schizophrenia spectrum. METHODS: Psychotic patients within the schizophrenia spectrum were included, and effectiveness was analyzed with latent growth curve modeling. RESULTS: Of the 144 patients, 51 (35%) were women, the mean age was 31.7 (SD 12.7), and 39% were antipsychotic naive. At inclusion, 68 (47%) participants had a Calgary Depression Scale for Schizophrenia sum score >6, indicating severe depressive symptoms. Across the 12-month follow-up, there was a depressive symptom reduction in all medication groups, but no statistically significant differences between the study drugs. Separate analyses of the subcohort with elevated depressive symptoms at inclusion also failed to find differences in depressive symptom reduction between study drugs. The reduction in depressive symptoms mainly occurred within 6 weeks after randomization. CONCLUSIONS: There was a reduction in depressive symptoms under treatment with amisulpride, aripiprazole, and olanzapine in acutely psychotic patients with schizophrenia spectrum disorder, but no differences between the drugs.

Objective assessment of motor activity in a clinical sample of adults with attention-deficit/hyperactivity disorder and/or cyclothymic temperament.

BACKGROUND: Most research on patterns of motor activity has been conducted on adults with mood disorders, but few studies have investigated comorbid attention-deficit/hyperactivity disorder (ADHD) or temperamental factors that may influence the clinical course and symptoms. Cyclothymic temperament (CT) is particularly associated with functional impairment. Clinical features define both disorders, but objective, biological markers for these disorders could give important insights with regard to pathophysiology and classification. METHODS: Seventy-six patients, requiring diagnostic evaluation of ADHD, mood or anxiety disorders were recruited. A comprehensive diagnostic evaluation, including the CT scale of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego - Auto-questionnaire (TEMPS-A), neuropsychological tests and actigraphy, was performed. ADHD was diagnosed according to the DSM-IV criteria. There was a range of different conditions in this clinical sample, but here we report on the presence of CT and ADHD in relation to motor activity. Twenty-nine healthy controls were recruited. We analyzed motor activity time series using linear and nonlinear mathematical methods, with a special focus on active and inactive periods in the actigraphic recordings. RESULTS: Forty patients fulfilled the criteria for ADHD, with the remainder receiving other psychiatric diagnoses (clinical controls). Forty-two patients fulfilled the criteria for CT. Twenty-two patients fulfilled the criteria for ADHD and CT, 18 patients met the criteria for ADHD without CT, and 15 patients had neither. The ratio duration of active/inactive periods was significantly lower in patients with CT than in patients without CT, in both the total sample, and in the ADHD subsample. CONCLUSIONS: CT is associated with objectively assessed changes in motor activity, implying that the systems regulating motor behavior in these patients are different from both healthy controls and clinical controls without CT. Findings suggest that actigraphy may supplement clinical assessments of CT and ADHD, and may provide an objective marker for CT.

Linear and non-linear analyses of Conner's Continuous Performance Test-II discriminate adult patients with attention deficit hyperactivity disorder from patients with mood and anxiety disorders.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is a heterogeneous disorder. Therefore it is important to look for factors that can contribute to better diagnosis and classification of these patients. The aims of the study were to characterize adult psychiatric out-patients with a mixture of mood, anxiety and attentional problems using an objective neuropsychological test of attention combined with an assessment of mood instability. METHOD: Newly referred patients (n = 99; aged 18-65 years) requiring diagnostic evaluation of ADHD, mood or anxiety disorders were recruited, and were given a comprehensive diagnostic evaluation including the self-report form of the cyclothymic temperament scale and Conner's Continuous Performance Test II (CPT-II). In addition to the traditional measures from this test we have extracted raw data and analysed time series using linear and non-linear mathematical methods. RESULTS: Fifty patients fulfilled criteria for ADHD, while 49 did not, and were given other psychiatric diagnoses (clinical controls). When compared to the clinical controls the ADHD patients had more omission and commission errors, and higher reaction time variability. Analyses of response times showed higher values for skewness in the ADHD patients, and lower values for sample entropy and symbolic dynamics. Among the ADHD patients 59 % fulfilled criteria for a cyclothymic temperament, and this group had higher reaction time variability and lower scores on complexity than the group without this temperament. CONCLUSION: The CPT-II is a useful instrument in the assessment of ADHD in adult patients. Additional information from this test was obtained by analyzing response times using linear and non-linear methods, and this showed that ADHD patients with a cyclothymic temperament were different from those without this temperament.

Depression and anxiety in women with epilepsy during pregnancy and after delivery: a prospective population-based cohort study on frequency, risk factors, medication, and prognosis.

OBJECTIVE: To assess incidence, prevalence, risk factors, and prognosis of peripartum depression and anxiety in a prospective study of women with epilepsy. METHOD: Pregnancies in women with epilepsy (n=706) were compared to pregnancies in all women without epilepsy (n=106,511) including women with specified nonepileptic chronic diseases (n=8,372) in the Norwegian Mother and Child Cohort Study. The database was linked to the Medical Birth Registry of Norway. Depression and anxiety were assessed with validated questionnaires five times from the second trimester to 36 months after delivery. Blood was drawn for analysis of antiepileptic drug (AED) concentrations. RESULTS: Women with epilepsy more often had peripartum depression (26.7%) or anxiety (22.4%) than women without epilepsy (18.9% and 14.8%, respectively, p<0.001 for both comparisons) and women with other chronic diseases (23.1% and 18.4%, respectively, p=0.03 and 0.01). Women using AEDs during pregnancy were especially at risk regardless of AED type. The risk further increased with the use of multiple AEDs and with high doses and/or plasma levels. Risk factors associated with peripartum depression and/or anxiety in the epilepsy cohort were high seizure frequency, a history of physical and/or sexual abuse, adverse socioeconomic factors, previous loss of a child, AED use, unplanned pregnancy, and prepregnancy depression and/or anxiety. The recovery rate 3 years after delivery was lower for women with epilepsy with a history of depression/anxiety or physical/sexual abuse than for women without epilepsy. Depressed women with epilepsy were less frequently treated with antidepressive drugs during pregnancy than women without epilepsy. SIGNIFICANCE: Women with epilepsy frequently have depression and anxiety during and after pregnancy. Patients at risk should be identified before delivery as depressive symptoms could be undertreated in this group.

Dichotic listening, executive functions and grey matter cortical volume in patients with schizophrenia and healthy controls.

Schizophrenia is characterized by cognitive impairment, especially in relation to executive functions. Brain structural abnormalities are also often seen in schizophrenia although little is known of the relationship between cognitive impairment and structural brain changes. Our aim was therefore to investigate this relationship further using MRI and a dichotic listening (DL) task with simple speech sounds and with instructions to focus attention and report only from the left or right ear stimulus. When instructed to focus attention on the left ear syllable a cognitive conflict is induced requiring the allocation of executive resources to be resolved. Grey matter (GM) volume was measured with MRI from four volumes of interests (VOIs), left and right frontal and temporal cortex, respectively, and correlated with DL performance. The results showed significant differences between the groups in their ability to focus attention on and report the left ear stimulus, which was accompanied by reduced GM volume in the left frontal and right temporal lobe VOIs. There was also a significant positive correlation between left frontal GM volume and performance on the DL task, for the groups combined. The results did not support a conclusion that an impairment in cognitive function in schizophrenia was driven by an corresponding impairment in brain structure, since there were no significant correlations when the groups were analyzed separately. It is however concluded that patients with schizophrenia are impaired in executive functions and that they also show reduced GM volumes in left frontal and right temporal lobe areas, compared to healthy controls.

[Treatment of bipolar disorder during pregnancy and in the postpartum period]. / Behandling av bipolar lidelse under svangerskap og etter fødsel.

BACKGROUND: Pharmacological treatment and prophylaxis of bipolar disorders during pregnancy and in the postpartum period imply complicated clinical assessments. MATERIAL AND METHOD: This article is based on a non-systematic search in PubMed and the authors' clinical experience. RESULTS: If a woman is already using a prophylactic drug at the time of pregnancy, she can in general continue to do so during pregnancy, with the exception of valproate. If the disorder starts during pregnancy; lithium, lamotrigine or second generation antipsychotic drugs are suitable alternatives. In general, drugs used during pregnancy can also be used in the postpartum period, although some require special precautions if the mother wishes to breast-feed. If treatment is initiated after delivery, the mother's wish to breast-feed should be taken into consideration when choosing a drug. INTERPRETATION: Although existing studies have weaknesses, there is sufficient evidence to give qualified advice regarding choice of medication for bipolar disorder during pregnancy and in the postpartum period.

Diurnal variation of motor activity in adult ADHD patients analyzed with methods from graph theory.

Attention-deficit /hyperactivity disorder (ADHD) is a common neurodevelopmental syndrome characterized by age-inappropriate levels of motor activity, impulsivity and attention. The aim of the present study was to study diurnal variation of motor activity in adult ADHD patients, compared to healthy controls and clinical controls with mood and anxiety disorders. Wrist-worn actigraphs were used to record motor activity in a sample of 81 patients and 30 healthy controls. Time series from registrations in the morning and evening were analyzed using measures of variability, complexity and a newly developed method, the similarity algorithm, based on transforming time series into graphs. In healthy controls the evening registrations showed higher variability and lower complexity compared to morning registrations, however this was evident only in the female controls. In the two patient groups the same measures were not significantly different, with one exception, the graph measure bridges. This was the measure that most clearly separated morning and evening registrations and was significantly different both in healthy controls and in patients with a diagnosis of ADHD. These findings suggest that actigraph registrations, combined with mathematical methods based on graph theory, may be used to elucidate the mechanisms responsible for the diurnal regulation of motor activity.

Amisulpride, aripiprazole, and olanzapine in patients with schizophrenia-spectrum disorders (BeSt InTro): a pragmatic, rater-blind, semi-randomised trial.

BACKGROUND: Amisulpride, aripiprazole, and olanzapine are first-line atypical antipsychotics that have not previously been compared head-to-head in a pragmatic trial. We aimed to compare the efficacy and safety of these agents in a controlled trial. METHODS: This pragmatic, rater-blind, randomised controlled trial was done in three academic centres of psychiatry in Norway, and one in Austria. Eligible patients were aged 18 years or older, met ICD-10 criteria for schizophrenia-spectrum disorders (F20-29), and had symptoms of active psychosis. Eligible patients were randomly assigned to receive oral amisulpride, aripiprazole, or olanzapine. Treatment allocation was open to patients and staff, and starting dose, treatment changes, and adjustments were left to the discretion of the treating physician. Computer-generated randomisation lists for each study centre were prepared by independent statisticians. Patients were followed up for 52 weeks after random assignment, during which assessments were done 8 times by researchers masked to treatment. The primary outcome was reduction of the Positive And Negative Syndrome Scale (PANSS) total score at 52 weeks, and primary analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01446328. FINDINGS: Between Oct 20, 2011, and Dec 30, 2016, we assessed 359 patients for eligibility. 215 patients were excluded (107 did not meet inclusion criteria, 82 declined to participate, 26 other reasons). 144 patients (mean baseline PANSS total estimated score 78·4 [SD 1·4]) were randomly assigned 1:1:1 to receive amisulpride (44 patients), aripiprazole (48 patients) or olanzapine (52 patients). After 52 weeks, the patients allocated to amisulpride had a PANSS total score reduction of 32·7 points (SD 3·1) compared with 21·9 points reduction with aripiprazole (SD 3·9, p=0·027) and 23·3 points with olanzapine (2·9, p=0·025). We observed weight gain and increases of serum lipids and prolactin in all groups. 26 serious adverse events (SAEs) among 20 patients were registered (four [9%] of 44 patients allocated to amisulpride, ten [21%] of 48 patients allocated to aripiprazole, and six [12%] of 52 patients allocated to olanzapine), with no statistically significant differences between the study drugs. 17 (65%) of the 26 SAEs occurred during the use of the study drug, with readmission or protracted hospital admission accounting for 13 SAEs. One death by suicide, one unspecified death, and one life-threatening accident occurred during follow-up, after cessation of treatment. INTERPRETATION: Amisulpride was more efficacious than aripiprazole or olanzapine for reducing the PANSS total scores in adults with schizophrenia-spectrum disorders. Side-effect differences among the groups were generally small. This study supports the notion that clinically relevant efficacy differences exist between antipsychotic drugs. Future research should aim to compare first-line antipsychotics directly in pragmatic clinical trials that reflect everyday clinical practice. FUNDING: The Research Council of Norway, the Western Norway Regional Health Trust, and participating hospitals and universities.

Graph theory applied to the analysis of motor activity in patients with schizophrenia and depression.

Depression and schizophrenia are defined only by their clinical features, and diagnostic separation between them can be difficult. Disturbances in motor activity pattern are central features of both types of disorders. We introduce a new method to analyze time series, called the similarity graph algorithm. Time series of motor activity, obtained from actigraph registrations over 12 days in depressed and schizophrenic patients, were mapped into a graph and we then applied techniques from graph theory to characterize these time series, primarily looking for changes in complexity. The most marked finding was that depressed patients were found to be significantly different from both controls and schizophrenic patients, with evidence of less regularity of the time series, when analyzing the recordings with one hour intervals. These findings support the contention that there are important differences in control systems regulating motor behavior in patients with depression and schizophrenia. The similarity graph algorithm we have described can easily be applied to the study of other types of time series.

Affective facial expression in sub-clinically depressed and non-depressed mothers during contingent and non-contingent face-to-face interactions with their infants.

BACKGROUND: Depression in the postpartum period involves feelings of sadness, anxiety and irritability, and attenuated feelings of pleasure and comfort with the infant. Even mild- to- moderate symptoms of depression seem to have an impact on caregivers affective availability and contingent responsiveness. The aim of the present study was to investigate non-depressed and sub-clinically depressed mothers interest and affective expression during contingent and non-contingent face-to-face interaction with their infant. METHODS: The study utilized a double video (DV) set-up. The mother and the infant were presented with live real-time video sequences, which allowed for mutually responsive interaction between the mother and the infant (Live contingent sequences), or replay sequences where the interaction was set out of phase (Replay non-contingent sequences). The DV set-up consisted of five sequences: Live1-Replay1-Live2-Replay2-Live3. Based on their scores on the Edinburgh Postnatal Depression Scale (EPDS), the mothers were divided into a non-depressed and a sub-clinically depressed group (EPDS score≥6). RESULTS: A three-way split-plot ANOVA showed that the sub-clinically depressed mothers displayed the same amount of positive and negative facial affect independent of the quality of the interaction with the infants. The non-depressed mothers displayed more positive facial affect during the non-contingent than the contingent interaction sequences, while there was no such effect for negative facial affect. CONCLUSIONS: The results indicate that sub-clinically level depressive symptoms influence the mothers' affective facial expression during early face-to-face interaction with their infants. One of the clinical implications is to consider even sub-clinical depressive symptoms as a risk factor for mother-infant relationship disturbances.

Distribution of Active and Resting Periods in the Motor Activity of Patients with Depression and Schizophrenia.

OBJECTIVE: Alterations of activity are prominent features of the major functional psychiatric disorders. Motor activity patterns are characterized by bursts of activity separated by periods with inactivity. The purpose of the present study has been to analyze such active and inactive periods in patients with depression and schizophrenia. METHODS: Actigraph registrations for 12 days from 24 patients with schizophrenia, 23 with depression and 29 healthy controls. RESULTS: Patients with schizophrenia and depression have distinctly different profiles with regard to the characterization and distribution of active and inactive periods. The mean duration of active periods is lowest in the depressed patients, and the duration of inactive periods is highest in the patients with schizophrenia. For active periods the cumulative probability distribution, using lengths from 1 to 35 min, follows a straight line on a log-log plot, suggestive of a power law function, and a similar relationship is found for inactive periods, using lengths from 1 to 20 min. For both active and inactive periods the scaling exponent is higher in the depressed compared to the schizophrenic patients. CONCLUSION: The present findings add to previously published results, with other mathematical methods, suggesting there are important differences in control systems regulating motor behavior in these two major groups of psychiatric disorders.

[Are mood stabilizers beneficial in the treatment of schizophrenia?]. / Har stemningsstabiliserende legemidler noen plass i behandlingen av schizofreni?

BACKGROUND: Antipsychotic agents are the drugs of choice in the treatment of schizophrenia. However, some patients profit only modestly from such therapy and thus represent a clinical challenge. MATERIAL AND METHODS: This article is based upon a review of relevant literature on treatment with the mood stabilizers lithium, carbamazepine, valproate and lamotrigine in patients with schizophrenia. RESULTS: Few well-designed studies exist on the use of mood stabilizers in schizophrenia. In monotherapy, these drugs have no documented beneficial effect, but when used as adjunct therapies to antipsychotics, some positive effects are described. Best evidence for an anti-aggressive effect exists for lithium, but it is described also for carbamazepine. Lithium also has some effects on affective symptoms. Valproate has not shown a consistently positive effect. Lamotrigine has demonstrated a beneficial effect in a placebo-controlled study, but this finding should be verified by others before its place in the treatment of schizophrenia can be established. INTERPRETATION: Mood stabilizers are not the drugs of choice in the treatment of schizophrenia but could be considered as potential adjuncts to antipsychotics in patients with treatment-resistant schizophrenia, although the documentation is sparse.

Motor Activity in Adult Patients with Attention Deficit Hyperactivity Disorder.

OBJECTIVE: Hyperactivity is a core symptom of attention-deficit hyperactivity disorder (ADHD), but limited information is available on analysis of activity patterns in this disorder. The aim of the study was to analyze motor activity during daily living in adult patients with ADHD. METHODS: Patients (n=76) from the private psychiatric practice of two of the authors were recruited, and were compared to patients with other psychiatric disorders and to normal controls. Actigraphs were used to record motor activity for six days, with one minute intervals, and data were analysed using linear and non-linear mathematical methods. RESULTS: For short recording periods (300 minutes) the activity levels of ADHD patients do not differ from normal controls, but the autocorrelation (lag 1) is lower and Fourier analysis shows higher power in the high frequency range, corresponding to the period from 2-8 min. During recordings for six days there are no significant differences between ADHD patients and the control groups. The combined and inattentive subgroups differ only in the six days recordings. The Fourier analyses show that the combined type has lower power in the high frequency range, corresponding to the period from 4-8 hours, and in the analysis of rhythms the intra-daily variability is lower, compared to the inattentive type. CONCLUSION: Adult ADHD patients do not show evidence of hyperactivity, but have levels of activity similar to normal controls. However, on several measures ADHD patients display altered activity patterns, indicating that the regulation of motor activity in this disorder is different from controls.

Glutamate as a mediating transmitter for auditory hallucinations in schizophrenia: a (1)H MRS study.

This is a (1)H MR spectroscopy (MRS) study of glutamate (Glu), measured as Glx, levels in temporal and frontal lobe regions in patients with schizophrenia compared with a healthy control group with the objective of revealing aspects of the underlying neurochemistry of auditory hallucinations. We further compared and correlated Glu(Glx) levels for the patients-only against frequency and severity of auditory hallucinations and the sum of Positive symptoms, and also for frequency and severity of emotional withdrawal, and sum of Negative symptoms. The sample included 23 patients with an ICD-10 and DSM-IV diagnosis of schizophrenia, and 26 healthy control subjects without any known psychiatric or neurological disorders. Symptom scores were obtained from the Positive and Negative Syndrome Scale (PANSS). (1)H MRS data were acquired on a 3T MR scanner from two temporal and two frontal voxels, using standard sequences and analysis parameters. The results showed that schizophrenia patients as a group had reduced Glu(Glx) levels in the voxels of interest compared to the healthy control subjects, while increased levels were found for patients with frequent and severe auditory hallucinations, relative to patients with less frequent and severe hallucination. We further found significant positive correlations between frequency and severity of auditory hallucinations, and for sum Positive symptoms, and Glu(Glx) levels in all regions, not seen when the analysis was done for negative symptoms. It is concluded that the results show for the first time that glutamate may be a mediating factor in auditory hallucinations in schizophrenia.

Breastfeeding during maternal antidepressant treatment with serotonin reuptake inhibitors: infant exposure, clinical symptoms, and cytochrome p450 genotypes.

BACKGROUND: The aims of the study were to quantify the drug exposure in breastfed infants of antidepressant-treated mothers, to identify possible adverse events, and to correlate these variables to maternal and infant drug metabolism-relevant genotypes and milk triglyceride content. METHOD: The study included 25 lactating women treated with citalopram (N = 9), sertraline (N = 6), paroxetine (N = 6), fluoxetine (N = 1), or venlafaxine (N = 3) and their 26 breastfed infants. Drug concentrations in maternal and infant serum and milk were analyzed using liquid chromotography mass spectrometry methods; milk triglyceride levels were measured with a commercial kit. Cytochrome P450 (CYP) 2D6 and CYP2C19 activity was determined by polymerase chain reaction-based genotyping of the mothers and infants. An infant adverse event questionnaire was completed by the medication-treated mothers as well as by a control group of medication-free breastfeeding mothers of 68 infants. RESULTS: Sertraline and paroxetine were not detected in any of the drug-exposed infants. The infant serum level of citalopram was either undetectable (N = 4) or low (N = 6). All venlafaxine-exposed infants had measurable drug concentrations. We identified a paroxetine-treated mother and her infant who were both CYP2D6 poor metabolizers, as well as a citalopram-treated mother with CYP2C19 poor metabolizer status, but the serum drug levels of their infants were still either undetectable (paroxetine) or low (citalopram). There was no evidence of adverse events in the drug-exposed infants. CONCLUSION: Serum drug levels in breastfed infants of antidepressant-treated mothers were undetectable or low. This study adds further evidence to previously published data indicating that breastfeeding should not be generally discouraged in women using serotonin reuptake inhibitor anti-depressants.

[Psychiatric disorders during pregnancy and lactation]. / Behandling av svangerskapsrelatert psykisk sykdom.

BACKGROUND: Psychiatric disorders occur both during pregnancy and postpartum. The consequences of inadequate treatment in these periods can be dramatic, not only for the mother but also for the infant. The reference books and textbooks used in Norway provide very scanty information on the treatment of psychiatric disorders during pregnancy and postpartum. The use of drugs is a particularly difficult issue, as detrimental effects may arise in the fetus and in the suckling infant. MATERIAL AND METHODS: This article is based upon a review of relevant literature supplemented by our own experience in the field. RESULTS AND INTERPRETATION: In general, the effect is better documented for drug treatment than for other therapeutic modalities. Some drugs can be used without particular problems during pregnancy and lactation while others have potentially detrimental effects. Often the risk of not giving the mother adequate treatment must be weighed against the potential risks of drug exposure to the infant. Pregnancy-related psychiatric illness would, when recognized, in most cases have a favourable prognosis provided that adequate treatment is given.

The Cannabis Pathway to Non-Affective Psychosis may Reflect Less Neurobiological Vulnerability.

There is a high prevalence of cannabis use reported in non-affective psychosis. Early prospective longitudinal studies conclude that cannabis use is a risk factor for psychosis, and neurochemical studies on cannabis have suggested potential mechanisms for this effect. Recent advances in the field of neuroscience and genetics may have important implications for our understanding of this relationship. Importantly, we need to better understand the vulnerability × cannabis interaction to shed light on the mediators of cannabis as a risk factor for psychosis. Thus, the present study reviews recent literature on several variables relevant for understanding the relationship between cannabis and psychosis, including age of onset, cognition, brain functioning, family history, genetics, and neurological soft signs (NSS) in non-affective psychosis. Compared with non-using non-affective psychosis, the present review shows that there seem to be fewer stable cognitive deficits in patients with cannabis use and psychosis, in addition to fewer NSS and possibly more normalized brain functioning, indicating less neurobiological vulnerability for psychosis. There are, however, some familiar and genetic vulnerabilities present in the cannabis psychosis group, which may influence the cannabis pathway to psychosis by increasing sensitivity to cannabis. Furthermore, an earlier age of onset suggests a different pathway to psychosis in the cannabis-using patients. Two alternative vulnerability models are presented to integrate these seemingly paradoxical findings.