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BACKGROUND AND OBJECTIVES: Sleep disturbance is one of the hallmarks of cannabis withdrawal. Studies have indicated that treatment of this key symptom may facilitate abstinence. In the present paper we aim to provide a systematic review of the extant literature on pharmacological management of sleep disturbance associated with cannabis withdrawal. METHOD: We conducted a systematic literature search across five electronic databases including PubMed, Psycinfo, MEDLINE, Cochrane review and Embase. Human studies using a pharmacological treatment for sleep disturbances associated with cannabis withdrawal were included. Review articles, case-series, open trials, posters, and editorials were excluded. RESULTS: Seventeen publications, involving 562 participants, were included in this review. Major limitations involved small sample size, high dropout rate, methodological limitations, and heterogeneity of participants. Most of the studies were at high risk of bias, further downgrading the level of evidence. A meta-analysis was not performed due to lack of quantitative data, marked heterogeneity and low quality of the included studies. CONCLUSION: There is not sufficient evidence for any of the reviewed treatment options. Methodological limitations in a majority of the studies rendered their findings preliminary. Of the twelve investigated pharmacological agents, Gabapentin, Lofexidine, Mirtazapine, Quetiapine, and Zolpidem showed some primary benefits for treatment of sleep difficulties associated with cannabis withdrawal; however, future prospective studies are required to confirm such results. SCIENTIFIC SIGNIFICANCE: This review examines the current evidence for potential pharmacological options for treatment of cannabis withdrawal and associated sleep disturbance. It furthers our knowledge and provides groundwork for future research. (Am J Addict 2018;27:453-464).

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OBJECTIVE: This study evaluated the effectiveness of a school-based mental health literacy intervention for adolescents on knowledge and stigma. METHOD: A total of 24 high schools and 534 students in the regional area of Ottawa, Ontario, Canada participated in this randomized controlled trial. Schools were randomly assigned to either the curriculum or control condition. The curriculum was integrated into the province's grade 11 and 12 "Healthy Living" courses and was delivered by teachers. Changes in mental health knowledge and stigma were measured using pre- and posttest questionnaires. Descriptive analyses were conducted to provide sample characteristics, and multilevel modeling was used to examine study outcomes. RESULTS: For the curriculum condition, there was a significant change in stigma scores over time (p = .001), with positive attitudes toward mental illness increasing from pre to post. There was also a significant change in knowledge scores over time (p < .001), with knowledge scores increasing from pre to post. No significant changes in knowledge or stigma were found for participants in the control condition. A meaningful relationship was found whereby increases in knowledge significantly predicted increases in positive attitudes toward mental health (p < .001). CONCLUSION: This is the first large randomized controlled trial to demonstrate the effectiveness in mental health literacy of an integrated, manualized mental health educational resource for high school students on knowledge and stigma. Findings also support the applicability by teachers and suggest the potential for broad-based implementation of the educational curriculum in high schools. Replication and further studies are warranted. Clinical trial registration information-Impact of a Mental Health Curriculum for High School Students on Knowledge and Stigma; http://clinicaltrials.gov/; NCT02561780.

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BACKGROUND: It is important to evaluate the impact of cannabis use on onset and course of psychotic illness, as the increasing number of novice cannabis users may translate into a greater public health burden. This study aims to examine the relationship between adolescent onset of regular marijuana use and age of onset of prodromal symptoms, or first episode psychosis, and the manifestation of psychotic symptoms in those adolescents who use cannabis regularly. METHODS: A review was conducted of the current literature for youth who initiated cannabis use prior to the age of 18 and experienced psychotic symptoms at, or prior to, the age of 25. Seventeen studies met eligibility criteria and were included in this review. RESULTS: The current weight of evidence supports the hypothesis that early initiation of cannabis use increases the risk of early onset psychotic disorder, especially for those with a preexisting vulnerability and who have greater severity of use. There is also a dose-response association between cannabis use and symptoms, such that those who use more tend to experience greater number and severity of prodromal and diagnostic psychotic symptoms. Those with early-onset psychotic disorder and comorbid cannabis use show a poorer course of illness in regards to psychotic symptoms, treatment, and functional outcomes. However, those with early initiation of cannabis use appear to show a higher level of social functioning than non-cannabis users. CONCLUSIONS: Adolescent initiation of cannabis use is associated, in a dose-dependent fashion, with emergence and severity of psychotic symptoms and functional impairment such that those who initiate use earlier and use at higher frequencies demonstrate poorer illness and treatment outcomes. These associations appear more robust for adolescents at high risk for developing a psychotic disorder.

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OBJECTIVE: Second generation antipsychotics (SGA) have gained increased evidence for the treatment of irritability and aggression in children and adolescents with lower functioning autistic disorder. Individuals with Asperger's Disorder (AD) and High Functioning Autism (HFA) experience significant emotional and behavioral problems and psychiatric comorbidity. There is a need to review the published literature on SGA treatment efficacy in the AD and HFA populations to provide more effective treatment choices for these subgroups. METHODS: We conducted a systematic review and meta-analysis of the recent English literature on SGA use in children and adolescents (ages 0-24 years) with AD and HFA using the Medline/PubMed and PsychINFO computerized databases. Key search words were 'Asperger', 'high functioning autism', 'autism spectrum disorders (ASD)', and 'pervasive developmental disorder (PDD)' in combination with 'second generation antipsychotics', 'aripiprazole; 'olanzapine', 'quetiapine', 'risperidone', or 'ziprasidone'. RESULTS: Our search yielded 214 citations, however only open-label or randomized-controlled trials (RCT) with ≥25% of their subjects having an IQ≥71 were included in our review. Eleven original studies met our inclusion parameters for review; eight studies for the meta-analysis. These studies, although limited in methodological rigor, and the meta-analytic results suggest that SGAs provide improvement in behavioral symptoms associated with AD and HFA. The majority of the studies reported weight gain as a potentially concerning adverse effect. CONCLUSION: There is a lack of robustly conducted trials on the use of SGAs in the management of AD and HFA. More research in pharmacological and psychosocial treatments is warranted. Clinicians are cautioned to approach pharmacological treatment prudently balancing benefit with potential cardiometabolic risk.

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BACKGROUND: There is a paucity of longitudinal data characterizing the relationship between substance use disorder (SUD) and the early clinical course of bipolar disorder (BD). We studied this relationship in a prospectively assessed cohort of high-risk offspring. METHODS: Eligible families had one parent with confirmed BD based on SADS-L interviews and best estimate diagnostic procedure. Offspring completed KSADS-PL interviews at baseline and were reassessed prospectively. DSM-IV diagnoses were made on blind consensus review using all available information. This analysis included 211 offspring ≥12 years, and used GEE and linear mixed models to determine clinical characteristics differentiating those with compared to those without SUD, and CPH models to assess the relationship between SUD and the early stages of BD. RESULTS: Lifetime SUD was diagnosed in 24% of offspring; cannabis use being most common. The peak hazard of SUD was between 14 and 20 years of age. Male sex (HR 3.285; p=.0007), a prior mood disorder (HR 2.437; p=.0091) and parental history of SUD (HR 2.999; p=.0027) contributed to the risk of SUD in the offspring, while SUD predicted an increased risk of psychosis (HR 3.225; p=.0074). The estimated hazard of a major mood disorder in those offspring with compared to those without a prior SUD was almost 3-fold (HR 2.990 (p≤0.01). LIMITATIONS: The novel clinical staging model requires independent replication. CONCLUSIONS: SUD is a common comorbidity arising during the early course of BD, even before the first activated episode. Further research is needed to understand causative factors and to develop effective early intervention and prevention strategies.

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BACKGROUND: Given that smoking is typically initiated during adolescence, and that this period in brain development seems to be uniquely sensitive to nicotine, depressed youth may be most susceptible to the neuromodulatory and mood-altering effects of nicotine. Electroencephalographic (EEG) studies suggest that individuals with major depressive disorder (MDD) exhibit left frontal lobe hypoactivation (indexed by increased EEG alpha), a region implicated in positive affect regulation, as well as right parietal hypoactivation. Smoking/nicotine abstinence has been associated with increased left frontal and right parietal alpha activity (reduced activation), which has been correlated with increased depression ratings; nicotine administration seems to normalize this depression-associated asymmetry. OBJECTIVES: This pilot study investigated whether acute nicotine administration in adolescent female smokers with MDD would alter resting EEG activity and affect. METHODS: Subjective mood ratings and EEG recordings were acquired before and 2 hours after administering a transdermal placebo or nicotine (21 mg) patch to 8 adolescent female smokers with MDD. RESULTS: Nicotine induced a modest increase in alpha1 amplitude in the right hemisphere and simultaneously decreased left-favoring alpha1 amplitude asymmetry. It also attenuated left alpha1 and alpha2 amplitude in the central region. Consistent with nicotine's stimulatory action, nicotine decreased theta amplitude in the right parietal region. No accompanying mood alterations were found, although smoking withdrawal and craving as well as physical symptom scores were reduced with nicotine. CONCLUSIONS: The results of this pilot study, the first to examine the electrocortical effects of nicotine in depressed adolescents, indicate that nicotine modulates EEG asymmetry measures, laying the stage for further research regarding the role of nicotine on affective neurocircuitry in this population.

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INTRODUCTION: Cognitive deficits, including deficits in early information processing, are associated with remitted bipolar disorder. The temporal relationship between these deficits and the clinical course is not known. The current study investigated whether or not deficits in early information processing were present before the onset and/or during the early stages of bipolar disorder. METHODS: Unaffected and remitted high risk offspring of well-characterized bipolar parents completed a visual backward masking task. For comparison we included a cohort of unaffected offspring of well parents and a clinically referred group of remitted bipolar patients. RESULTS: There was no evidence of a deficit in early information processing in well high risk subjects. As expected, the referred patient group had the highest error rates. After excluding the patients, interaction effect showed that the affected remitted high risk subjects performed differently in terms of error rates than unaffected high risk and control subjects. There were no significant differences in response times across study groups. Exploratory analyses revealed an association between a lifetime history of psychosis and increased errors on the task. CONCLUSIONS: There was no evidence of a vulnerability in early information processing in offspring at risk for bipolar disorder. However, there were emergent changes in performance in the affected remitted high risk group. Psychosis appears to be an important clinical correlate associated with cognitive deficits. Mapping of the early course of bipolar disorder and associated changes in cognition has important implications for establishing critical periods for intervention.

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BACKGROUND: The purpose of the study was to determine the effectiveness and tolerability of quetiapine as a maintenance treatment preventing against relapse or recurrence of acute mood episodes in adolescent patients diagnosed with bipolar disorder. METHODS: Consenting patients meeting DSM-IV lifetime criteria for a bipolar disorder and clinically appropriate for maintenance treatment were enrolled in a 48-week open prospective study. After being acutely stabilized (CGI-S < or = 3 for 4 consecutive weeks), patients were started or continued on quetiapine and other medications were weaned off over an 8-week period. Quetiapine monotherapy was continued for 40-weeks and other mood stabilizers or antidepressants were added if clinically indicated. A neurocognitive test battery assessing the most reliable findings in adult patients was administered at fixed time points throughout the study to patients and matched controls. RESULTS: Of the 21 enrolled patients, 18 completed the 48-week study. Thirteen patients were able to be maintained without relapse or recurrence in good quality remission on quetiapine monotherapy, while 5 patients required additional medication to treat impairing residual depressive and/or anxiety symptoms. According to symptom ratings and global functioning scores, the quality of remission for all patients was very good.Neurocognitive test performance over treatment was equivalent to that of a matched control group of never ill adolescents. Quetiapine was generally well tolerated with no serious adverse effects. CONCLUSION: This study suggests that a proportion of adolescent patients diagnosed with bipolar disorder can be successfully maintained on quetiapine monotherapy. The good quality of clinical remission and preserved neurocognitive functioning underscores the importance of early diagnosis and effective stabilization. CLINICAL TRIALS REGISTRY: D1441L00024.

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OBJECTIVE: To prospectively identify and assess withdrawal symptoms in adolescents with cannabis dependence. METHOD: Twenty-one adolescents ages 13 to 19 years voluntarily entering residential and day/outpatient substance abuse programs, with cannabis dependence as their only current substance of dependence, were assessed using the Teen-Addiction Severity Index, Substance Use Survey, Cannabis Withdrawal Scale, and the Structured Clinical Interview for DSM-IV Childhood Diagnoses Substance Use Disorders Module. Weekly assessments continued for 4 weeks. Thirteen youths attained a minimum of 2 weeks of abstinence. RESULTS: Cannabis withdrawal symptoms were present in adolescents. Cannabis withdrawal was greatest in the first 2 weeks of abstinence with evidence that it continued well into week 3. Most withdrawal symptoms were endorsed with a high degree of frequency. Those symptoms endorsed with the greatest severity were restlessness, appetite change, and thoughts of and cravings for cannabis, with the highest ratings occurring in week 1. Over the course of the study, participants reported fewer symptoms with decreasing levels of severity. Youth ratings of overall severity of withdrawal were significantly and positively correlated with withdrawal symptoms of irritability (r = 0.56), depression (r = 0.56), twitches and shakes (r = 0.57), perspiring (r = 0.57), thoughts of (r = 0.86), and cravings for (r = 0.69) cannabis. CONCLUSIONS: Findings support the presence of clinically significant cannabis withdrawal symptoms in adolescents with cannabis dependence seeking substance abuse treatment. This study also provides supporting evidence suggesting a vulnerability of adolescents to physiological cannabis dependence. The study supports the addition of cannabis withdrawal as a distinct entity for inclusion in DSM-V.

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OBJECTIVE: A major aim of this longitudinal high-risk study is to identify reliable early indicators of emerging bipolar disorder (BD) among offspring from well-characterized parents. METHODS: High-risk offspring were recruited from families in which one parent had BD diagnosed on the basis of the Schedule for Affective Disorders and Schizophrenia - Lifetime version (SADS-L) interviews and DSM-IV diagnostic criteria and the other parent was well. Bipolar parents were further subdivided on the basis of response or non-response to long-term lithium. A comparison group of offspring was recruited from well parents diagnosed on the basis of either SADS-L interviews or the family history method. All consenting offspring from high-risk and control families were assessed longitudinally with the Schedule for Affective Disorders and Schizophrenia for School-aged Children - Present and Lifetime version (KSADS-PL) interviews and DSM-IV diagnoses were made on a blind consensus review. The offspring were reassessed on average annually, as well as at any time symptoms developed. RESULTS: Antecedent conditions to BD in both high-risk groups included sleep and anxiety disorders, while attention-deficit hyperactivity disorder and pre-psychotic conditions were antecedents among the offspring of lithium non-responders only. Among those offspring developing BD, the index mood episode was almost always depressive. CONCLUSIONS: Despite a specific genetic risk, BD began with non-specific psychopathology and/or depressive disorders in a majority of offspring. Therefore, diagnosis based only on cross-sectional assessment of symptoms appears to be insufficient for the accurate early detection of emerging BD. Other parameters such as family history and associated antecedents should be taken into account.

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OBJECTIVE: In adults with established bipolar disorder (BD), differential response to mood stabilizers has been associated with the clinical profile. Long-term treatment studies of youth with BD are lacking. This paper provides longitudinal observations of response to mood stabilizers early in the course of illness in youth with BD. METHOD: We report on 15 research patients who, as adolescents, met DSM-IV lifetime criteria for a bipolar spectrum disorder and required long-term treatment. These youths derived from families with one parent having BD whose course and long-term treatment response were determined in accordance with research criteria. The patients were offered lithium, and if they failed to respond or refused it, they were treated with either an anticonvulsant or an atypical antipsychotic. Using a validated scale, an independent rater retrospectively blindly scored the response to long-term treatment. RESULTS: Those patients who stabilized on lithium derived from lithium-responsive families, whereas those who stabilized on an antipsychotic derived from lithium-nonresponsive families. The clinical course in the youths stabilized by lithium differed from that in the youths stabilized by an atypical antipsychotic. CONCLUSIONS: Our findings suggest that the clinical profile may help in selecting effective stabilizing treatment and that a proportion of youth can be stabilized on monotherapy. This is a small case series with nonrandom treatment assignment, and the findings should be considered tentative.

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OBJECTIVE: To contrast the effect of a typical antipsychotic (haloperidol) and an atypical antipsychotic (olanzapine) on neurocognitive functioning in schizophrenia when learning and practice (LP) effects are controlled. METHODS: Two groups of participants were recruited, 27 schizophrenia patients in their first 5 years of illness and 13 normal controls. Prior to double-blind randomisation, all subjects were assessed on four occasions within 5 days (prerandomisation period) on the same neurocognitive battery. Repeated assessment prior to randomisation was chosen as a method to control for LP effects. Patients were then randomised to 56 days of treatment with haloperidol or olanzapine (postrandomisation). All subjects were assessed on neurocognitive measures at Days 28 and 56. RESULTS: LP effects were present during the prerandomisation period on motor tasks, verbal and visual short-term memory, attention, and on a measure of verbal working memory. There were no changes in performance for patients randomised to treatment with olanzapine or haloperidol or the normal control group during the postrandomisation period. CONCLUSIONS: Once LP effects are controlled, olanzapine and haloperidol do not affect performance on measures of motor functioning, verbal short-term memory, attention, verbal working memory, reaction time, visuospatial short-term memory, and visual working memory beyond that observed from LP effects.

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AIM: Clinical experience suggests the use of alternative remedies, such as St. John's Wort (SJW), in adolescents with affective disorders is increasing. In view of the paucity of documented, well-established, and safe antidepressant medications for children and adolescents, it was important to investigate the potential usefulness of SJW in adolescents with major depressive disorders (MDD). METHODS AND RESULTS: An 8-week, open-label study evaluated the potential efficacy and safety of SJW (300 mg TID) in adolescents with MDD. Twenty-six patients, 12-17 years of age (mean age, 14.8 years) were enrolled in the study. Of the 11 patients who completed the study, 9 patients (82%) showed significant clinical improvement based on Clinical Global Improvement (CGI) change scores (treatment response was indicated by a clinical improvement rating of either very much improved or much improved at the final visit). Of the 15 patients (58%) who did not complete the study, 8 patients were noncompliant and 7 patients were discontinued because of persisting or worsening depression. Of the 8 noncompliant patients, at week 8, 2 patients (25%) remained unchanged, 1 patient (12.5%) was minimally improved, 4 patients (75%) were much improved, and 1 patient (12.5%) was very much improved, based on the CGI change score. CONCLUSION: Preliminary findings suggest that SJW is well tolerated and may be clinically effective in the treatment of some adolescents with mild depression. Controlled trials of SJW in adolescents with MDD are suggested.

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OBJECTIVE: Treating adolescents with depression remains a major clinical and public health challenge. Because of the serious morbidity and mortality associated with adolescent major depressive disorder (MDD), there is a need to review the published literature on treatment efficacy to establish effective treatment choices for these adolescents. METHOD: We reviewed the recent literature on the treatment of MDD in adolescents using the Medline and PsycINFO computerized databases. RESULTS: Results of open studies of MDD treatment in adolescents suggested therapeutic efficacy; however, later, better-controlled studies are more difficult to interpret, owing to the high rate of improvement with placebo. Currently, there is limited evidence of robust, effective therapeutic interventions in children and in adolescent depressive disorders. CONCLUSIONS: Despite limitations, current findings from studies investigating selective serotonin reuptake inhibitors (SSRIs), cognitive-behavioural therapy, and interpersonal therapy generally support these treatments as safe and effective for adolescent MDD. Still, further investigations into these treatments for adolescent depression are warranted.

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Antipsychotic drugs are used to treat a wide variety of child psychiatric disorders characterized by psychotic symptoms, aggression, excitement, tics, stereotypies and hyperactivity nonresponsive to other therapies. Unfortunately, typical antipsychotics have many adverse effects limiting their long-term use. Novel antipsychotics with combined dopaminergic and serotonergic action, such as risperidone, appear to offer better safety and efficacy profiles in controlled studies of adult patients, and therefore appeared as promising pharmacotherapeutic agents in child psychiatry. The purpose of this retrospective chart review was to obtain data on the potential effectiveness and tolerability of risperidone in children and adolescents presenting with a variety of chronic and severe psychiatric disorders who had been unresponsive to previous pharmacological treatments. Charts for 106 children and adolescents (males n = 81 or 76.4%; females n = 25 or 23.6%), presenting with attention deficit and/or hyperactivity disorder (n = 49 or 46.2%), conduct disorder (n = 13 or 12.3%), oppositional-defiant disorder (n = 5 or 4.7%), behavioural problems not otherwise specified (n = 2 or 1.9%), autism (n = 8 or 7.5%), Asperger's syndrome (n = 8 or 7.5%), pervasive developmental disorder (PDD) not otherwise specified (n = 4 or 3.8%), anxiety (n = 6 or 5.7%), depression (n = 2 or 1.9%), dysthymia (n = 2 or 1.9%), schizophrenia (n = 4 or 3.8%), adjustment disorder (n = 1 or 0.9%) and obsessive-compulsive disorder (n = 2 or 1.9%) were reviewed retrospectively to determine the tolerability and potential efficacy of risperidone treatment for a variety of psychiatric disorders. Six subjects also presented with mental retardation. The average length of illness prior to risperidone treatment was 5 years and the average age of risperidone treatment onset was 11 years. The mean daily dose of risperidone was 1.2 mg (range = 0.25 to 8.0 mg). Very few adverse effects were reported. The average length of risperidone treatment was 11 months with the majority (n = 75 or 76%) of patients maintained on risperidone following study termination. Seven cases (6.6%) were missing follow-up data. The majority (n = 78 or 74%) of patients were taking concurrent psychiatric medications, most commonly stimulants for the treatment of ADHD. Clinical global improvements for children and adolescents at the final study visit were marked (n = .37 or 34.9%), moderate (n = .40 or 37.7%), mild (n = 13 or 12.4%), none (n = 12 or 11.3%), or worse (n = 1 or 1%). Three cases (2.9%) were missing clinical improvement data. Results suggest that risperidone may be useful for managing behavioural disturbances and psychotic symptoms associated with a wide variety of childhood psychiatric disorders. For most patients in the study, a combination of risperidone and adjunctive pharmacotherapy was beneficial. Controlled and discontinuation studies of risperidone treatment in children and adolescents with behavioural and psychotic disorders are recommended.

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