Reward-related neural activity and structure predict future substance use in dysregulated youth.

BACKGROUND: Identifying youth who may engage in future substance use could facilitate early identification of substance use disorder vulnerability. We aimed to identify biomarkers that predicted future substance use in psychiatrically un-well youth. METHOD: LASSO regression for variable selection was used to predict substance use 24.3 months after neuroimaging assessment in 73 behaviorally and emotionally dysregulated youth aged 13.9 (s.d. = 2.0) years, 30 female, from three clinical sites in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Predictor variables included neural activity during a reward task, cortical thickness, and clinical and demographic variables. RESULTS: Future substance use was associated with higher left middle prefrontal cortex activity, lower left ventral anterior insula activity, thicker caudal anterior cingulate cortex, higher depression and lower mania scores, not using antipsychotic medication, more parental stress, older age. This combination of variables explained 60.4% of the variance in future substance use, and accurately classified 83.6%. CONCLUSIONS: These variables explained a large proportion of the variance, were useful classifiers of future substance use, and showed the value of combining multiple domains to provide a comprehensive understanding of substance use development. This may be a step toward identifying neural measures that can identify future substance use disorder risk, and act as targets for therapeutic interventions.

Predicting clinical outcome from reward circuitry function and white matter structure in behaviorally and emotionally dysregulated youth.

Behavioral and emotional dysregulation in childhood may be understood as prodromal to adult psychopathology. Additionally, there is a critical need to identify biomarkers reflecting underlying neuropathological processes that predict clinical/behavioral outcomes in youth. We aimed to identify such biomarkers in youth with behavioral and emotional dysregulation in the Longitudinal Assessment of Manic Symptoms (LAMS) study. We examined neuroimaging measures of function and white matter in the whole brain using 80 youth aged 14.0 (s.d.=2.0) from three clinical sites. Linear regression using the LASSO (Least Absolute Shrinkage and Selection Operator) method for variable selection was used to predict severity of future behavioral and emotional dysregulation measured by the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M)) at a mean of 14.2 months follow-up after neuroimaging assessment. Neuroimaging measures, together with near-scan PGBI-10M, a score of manic behaviors, depressive behaviors and sex, explained 28% of the variance in follow-up PGBI-10M. Neuroimaging measures alone, after accounting for other identified predictors, explained ~1/3 of the explained variance, in follow-up PGBI-10M. Specifically, greater bilateral cingulum length predicted lower PGBI-10M at follow-up. Greater functional connectivity in parietal-subcortical reward circuitry predicted greater PGBI-10M at follow-up. For the first time, data suggest that multimodal neuroimaging measures of underlying neuropathologic processes account for over a third of the explained variance in clinical outcome in a large sample of behaviorally and emotionally dysregulated youth. This may be an important first step toward identifying neurobiological measures with the potential to act as novel targets for early detection and future therapeutic interventions.

Behavioral and emotional dysregulation trajectories marked by prefrontal-amygdala function in symptomatic youth.

BACKGROUND: Neuroimaging measures of behavioral and emotional dysregulation can yield biomarkers denoting developmental trajectories of psychiatric pathology in youth. We aimed to identify functional abnormalities in emotion regulation (ER) neural circuitry associated with different behavioral and emotional dysregulation trajectories using latent class growth analysis (LCGA) and neuroimaging. METHOD: A total of 61 youth (9-17 years) from the Longitudinal Assessment of Manic Symptoms study, and 24 healthy control youth, completed an emotional face n-back ER task during scanning. LCGA was performed on 12 biannual reports completed over 5 years of the Parent General Behavior Inventory 10-Item Mania Scale (PGBI-10M), a parental report of the child's difficulty regulating positive mood and energy. RESULTS: There were two latent classes of PGBI-10M trajectories: high and decreasing (HighD; n=22) and low and decreasing (LowD; n=39) course of behavioral and emotional dysregulation over the 12 time points. Task performance was >89% in all youth, but more accurate in healthy controls and LowD versus HighD (p<0.001). During ER, LowD had greater activity than HighD and healthy controls in the dorsolateral prefrontal cortex, a key ER region, and greater functional connectivity than HighD between the amygdala and ventrolateral prefrontal cortex (p's<0.001, corrected). CONCLUSIONS: Patterns of function in lateral prefrontal cortical-amygdala circuitry in youth denote the severity of the developmental trajectory of behavioral and emotional dysregulation over time, and may be biological targets to guide differential treatment and novel treatment development for different levels of behavioral and emotional dysregulation in youth.

Comorbid anxiety and substance use disorders associated with a lower use of mood stabilisers in patients with rapid cycling bipolar disorder: a descriptive analysis of the cross-sectional data of 566 patients.

OBJECTIVE: To study mood stabiliser treatment in patients with bipolar disorder with or without anxiety disorders (ADs) and/or substance use disorders (SUDs). METHODS: Extensive clinical interview and Mini-International Neuropsychiatric Interview were used to ascertain DSM-IV diagnoses of rapid cycling bipolar I (RCBDI) or II (RCBDII), SUDs and ADs. Previous treatment statuses with a mood stabiliser after the first onset of mania/hypomania (unmedicated, mismedicated and correctly medicated) were retrospectively determined in patients enrolled into four similar clinical trials. T-test and chi-square/Fisher's exact were used wherever appropriate. RESULTS: Of 566 patients (RCBDI n = 320, RCBDII n = 246), 46% had any lifetime AD, 67% had any lifetime SUD and 40% had any recent SUD. Overall, 12% of patients were unmedicated, 37% were mismedicated at the onset of first mania/hypomania and 51% were correctly medicated. Presence of lifetime ADs and recent SUDs was associated with fewer mood stabiliser treatments. Patients with RCBDI were more likely correctly medicated than those with RCBDII (OR = 3.64) regardless of the presence (OR = 2.6) or absence (OR = 4.2) of ADs, or the presence (OR = 2.8) or absence (OR = 3.13) of recent SUDs. Presence of lifetime ADs and recent SUDs increased the risk for mismedicated in RCBDI with odds ratios of 1.8 and 1.9, respectively, but not in RCBDII. CONCLUSION: In this multi-morbid cohort of patients with RCBD, 51% of patients (64% of RCBDI and 33% with RCDBII) were correctly medicated with a mood stabiliser after the onset of first mania/hypomania. The presence of ADs and SUDs was associated with an increased risk of mismedicated in patients with RCBDI, but not with RCBDII.

Altered prefrontal lobe oxygenation in bipolar disorder: a study by near-infrared spectroscopy.

BACKGROUND: Previous studies have reported prefrontal cortex (PFC) pathophysiology in bipolar disorder. METHOD: We examined the hemodynamics of the PFC during resting and cognitive tasks in 29 patients with bipolar disorder and 27 healthy controls, matched for age, verbal abilities and education. The cognitive test battery consisted of letter and category fluency (LF and CF), Sets A and B of the Raven's Colored Progressive Matrices (RCPM-A and RCPM-B) and the letter cancellation test (LCT). The tissue oxygenation index (TOI), the ratio of oxygenated hemoglobin (HbO2) concentration to total hemoglobin concentration, was measured in the bilateral PFC by spatially resolved near-infrared spectroscopy. Changes in HbO2 concentration were also measured. RESULTS: The bipolar group showed slight but significant impairment in performance for the non-verbal tasks (RCPM-A, RCPM-B and LCT), with no significant between-group differences for the two verbal tasks (LF and CF). A group x task x hemisphere analysis of variance (ANOVA) on the TOI revealed an abnormal pattern of prefrontal oxygenation across different types of cognitive processing in the bipolar group. Post hoc analyses following a group x task x hemisphere ANOVA on HbO2 concentration revealed that the bipolar group showed a greater increase in HbO2 concentration in the LCT and in RCPM-B, relative to controls. CONCLUSIONS: Both indices of cortical activation (TOI and HbO2 concentration) indicated a discrepancy in the PFC function between verbal versus non-verbal processing, indicating task-specific abnormalities in the hemodynamic control of the PFC in bipolar disorder.

Diffusion imaging markers of bipolar versus general psychopathology risk in youth at-risk.

Bipolar disorder (BD) is highly heritable. Thus, studies in first-degree relatives of individuals with BD could lead to the discovery of objective risk markers of BD. Abnormalities in white matter structure reported in at-risk individuals could play an important role in the pathophysiology of BD. Due to the lack of studies with other at-risk offspring, however, it remains unclear whether such abnormalities reflect BD-specific or generic risk markers for future psychopathology. Using a tract-profile approach, we examined 18 major white matter tracts in 38 offspring of BD parents, 36 offspring of comparison parents with non-BD psychopathology (depression, attention-deficit/hyperactivity disorder), and 41 offspring of healthy parents. Both at-risk groups showed significantly lower fractional anisotropy (FA) in left-sided tracts (cingulum, inferior longitudinal fasciculus, forceps minor), and significantly greater FA in right-sided tracts (uncinate fasciculus and inferior longitudinal fasciculus), relative to offspring of healthy parents (P < 0.05). These abnormalities were present in both healthy and affected youth in at-risk groups. Only offspring (particularly healthy offspring) of BD parents showed lower FA in the right superior longitudinal fasciculus relative to healthy offspring of healthy parents (P < 0.05). We show, for the first time, important similarities, and some differences, in white matter structure between offspring of BD and offspring of non-BD parents. Findings suggest that lower left-sided and higher right-sided FA in tracts important for emotional regulation may represent markers of risk for general, rather than BD-specific, psychopathology. Lower FA in the right superior longitudinal fasciculus may protect against development of BD in offspring of BD parents.

New data on the use of lithium, divalproate, and lamotrigine in rapid cycling bipolar disorder.

The rapid cycling variant of bipolar disorder is defined as the occurrence of four periods of either manic or depressive illness within 12 months. Patients suffering from this variant of bipolar disorder have an unmet need for effective treatment. This review examines two major studies in an attempt to update understanding of the current therapies available to treat rapid cycling patients. The first trial compares lamotrigine versus placebo in 182 patients studied for 6 months. The second is a recently completed, 20-month trial comparing divalproate and lithium in 60 patients. Both trials had a double-blind, randomized parallel-group design. The data from the latter study indicate that there are no large differences in efficacy between lithium and divalproate in the long-term treatment of rapid cycling bipolar disorder. In addition, lamotrigine has the potential to complement the spectrum of lithium and divalproate through its greater efficacy for depressive symptoms.

An MRI study of adolescent patients with either schizophrenia or bipolar disorder as compared to healthy control subjects.

BACKGROUND: There are few imaging studies in adolescent patients with either schizophrenia or bipolar disorder. Such studies are of interest because adolescents may have a more severe illness and neurodevelopmental events may have a greater role in their pathophysiology. METHODS: We compared 20 patients with schizophrenia and 15 patients with bipolar disorder (10 to 18 years) to 16 normal adolescents on magnetic resonance imaging (MRI) measures of intracranial volume and ventricular and sulcal enlargement. Two planned comparison contrasts were employed, one comparing the two patient groups to each other (contrast 1), and one comparing both patient groups combined to control subjects (contrast 2). RESULTS: None of the contrast 1 comparisons (schizophrenia vs bipolar) were statistically significant. Contrast 2 comparisons (control subjects vs patients) were statistically significant for intracranial volume (reduced in patients) as well as frontal and temporal sulcal size (increased in patients). CONCLUSIONS: The patient groups were not statistically significantly different from each other on any measure. The combined patient groups were different from control subjects on intracranial volume and frontal and temporal sulcal size. Also, there was evidence for ventricular enlargement, after removal of a control subject with an extreme value. These findings indicate that the same abnormalities noted in adult populations are present in adolescents.

Antidepressant treatment during breast-feeding.

OBJECTIVE: The primary purpose of this article is to review critically the literature about use of antidepressants during lactation. Strategies for the clinical management of depressed breast-feeding mothers are also suggested. METHOD: The authors conducted a computerized search of MEDLINE for articles. The review includes studies in which serum levels of drugs were obtained from nursing infants. RESULTS: Fifteen published reports were located that provided information for the following nine antidepressants: amitriptyline, nortriptyline, desipramine, clomipramine, doxepin, dothiepin, fluoxetine, sertraline, and bupropion. CONCLUSIONS: Amitriptyline, nortriptyline, desipramine, clomipramine, dothiepin, and sertraline were not found in quantifiable amounts in nurslings, and no adverse effects were reported. Therefore, these are the drugs of choice for breast-feeding women. Adverse effects were described in some young infants whose mothers had been treated with doxepin or fluoxetine during breast-feeding. The collective serum level data suggest that infants older than 10 weeks are at low risk for adverse effects of tricyclics, and there is no evidence of accumulation. Research needs include an expanded database of mother-baby serum levels, behavioral assessments of infants during nursing, and longitudinal developmental evaluation of nurslings. Prescription of an antidepressant for a breast-feeding woman is a case-specific risk-benefit decision.

Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance.

OBJECTIVE: The age at onset of schizophrenia for males has usually but not always been reported to be less than that for females. Early onset has also been associated with poor response to neuroleptic treatment and worse long-term outcome. The authors compared age at onset in neuroleptic-resistant and -responsive schizophrenic patients to determine whether the gender difference in age at onset is related to response to neuroleptic treatment. METHOD: The subjects were 322 patients with schizophrenia or schizoaffective disorder who were consecutively admitted to a university hospital-based research program. RESULTS: Analysis of variance showed significant relationship between age at onset and both gender and longterm responsivity to neuroleptic drugs. The mean ages at onset in the neuroleptic-responsive men (mean = 21.2 years, SD = 6.1, N = 75), neuroleptic-resistant men (mean = 19.4 years, SD = 4.7, N = 119), and neuroleptic-resistant women (mean = 20.1 years, SD = 6.3, N = 77) were fairly similar, whereas that of the neuroleptic-responsive women (mean = 24.2 years, SD = 8.7, N = 51) was significantly greater than for all other groups. A simple effects model indicated that male and female neuroleptic-resistant patients did not differ significantly in mean age at onset, whereas male and female neuroleptic-responsive patients did. The effect of gender and neuroleptic responsivity on age at onset was related to schizophrenic subtype. CONCLUSIONS: These results confirm previous data indicating neuroleptic resistance is associated with early onset. The finding that the difference in age at onset between males and females is smaller in neuroleptic-resistant patients than in neuroleptic-responsive patients suggests that neuroleptic-resistant patients differ premorbidly as well as after onset of illness.

Cognitive impairment in adolescents with schizophrenia.

OBJECTIVE: The purpose of this study was to determine whether adolescent schizophrenia is characterized by neuropsychological deficits. METHOD: The performance on a battery of neuropsychological tests of 17 adolescents with schizophrenia (mean age = 15.71 years) was compared with that of 17 normal adolescents (mean age = 15.12 years). RESULTS: Compared with the normal subjects, the patients were impaired on 10 of the 13 measures; larger effect sizes were shown for measures involving working memory and attention than for those involving secondary memory, generative naming, and executive functions. CONCLUSIONS: Adolescents with schizophrenia have generalized cognitive dysfunction, which is most apparent on tests of attention and working memory.

Psychopharmacology of ADHD: children and adolescents.

Medications can provide significant salutary effects for children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Due to their well-established safety and efficacy, psychostimulants are generally considered first-line pharmacotherapy for most young patients with ADHD. Since psychostimulant treatment often requires frequent dosing and may be associated with unacceptable side effects and risks, other classes of medication have been studied as possible treatment alternatives. The most extensively researched nonstimulant medications are the tricyclic antidepressants. In addition, alpha2 agonists have also been shown to reduce symptoms of ADHD. However, concerns regarding potential cardiotoxicity have tempered the enthusiasm for both of these classes of medication. Newer antidepressants such as bupropion and venlafaxine may hold promise as treatments for ADHD.

Antipsychotic medications in children and adolescents.

Antipsychotic medications are commonly prescribed to children and adolescents. These medications, however, are not only prescribed for young patients with psychosis, but are often prescribed for youths with a variety of psychiatric disorders. Despite the fact that psychiatric illness in the pre-adult era is not rare, few controlled clinical trials have examined the short-term safety and efficacy of these agents in youths with psychosis. There are even fewer data regarding the long-term safety and efficacy of these agents in psychotic children and adolescents. As new antipsychotics become available, the study of these agents in youngsters with a variety of psychiatric illnesses may become an exciting new avenue for research.

Treatment and outcomes in adolescents with schizophrenia.

The pharmacologic treatment and assessment of outcomes in adolescents with schizophrenia have been inadequately addressed. Structural brain imaging and brain function studies both point to a continuity between adolescent and adult stages of schizophrenia. Because the teenage population seems to be less tolerant of physical side effects, the advent of atypical antipsychotic medications may offer increased safety and efficacy. Studies support the notion that adolescent illness is associated with a more severe form of schizophrenia and that length of illness before treatment is correlated with long-term outcome. As a consequence, the authors recommend assertive pharmacologic intervention in adolescents with schizophrenia and future research focused on the issues of treatment and outcome in teenagers suffering a psychotic disorder.

Venlafaxine in adults with attention-deficit/hyperactivity disorder: an open clinical trial.

BACKGROUND: It is becoming commonly recognized that adults suffer from attention-deficit/hyperactivity disorder (ADHD). Since medications used in the past of treat adults with ADHD may be ineffective or poorly tolerated by some patients, it is important to determine if newly available medications can safely ameliorate symptoms of ADHD in adults. METHOD: An open clinical trial was undertaken to examine whether venlafaxine was safe and effective in the treatment of adults with ADHD. Ten subjects who met DSM-IV criteria for ADHD were enrolled in this 8-week trial. Individuals were started on 37.5 mg of venlafaxine b.i.d. If moderate ADHD symptoms persisted at the end of Week 4, the dose of venlafaxine was increased to 75 mg b.i.d. Assessments of ADHD symptomatology included the ADHD Rating Scale, Self-Report Version (ARS) and the Clinical Global Impressions (CGI) scale. RESULTS: Nine patients completed the study. At the end of the study, 7 patients were receiving 37.5 mg b.i.d. of venlafaxine. Repeated measures ANOVA demonstrated that treatment with venlafaxine was associated with significant reductions in ADHD symptomatology (p < .02 for the ARS; p < .005 for the CGI). Of the 9 subjects who completed the trial, 7 were considered responders. Venlafaxine was well tolerated, and most patients experienced only mild side effects. CONCLUSION: Venlafaxine may be a promising agent for the treatment of ADHD in adults. Controlled clinical trials are needed to further examine this issue.

Prevention of recurrent postpartum depression: a randomized clinical trial.

BACKGROUND: Women who have suffered one episode of postpartum-onset major depression (PPMD) comprise a high-risk group for subsequent episodes. We conducted a double-blind, randomized clinical trial to test the efficacy of nortriptyline in the prevention of recurrent PPMD. METHOD: Nondepressed women who had at least one past episode of PPMD (Research Diagnostic Criteria) were recruited during pregnancy. Subjects were randomly assigned to nortriptyline or placebo. Treatment began immediately postpartum. Each subject was assessed for 20 sequential weeks with the Hamilton Rating Scale for Depression and Research Diagnostic Criteria for recurrence of major depression. RESULTS: No difference was found in the rate of recurrence in women treated with nortriptyline compared with those treated with placebo. Of 26 subjects who took nortriptyline preventively, 6 (0.23, 95% exact confidence interval [CI] = 0.09 to 0.44) suffered recurrences. Of 25 subjects who took placebo, 6 (0.24, 95% exact CI = 0.09 to 0.45) suffered recurrence (Fisher exact p = 1.00). CONCLUSION: Nortriptyline did not confer additional preventive efficacy beyond that of placebo. The rate of recurrence of PPMD (one fourth of women) was unacceptably high.

Developmental aspects of psychostimulant treatment in children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVES: To examine the relationship between age and short-term clinical response to psychostimulant treatment in youths with attention-deficit/hyperactivity disorder (ADHD) and to examine whether weight-corrected doses of optimized psychostimulant therapy varied as a function of patient age. METHOD: One hundred seventy-seven patients were treated with either methylphenidate (MPH) or Adderall (ADL). Sixty-six youths received ADL and 111 patients were treated with MPH. All youths were evaluated at baseline and after receiving a week of treatment at each blinded, randomized dose level (placebo, 5, 10, or 15 mg). A "best dose" for each patient was assigned before the medication blind was broken. Behavioral ratings by both teachers and parents were examined for dose and medication effects. RESULTS: The medications had similar efficacy in children and teenagers. Older youths, however, benefited from a smaller weight-adjusted dose of medication than did the younger children. Similar efficacy was observed between the medications. CONCLUSIONS: These data suggest that psychostimulants are equally effective in treating children and adolescents with ADHD. Adolescents with ADHD may not necessarily require more medication than younger children to achieve a similar therapeutic response.

Short-term cardiovascular effects of methylphenidate and adderall.

OBJECTIVE: The primary purpose of this study was to examine the cardiovascular effects of Adderall (ADL) in a clinic-based group of youths with attention-deficit/hyperactivity disorder ranging in age from 4 to 17 years. METHOD: One hundred thirty-seven patients were treated with either methylphenidate (MPH) or ADL. Youths prescribed MPH were given medication twice daily, and youths treated with ADL received medication once daily. Patients were evaluated under five conditions: baseline, placebo, 5 mg/dose, 10 mg/dose, or 15 mg/dose. Resting pulse, diastolic blood pressure, and systolic blood pressure were examined after 1 week at each treatment condition. Changes from baseline on these parameters were examined. RESULTS: The short-term cardiovascular effects of both ADL and MPH were modest. No patients experienced any clinically significant change in these cardiovascular measures during the course of this brief trial. CONCLUSION: Since the short-term cardiovascular effects of ADL appear minimal, specific cardiovascular monitoring during short-term ADL treatment at doses of 15 mg/day or less does not appear to be indicated. In addition, under similar conditions, using similar methods, both medication treatments led to changes in blood pressure and pulse that were clinically insignificant.

Differential effectiveness of methylphenidate and Adderall in school-age youths with attention-deficit/hyperactivity disorder.

OBJECTIVE: To compare the effectiveness of a single dose of Adderall (q.d.) with that of 2 daily doses of methylphenidate (b.i.d.; MPH) as a treatment for attention-deficit/hyperactivity disorder (ADHD) in youths ranging in age from 5 to 17 years. Forty-two youths treated with MPH were compared with 42 youths treated with Adderall. Subjects were matched for age, sex, and DSM-IV diagnostic subtype. METHOD: Youths were assigned to the Adderall or MPH condition by their prescribing physician. All youths were evaluated under 5 conditions, including baseline, placebo, 5 mg, 10 mg, and 15 mg. The best dose was assigned prior to breaking the medication blind and was assigned by the consensus of the psychologist and psychiatrist. Subjective ratings by both teachers and parents were examined for dosage level effects and medication type effects. RESULTS: Best dose was always superior to baseline and placebo conditions. No differences between MPH and Adderall were observed on either teacher or parent ratings of behavior. CONCLUSIONS: Both MPH and Adderall have been shown to be effective treatments for children with ADHD. Both medications appear to improve teachers' and parents' ratings of behavior. Single-dose treatments of Adderall appear to be as effective as 2 daily doses of MPH and therefore increase the possibility of managing treatment without involving the school in medication administration. In addition, youths who have previously been unsuccessfully treated with MPH because of adverse side effects or poor response may be successfully treated with Adderall.

A double-blind pilot study of risperidone in the treatment of conduct disorder.

OBJECTIVE: To examine whether risperidone is superior to placebo in the treatment of youths with conduct disorder. METHOD: This was a 10-week, randomized, double-blind, placebo-controlled study with 2 parallel arms. Ten youths were randomly assigned to receive placebo and 10 youths were randomly assigned to receive risperidone. Patients were seen weekly throughout the trial. Medications could be increased at weekly intervals during the first 6 weeks of the study from an initial dose of 0.25 mg or 0.50 mg each morning, depending on patient weight. Patients weighing less than 50 kg had a maximum total daily dose of risperidone of 1.5 mg. Patients weighing 50 kg or greater had a maximum total daily dose of risperidone of 3.0 mg. The primary outcome measure was the Rating of Aggression Against People and/or Property Scale. RESULTS: Risperidone was superior to placebo in ameliorating aggression on most measures. Risperidone was reasonably well tolerated, with none of the risperidone-treated patients developing extrapyramidal side effects. CONCLUSIONS: These data provide preliminary evidence that risperidone may have efficacy in the treatment of youths with conduct disorder. Because of the small sample size and the brief length of this study, further research is necessary to confirm these findings.