The characteristics of asymptomatic female adolescents at high risk for depression: the baseline assessment from a prospective 8-year study.

OBJECTIVES: This longitudinal 8-year study assesses potential predictors of major depressive disorder (MDD) in a cohort of healthy adolescent females at high familial risk for MDD. The objective of this study was to ascertain whether risk factors for female onset MDD would differentiate youth at high or usual risk for MDD, prior to the onset of depressive symptomology. METHODS: Subjects (ages 12-15 years) were assigned to a high (n=43) or usual (n=40) risk group according to maternal history of MDD. Depressive symptomatology (Beck Depression Inventory, Hamilton Rating Scale for Depression), pubertal development (Pubertal Developmental Staging Questionnaire), social support (Social Support Scale), and cognitive vulnerability (Depressive Experiences Questionnaire) were assessed. RESULTS: High risk and usual risk group demonstrated no significant differences in demographic variables such as age, body mass index, and grade. Significantly more youth in the high risk group (n=40, 93%) had started menstruation, compared to youth in the usual risk group (n=31, 77.5%). There were no significant differences between the groups on measures of dysphoric cognitive style, perceived overall number of social supports, or satisfaction with social support. CONCLUSIONS: Females at high familial risk for the onset of depression have significant differences in pubertal development, but not in demographics, depressive symptoms, social supports, or dysphoric cognitive style, when compared to females at usual risk for depression. These findings suggest that in prevention trials for depression in asymptomatic young women no non-biological risk factors for MDD aid in identifying females at higher risk for MDD.

A pilot study of loading versus titration of valproate in the treatment of acute mania.

OBJECTIVE: This double-blind pilot study compares the effectiveness and incidence of adverse effects of oral loading versus titration schedules of valproate in acute mania. METHOD: Consecutive new admissions for an acute manic episode were prescribed either an oral loading dose (20 mg/kg/day; n = 5; mean age = 33.4) or slower titration dose (10 mg/kg/day, n = 6. mean age = 30.6) of valproate for 7 days without other psychotropic agents. with the exception of benzodiazepines. Daily outcome measures included: serum valproic acid levels, the Young Mania Rating Scale (YMRS), the Brief Psychiatry Rating Scale (BPRS), the Clinical Global Impression Scale (CGI) and the Adverse Effect Rating Scale. RESULTS: The mean serum valproic acid levels were significantly higher in the loading group when compared with the titration group after 1 and 2 days following the initiation of treatment (p < 0.05). After 3 days of treatment there was a trend for the group that received the loading regimen to have slightly more improvement in YMRS scores compared with the titration group. Side-effects were minor for both treatments, however, a higher incidence of side-effects was reported in the titration group, with 50% of patients reporting sedation most likely because of increased use of benzodiazepines. CONCLUSION: This suggests that a loading dose of valproate is likely safe and may provide an earlier onset of antimanic effects in patients with bipolar disorder. Future studies with larger sample sizes are indicated.

Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial.

OBJECTIVE: To compare paroxetine with placebo and imipramine with placebo for the treatment of adolescent depression. METHOD: After a 7- to 14-day screening period, 275 adolescents with major depression began 8 weeks of double-blind paroxetine (20-40 mg), imipramine (gradual upward titration to 200-300 mg), or placebo. The two primary outcome measures were endpoint response (Hamilton Rating Scale for Depression [HAM-D] score < or = 8 or > or = 50% reduction in baseline HAM-D) and change from baseline HAM-D score. Other depression-related variables were (1) HAM-D depressed mood item; (2) depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version (K-SADS-L); (3) Clinical Global Impression (CGI) improvement scores of 1 or 2; (4) nine-item depression subscale of K-SADS-L; and (5) mean CGI improvement scores. RESULTS: Paroxetine demonstrated significantly greater improvement compared with placebo in HAM-D total score < or = 8, HAM-D depressed mood item, K-SADS-L depressed mood item, and CGI score of 1 or 2. The response to imipramine was not significantly different from placebo for any measure. Neither paroxetine nor imipramine differed significantly from placebo on parent- or self-rating measures. Withdrawal rates for adverse effects were 9.7% and 6.9% for paroxetine and placebo, respectively. Of 31.5% of subjects stopping imipramine therapy because of adverse effects, nearly one third did so because of adverse cardiovascular effects. CONCLUSIONS: Paroxetine is generally well tolerated and effective for major depression in adolescents.

Open trial of interpersonal therapy in adolescents with moderate to severe major depression: effectiveness of novice IPT therapists.

OBJECTIVE: To evaluate the effectiveness of interpersonal therapy (IPT) implemented by well-supervised, novice IPT therapists in treating adolescents with moderate to severe mood disorders of lengthy duration. METHOD: Twenty-five adolescents with moderate to severe major depression, lasting an average of 8 months, received 12 weeks of IPT. All participants were assessed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version, the Beck Depression Inventory (BDI), the Hamilton Rating Scale for Depression (HRSD), and the Children's Global Assessment Scale (C-GAS) at baseline and follow-up. RESULTS: The majority of participants improved substantially on the BDI, the HRSD, and the C-GAS; 84% met remission criteria on the HRSD (score < 7); and 80% met remission criteria on the BDI (score < 10). CONCLUSIONS: Results demonstrate that IPT is effective in treating moderately to severely depressed adolescents, that IPT is effective with depression lasting several months, and that IPT can be effectively implemented by well-supervised clinicians with no prior training in IPT.

Left medial temporal cytosolic choline in early onset depression.

OBJECTIVE: Previous studies have linked the choline (Cho) resonance seen in proton magnetic resonance spectroscopy (1H-MRS) to major depressive disorder (MDD). We endeavoured to clarify the possible involvement of cytosolic choline in the amygdala (anterior medial temporal region) of juvenile subjects with MDD. METHOD: A total of 11 age- and sex-matched MDD and control pairs aged 14 to 18 years participated in long-echo proton magnetic resonance spectroscopic imaging (1H-MRSI) of the amygdala. Compounds available include N-acetyl-aspartate (NAA), creatine-phosphocreatine (Cr) and choline-containing compounds. RESULTS: Subjects with depression demonstrated lower left amygdala Cho-Cr ratios, compared with control subjects (paired t = 2.624, df 10, P = 0.025). Left amygdala NAA-Cr and right amygdala Cho-Cr and NAA-Cr did not differ significantly between subjects with depression and control subjects. In subjects with depression, simple regression revealed a negative trend between left amygdala Cho-Cr and Beck Depression Inventory (BDI) score (F = 3.509, P = 0.098). Right amygdala NAA-Cr and Cho-Cr did not differ significantly. CONCLUSION: Cytosolic choline appears to be involved in the pathophysiology of early-onset MDD, likely secondary to corticosteroid-neuroendocrine-driven changes.

A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group.

BACKGROUND: Patients with rapid-cycling bipolar disorder are often treatment refractory. This study examined lamotrigine as maintenance monotherapy for rapid-cycling bipolar disorder. METHOD: Lamotrigine was added to patients' current psychotropic regimens and titrated to clinical effect during an open-label treatment phase. Stabilized patients were tapered off other psychotropics and randomly assigned to lamotrigine or placebo monotherapy for 6 months. Time to additional pharmacotherapy for emerging symptoms was the primary outcome measure. Secondary efficacy measures included survival in study (time to any premature discontinuation), percentage of patients stable without relapse for 6 months, and changes in the Global Assessment Scale and Clinical Global Impressions-Severity scale. Safety was assessed from adverse event, physical examination, and laboratory data. RESULTS: 324 patients with rapid-cycling bipolar disorder (DSM-IV criteria) received open-label lamotrigine, and 182 patients were randomly assigned to the double-blind maintenance phase. The difference between the treatment groups in time to additional pharmacotherapy did not achieve statistical significance in the overall efficacy population. However, survival in study was statistically different between the treatment groups (p = .036). Analyses also indicated a 6-week difference in median survival time favoring lamotrigine. Forty-one percent of lamotrigine patients versus 26% of placebo patients (p = .03) were stable without relapse for 6 months of monotherapy. Lamotrigine was well tolerated; there were no treatment-related changes in laboratory parameters, vital signs, or body weight. No serious rashes occurred. CONCLUSION: This was the largest and only prospective placebo-controlled study of rapid-cycling bipolar disorder patients to date; results indicate lamotrigine monotherapy is a useful treatment for some patients with rapid-cycling bipolar disorder.

An open study of lamotrigine in refractory bipolar depression.

Bipolar depressed patients (n = 22) who were refractory to treatment with a combination of divalproex sodium (DVP) and another mood stabilizer or DVP and an antidepressant for 6 weeks were treated in an open naturalistic study with an addition of lamotrigine to DVP. Sixteen out of 22 (72%) responded by the end of week 4 and none developed rash or switched to mania. The results of this preliminary study suggest that lamotrigine may be useful in bipolar depression.

The foundations of effective management of bipolar disorder.

OBJECTIVES: To understand the epidemiology and course of bipolar disorder; to outline the importance of accurate and reliable diagnosis of bipolar disorder both on a cross-sectional and longitudinal basis; and to emphasize the value of a collaborative therapeutic relationship, psychoeducation, and psychotherapy. METHODS: A brief review of relevant literature to deal with the issues of diagnosis and laying the foundations for effective treatment. RESULTS: Bipolar disorder may well be a heterogeneous group of conditions with varying forms of biphasic mood dysregulation and a changing course across a lifetime. A collaborative therapeutic relationship, psychoeducation, and psychotherapy can be the basis for effective management. CONCLUSIONS: As the concept of bipolar disorder has broadened, the condition is being identified with increasing frequency in many clinical settings. It is a relapsing and recurring condition. It is now recognized that in addition to rational pharmacotherapy, there is a need to encourage a high level of treatment adherence while providing a holistic package of interventions.

Psychosocial interventions as an adjunct to pharmacotherapy in bipolar disorder.

OBJECTIVE: To summarize the evidence and make treatment recommendations regarding the use of psychosocial interventions as an adjunct to pharmacotherapy for bipolar disorder. METHODS: We reviewed published outcome studies since 1975 identified in MEDLINE and PsychLIT searches. RESULTS: Available studies are initial and of highly variable methodological rigour. Evidence is most robust for the efficacy of psychoeducation and family therapy, and these received the highest level of recommendation as interventions. Group therapy, cognitive-behavioural therapy, and behavioural family management therapy are supported by weaker evidence and received a lower-level treatment recommendation. Availability of only a single interpersonal and social rhythms therapy trial limited the confidence of the recommendation for this intervention. CONCLUSIONS: Controlled trials are needed to replicate early outcome studies and guide treatment recommendations. Accumulated evidence of favourable psychosocial intervention outcomes supports, with variable confidence, their use as adjuncts to pharmacotherapy in the treatment of bipolar disorder.

Treatment of mania, mixed state, and rapid cycling.

OBJECTIVES: To summarize the quality of evidence for the efficacy of different biological treatments in mania, mixed state, and rapid cycling and to propose guidelines for treatment of these conditions. METHOD: Articles published on treatment of acute mania, mixed states, and rapid cycling were reviewed and rated for quality of evidence using Periodic Health Examination guidelines. RESULTS: Lithium and divalproex sodium are effective in classical pure mania, whereas divalproex sodium and carbamazepine are likely more effective in mixed states. Divalproex sodium is likely more efficacious than carbamazepine and lithium when the mania is part of a rapid-cycling course. Typical neuroleptics are efficacious in acute mania, particularly in the presence of marked psychotic symptoms. Atypical neuroleptics can be useful in refractory mania. Some benzodiazepines do have antimanic effects, but they are increasingly being shown to have usefulness as adjuncts to mood stabilizers or neuroleptics rather than as primary antimanic agents. Electroconvulsive therapy (ECT) is an efficacious and broad-spectrum treatment. CONCLUSIONS: Mania can present with or without mood-congruent or mood-incongruent psychotic features and as part of a rapid-cycling or nonrapid-cycling course. Mixed state is a common presentation in an acutely manic patient. The accurate assessment of these issues can serve as a guide in determining treatment options and choices.

Bipolar depression: treatment options.

OBJECTIVE: To review studies on treatments for bipolar depression and make recommendations for practising clinicians treating patients with bipolar depression. METHOD: Studies that examined various treatments for bipolar depression were evaluated and rated for evidence of efficacy using Periodic Health Examination criteria. The rating for classification of recommendation for an intervention was made taking both the efficacy and the side effects into consideration. RESULTS: Mood stabilizers, cyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and electroconvulsive therapy (ECT) are all effective in treating bipolar depression. Almost all antidepressant treatments with the exception of mood stabilizers have been reported to induce a manic-hypomanic switch and rapid cycling. CONCLUSIONS: Mood stabilizers, lithium in particular, are recommended as the first-line treatment. Addition of a second mood stabilizer or a cyclic antidepressant would be an appropriate next step. Newer agents such as lamotrigine offer considerable promise in treating bipolar depressed patients.

Continuation and prophylactic treatment of bipolar disorder.

OBJECTIVES: To summarize the evidence for efficacy from published literature of biological treatments in the continuation and maintenance phases of bipolar disorder, as well as the recommendations about different treatment options made by the working group within the Bipolar Sub-Committee of the Canadian Network for Mood and Anxiety Treatments (CANMAT). METHODS: A review of relevant published literature and proceedings of international conferences was conducted. The quality of evidence was assessed and classified according to the Periodic Health Examination criteria. Treatment recommendations of the working group were based on quality of evidence, a consensus of expert views, and the opinions of psychiatrists and family physicians from across Canada. RESULTS: There is overwhelming evidence for the efficacy of lithium in the prophylaxis of bipolar disorder. The evidence for carbamazepine is less robust. There are no published double-blind studies with adequate numbers of subjects treated with divalproex sodium. CONCLUSIONS: During and at the end of the continuation phase it is recommended that mood stabilizers should remain the mainstay of therapy and that other treatments should be gradually discontinued or maintained only if there is valid reason to do so. Efficacious maintenance treatment can reduce morbidity and mortality significantly and improve patients' quality of life.

Comparative studies of the biological distinction between unipolar and bipolar depressions.

Although unipolar depression and bipolar depression are considered distinct entities both by clinicians and researchers, it is not clear whether a pathophysiological distinction, which is the bridge between etiology and treatment, exists between these two conditions. The objective of this paper was to systematically review the studies that examined the biological differences between unipolar and bipolar depression. Using computerized Medline and manual searches, we located and reviewed studies that directly compared patients with unipolar depression with bipolar depressed patients on at least one biological variable. The results showed that patients with bipolar depression had lower levels of urinary NE and its metabolites and lower platelet MAO activity, and higher platelet free and stimulated intracellular calcium levels compared with unipolar depressed patients, but none of the variables examined appeared to differentiate the two groups consistently. We discuss some of the methodological flaws that might have contributed to this, and suggest that further studies should control for such confounding variables.

Assessment of noradrenergic functioning in patients with non-combat-related posttraumatic stress disorder: a study with desmethylimipramine and orthostatic challenges.

The functioning of the noradrenergic system was assessed in 16 patients with non-combat-related posttraumatic stress disorder (PTSD) and the same number of age- and sex-matched healthy subjects by measuring (1) plasma norepinephrine (NE) levels in supine and upright postures, and (2) growth hormone (GH) responses to challenge with desmethylimipramine (DMI), a NE reuptake inhibitor. Subjects were cannulated at 08:30 h after an overnight fast. Blood samples were drawn for NE levels with subjects in a supine position and after 5 min of standing. After subjects were allowed to rest for 30 min in a supine position, a blood sample was drawn for basal GH (T-15) levels. The second baseline sample was drawn 15 min later (T0), at which time DMI (1 mg/kg) was given orally, and further blood samples were drawn at 90, 120, and 180 min. PTSD patients had significantly higher baseline NE levels and blunted NE responsivity to postural challenge compared with normal subjects. Basal and DMI-induced GH levels, on the other hand, did not differ in PTSD versus normal subjects. Overall, these findings suggest that non-combat-related PTSD patients have peripheral noradrenergic dysregulation, but central postsynaptic alpha 2-adrenergic receptor sensitivity is not altered in this patient population.

Psychosocial adjustment in children with port-wine stains and prominent ears.

OBJECTIVE: To evaluate psychosocial adjustment in children with port-wine stain (PWS) and children with prominent ears (PE). METHOD: Thirty-two children aged 7 to 16 years with facial PWS and 42 children with PE were evaluated using the Harter Self-Perception Profile, the Revised Children's Manifest Anxiety Scale, the Children's Depression Inventory, the Disfigurement Perception Scale, and the Child Behavior Checklist. Results were compared with normative data for the local population or with a control group. Profile scores were correlated with severity of the PWS or prominence of the ears. RESULTS: Children with PE had poorer self-perception, higher concentration anxiety, and more internalizing and externalizing symptoms, and they were more withdrawn and had more social problems than children with PWS. The children with PWS functioned as well as or better than nondisfigured peers on measurements of psychosocial adjustment, while children with PE scored lower than nondisfigured peers on measures of self-perception and parent-rated social and attention problems. There was no correlation between degree of disfigurement and level of psychosocial adjustment. CONCLUSIONS: Psychosocial adjustment varied according to the nature of the disfigurement or deformity and was unrelated to the severity of the disfigurement.

Features of Coxsackie B virus (CBV) infection in children with prolonged physical and psychological morbidity.

A retrospective study of the clinical features in 39 children who were investigated for evidence of Coxsackie B virus (CBV) infection is reported. Eighteen children were found to have serological evidence of infection. An extensive range of features was elicited in both seropositive and seronegative patients, most children complaining of abnormalities referable to muscle and, in particular, of weakness and easy fatiguability. Children with evidence of CBV infection were significantly more likely to belong to social classes I and II, to have relatives with serological evidence of CBV infection, and to show certain dysphoric features as well as to complain of sore throats. The relationship between CBV infection and 'myalgic encephalomyelitis' or 'post-viral syndrome' is discussed, and it is suggested that these descriptions are inappropriate given our current knowledge, and inadequately describe the clinical features seen in the children under study. An alternative description, 'fatigue-dysphoria syndrome' is proposed.