Pharmacologic evidence to support clinical decision making for peripartum methadone treatment.

RATIONALE: Limited pharmacological data are available to guide methadone treatment during pregnancy and postpartum. OBJECTIVES: Study goals were to (1) characterize changes in methadone dose across childbearing, (2) determine enantiomer-specific methadone withdrawal kinetics from steady state during late pregnancy, (3) assess enantiomer-specific changes in methadone level/dose (L/D) ratios across childbearing, and (4) explore relationships between CYP2B6, CYP2C19, and CYP3A4 single-nucleotide polymorphisms and maternal dose, plasma concentration, and L/D. METHODS: Methadone dose changes and timed plasma samples were obtained for women on methadone (n = 25) followed prospectively from third trimester of pregnancy to 3 months postpartum. RESULTS: Participants were primarily white, Medicaid insured, and multiparous. All women increased their dose from first to end of second trimester (mean peak increase = 23 mg/day); 71 % of women increased from second trimester to delivery (mean peak increase = 19 mg/day). Half took a higher dose 3 months postpartum than at delivery despite significantly larger clearance during late pregnancy. Third trimester enantiomer-specific methadone half-lives (range R-methadone 14.7-24.9 h; S-methadone, 8.02-18.9 h) were about half of those reported in non-pregnant populations. In three women with weekly 24-h methadone levels after delivery, L/D increased within 1-2 weeks after delivery. Women with the CYP2B6 Q172 variant GT genotype have consistently higher L/D values for S-methadone across both pregnancy and postpartum. CONCLUSIONS: Most women require increases in methadone dose across pregnancy. Given the shorter half-life and larger clearances during pregnancy, many pregnant women may benefit from split methadone dosing. L/D increases quickly after delivery and doses should be lowered rapidly after delivery.

2nd year maintenance and discontinuation of imipramine in panic disorder with agoraphobia.

BACKGROUND: The results from our 1 year placebo-controlled maintenance/discontinuation study in remitted panic disorder with agoraphobia patients confirmed the significant prophylactic effectiveness of imipramine maintenance treatment but suggested that this may be necessary in only 37% of the patients who relapse following discontinuation of 6 months acute imipramine treatment. This paper presents pilot data from a second year extension of the above-mentioned study with the aim of exploring the putative protective effects of maintenance imipramine therapy beyond the 1st year. METHOD: Eighteen patients from the 30 who survived, in stable remission, the first 12 months of the maintenance/discontinuation study gave written consent to participate in a double-blind 2nd year extension phase with the knowledge that those on placebo will continue on the same condition (N = 7, PBO-PBO) and those on imipramine (N = 11) will be rerandomized to 2nd year maintenance (N = 4, IMI-IMI) or placebo substitution (N = 7, IMI-PBO). The procedures continued unchanged from that of the 1st year of the study and patients were followed with planned assessments every 2 months over the second 12-month experimental period of the study. RESULTS: None of the IMI-IMI patients relapsed, two (28.5%) of the IMI-PBO patients relapsed, and two (28.5%) of PBO-PBO patients relapsed. The mean estimated time without relapse was 10 months and 9 months for IMI-PBO and PBO-PBO, respectively. The estimated probability of not relapsing was .64 for IMI-PBO and .60 for PBO-PBO (Mantel-cox test chi2 =.84, p = .77). CONCLUSION: These interlocking controlled observations tentatively suggest that a substantial degree of prophylactic efficacy continues and that a substantial need for continued prophylaxis exists beyond the 1st year of maintenance imipramine treatment in panic disorder with agoraphobia patients.

Correlations between motor persistence and plasma levels in methylphenidate-treated boys with ADHD.

Following a 0.9 mg/kg methylphenidate loading dose, serial plasma level determinations, self-scored mood ratings, and measures of motor persistence were gathered on eight previously unmedicated boys with attention deficit disorder with hyperactivity (ADHD) during a 9-h period. The measures were repeated using the same loading dose after 6 months of maintenance treatment with methylphenidate (1.3 mg/kg x d). Kinetic-dynamic modelling suggests inverse correlative relationships between motor performance errors and plasma levels. Pharmacokinetic parameters did not change between acute and maintenance drug treatment phases, and there was no evidence of long-term tolerance.

Serum fluvoxamine levels in breastfed infants.

BACKGROUND: Between 10% and 15% of new mothers will experience an episode of postpartum depression. Although antidepressants are effective agents for the treatment of postpartum depression, minimal data are available to support their safety in infants of breastfeeding mothers. METHOD: In this article, we present 2 cases of nursing mother-infant pairs in which the mother was treated with fluvoxamine and in which infant serum fluvoxamine levels were obtained. Both mothers began the fluvoxamine treatment postpartum, and serum levels were obtained from mothers and infants after a minimum of 7 days on a stable maternal dose. One level was obtained from the infant in case 1, and 2 levels were obtained from the infant in case 2. RESULTS: Each of the infant serum fluvoxamine levels obtained was too low to quantify (at a limit of detection of 2.5 ng/mL). Neither of the infants experienced adverse events related to the mother's treatment with fluvoxamine. Each of the infants is reportedly healthy 2 to 3 years after the exposure. CONCLUSION: While these results are encouraging, they are limited and cannot be generalized to all cases of infants exposed to fluvoxamine. Additional mother-infant serum fluvoxamine levels and infant behavioral observations will facilitate the risk-benefit decision-making process for women who choose to breast-feed while taking fluvoxamine.

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.

Parent-child bonding and family functioning in depressed children and children at high risk and low risk for future depression.

OBJECTIVE: To evaluate parent-child bonding and familial functioning in depressed children, children at high risk for depression, and low-risk controls. METHOD: Diagnoses of children and their relatives were obtained via structured interviews with all available informants. Depressed children (n = 54) received a diagnosis of current major depressive disorder (MDD). The high-risk children (n = 21) had no lifetime diagnoses of mood disorders, but at least one first-degree relative with a lifetime history of depression. The low-risk controls (n = 23) had no lifetime psychiatric disorders and no first-degree relative with a lifetime history of mood disorders. Parent-child bonding was evaluated with the child's report on the Parental Bonding Instrument (PBI). Familial functioning was evaluated with each parent answering the Family Assessment Device (FAD). RESULTS: Significant differences were found between the MDD and low-risk children on most parameters of the PBI and FAD. The children with MDD reported significantly elevated maternal overprotection, and their fathers scored significantly lower on the FAD scales of Behavioral Control and General Functioning, compared with the high-risk children. Mothers of high-risk children had significantly lower scores on the Roles and Affective Involvement dimensions of the FAD compared with mothers of low-risk children. Current maternal depression had a deleterious effect on the child's perception of maternal protection and paternal care, mother's report on all FAD scales, and father's report on most FAD scales, whether interacting with the child's depression or existing even if the child was not depressed. CONCLUSION: Maternal depression and its interaction with the child's depression appear to have negative consequences for parent-child bonding and family functioning.

Growth hormone secretion in children and adolescents at high risk for major depressive disorder.

BACKGROUND: Decreased growth hormone (GH) response to pharmacologic stimulation has been found in children and adolescents during an episode of major depressive disorder and after recovery. In this study, we sought to determine whether GH secretion is similarly altered in children and adolescents who had never experienced depression but were at high risk of developing depression. METHODS: Subjects were 8 through 16 years of age and selected for high- and low-risk status according to familial loading for mood disorders. Sixty-four high-risk and 55 low-risk healthy subjects participated in the study, which assessed the following GH measures: (1) GH before growth hormone-releasing hormone (GHRH) infusion, every 15 minutes for 30 minutes; (2) GH response after intravenous infusion of GHRH (0.1 microg/kg), every 15 minutes for 90 minutes; and (3) nocturnal GH every 20 minutes from 9 PM until morning awakening. RESULTS: After stimulation with GHRH, the high-risk subjects secreted significantly less GH compared with the low-risk healthy controls (effect sizes for mean and peak GH, 0.52 [P =.007] and 0.40 [P =.04], respectively). In contrast, there were no between-group differences in the pre-GHRH and nocturnal GH secretion levels. Exposure to recent stressors was not associated with GH secretion. CONCLUSIONS: Taken together with previous evidence of decreased GH after GHRH infusion in acutely depressed and recovered children, these results indicate that the decreased GH response found in high-risk subjects may represent a trait marker for depression in children and adolescents.

The side effects burden of extended imipramine treatment of panic disorder.

In a recent study, the authors gauged the net effectiveness of imipramine to be 53%; that is, of 110 patients having panic disorder with agoraphobia who started a course of imipramine at a fixed, targeted, weight-adjusted dose of 2.25 mg x kg(-1) x day(-1), 59 adhered to the regimen and showed a marked and stable response. The present study investigated in detail the side effects burden of imipramine treatment in the same sample using hierarchical linear modeling in a short-term perspective, based on data at baseline (N = 110) and at weeks 1, 2, 4, 6, and 8 (N = 77) of treatment, and a long-term perspective, based on data at baseline and at weeks 8, 16 (N = 66), and 24 (N = 59). Deviations from the general pattern were explored by considering only severe side effects or only completers of treatment to better gauge the clinical significance of the findings. The results revealed that of 15 complaints systematically elicited using a side effects inventory, only 3--dry mouth, sweating, and constipation--continued as a substantial burden at the end of 6 months of treatment. On most other items, the initial increase was followed by a decrease to lower than baseline at the end of treatment. In the case of nausea, vomiting, increased energy, headache, and sexual disorders, the complaints were at their worst before treatment started and improved over the course of treatment. A sustained heart rate elevation between 10 and 15 beats per minute was found, but there were no significant effects on blood pressure or weight. The discussion underscores the need for more methodologically improved comparative studies with selective serotonin reuptake inhibitors in the treatment of panic disorder.

Fluoxetine versus placebo in depressed alcoholics: a 1-year follow-up study.

The authors conducted a first study to evaluate the long-term efficacy of fluoxetine for decreasing the depressive symptoms and the drinking of patients with comorbid major depressive disorder and alcohol dependence. This study consisted of a 1-year naturalistic follow-up of 31 patients who previously had completed a 3-month double-blind, placebo-controlled study of fluoxetine in depressed alcoholics. The fluoxetine group continued to demonstrate less depressive symptoms and less drinking than the placebo group at the 1-year follow-up evaluation. The results of the 1-year follow-up evaluation suggest persistent efficacy for fluoxetine for treating the depressive symptoms and the drinking of depressed alcoholics.

A double-blind, placebo-controlled assessment of nortriptyline's side-effects during 3-year maintenance treatment in elderly patients with recurrent major depression.

The authors assessed the severity of nortriptyline's side-effects in older patients with recurrent major depression during placebo-controlled, double-blind maintenance therapy. Data were from 37 patients completing 2-3 years of maintenance therapy; 29 were on nortriptyline and eight were on placebo. The authors detected a time-by-treatment interaction for dry mouth (greater in nortriptyline-treated patients), but no increased association of nortriptyline with constipation, weight change or orthostatic symptoms. Heart rate was consistently higher in nortriptyline-maintained patients as compared with placebo. The total 'side-effect' score on the Asberg Rating Scale, as well as complaints of physical tiredness, daytime sleepiness and nocturnal sleep disturbance, were related primarily to residual depression rather than treatment with nortriptyline.

Factors associated with the development of substance use disorder in depressed adolescents.

OBJECTIVE: To document rates of substance use disorders (SUD) in adolescents with unipolar major depressive disorder and to examine demographic, clinical, and biological factors associated with the development of SUD. METHOD: Twenty-eight adolescents with unipolar major depression and no SUD history and 35 group-matched normal controls who participated in a cross-sectional sleep polysomnography and neuroendocrine study were reassessed clinically 7 years later. RESULTS: The risk for SUD was high in both groups (34.6% in the depressed group and 24.2% in the controls). Depressed adolescents had earlier onset of SUD than controls. Depressed adolescents who developed SUD had more significant psychosocial impairment than depressed adolescents who did not develop SUD. More anxiety traits and elevated cortisol secretion near sleep onset were associated with SUD in depressed teenagers, whereas less emotional responsiveness to exciting stimuli and higher density of eye movements during REM sleep were related to depression without SUD. CONCLUSIONS: Depressed adolescents who have anxiety traits and whose hypothalamic-pituitary-adrenal axis is active when the system is normally quiescent may be at risk for developing SUD. Co-occurrence of depression and SUD is associated with serious psychosocial morbidity. Identification of risk factors for SUD in depressed teenagers may be helpful in developing more effective treatment and prevention programs.

Three-year outcomes of maintenance nortriptyline treatment in late-life depression: a study of two fixed plasma levels.

OBJECTIVE: This study compared the long-term efficacy of two fixed plasma levels of nortriptyline in preventing or delaying recurrence of major depression in elderly patients and in minimizing residual depressive symptoms and somatic complaints. METHOD: The authors randomly assigned 41 elderly patients with histories of recurrent major depression to 3-year, double-blind maintenance pharmacotherapy using nortriptyline, with controlled plasma concentrations of 80-120 ng/ml versus 40-60 ng/ml. The authors compared times to, and rates of, recurrence of major depression. They also compared frequencies of side effects, noncompliance episodes, and subsyndromal symptomatic flare-ups. RESULTS: Major depressive episodes recurred for six (29%) of 21 subjects in the 80-120-ng/ml condition and eight (40%) of 20 subjects in the 40-60-ng/ml condition, a nonsignificant difference. Most recurrences took place in the first year of maintenance treatment. Hamilton depression scores in the subsyndromal range (higher than either 10 or 7) occurred significantly more often at 40-60 ng/ml, while constipation occurred significantly more often at 80-120 ng/ml. The proportions of patients reporting missed doses did not differ. CONCLUSIONS: Maintenance pharmacotherapy with nortriptyline at 80-120 ng/ml is associated with fewer residual depressive symptoms, that is, a less variable long-term response, than pharmacotherapy at 40-60 ng/ml, but constipation is more frequent and there is no difference in recurrence of syndromal major depressive episodes. Treatment at 80-120 ng/ml may be preferable, because of fewer residual symptoms and less variability of response, as long as side effect burden can be managed successfully.

Effectiveness of treatments for major depression in primary medical care practice: a post hoc analysis of outcomes for African American and white patients.

OBJECTIVE: To retrospectively determine whether race differentially influences treatment adherence and clinical outcomes among 68 African Americans and 92 whites treated for major depression in four urban, primary care settings. METHOD: Study participants were randomly assigned to standardized interpersonal psychotherapy or pharmacotherapy with nortriptyline, and were assessed at baseline, and successive time points up to 8 months for severity of depression, and mental and physical health-related functioning. RESULTS: Intent-to-treat analyses revealed no treatment or race-specific differences in symptomatic recovery when both groups were provided standardized psychotherapy or pharmacotherapy. However, African Americans had poorer functional outcomes than whites. CONCLUSIONS: African American and white primary medical care patients are effectively treated with standardized psychotherapy and pharmacotherapy. Future research should assess the impact of cultural context on symptom presentation, psychosocial functioning, and treatment adherence and response.

Mood stabilizers in children and adolescents.

OBJECTIVE: The efficacy of mood stabilizers in children and adolescents has not been studied adequately. This article will review existing studies and highlight some important issues in designing future studies on these agents. METHOD: Electronic databases including Medline, Psycholnfo, and CRISP were searched for data in children receiving compounds that have mood-stabilizing properties in adults. RESULTS: Some open clinical data and an extremely modest amount of controlled research data suggest lithium, carbamazepine, and valproate may be effective mood stabilizers in children and adolescents. There are no controlled data on other potential mood stabilizers in children. CONCLUSIONS: The disorders that may be responsive to mood stabilizers are among the most morbid in child psychiatry. More studies are needed to clarify the efficacy of these compounds in children and adolescents and to provide a rational basis for choosing among them.

Comparative pharmacokinetics and tissue distribution of the d-enantiomers of para-substituted methylphenidate analogs.

A comparative study of the plasma pharmacokinetics and tissue distribution of the d-threo enantiomers of methylphenidate (MPH), para-bromomethylphenidate (p-Br MPH), and para-methoxymethylphenidate (p-OCH3 MPH) was conducted in rats after i.p. administration of a 37 micromol/kg dose. The plasma kinetic data was fit to a two-compartment model with absorption and lag time as well as evaluated by noncompartmental methods. All three compounds attained maximal concentration within 10 min of injection. Calculated mean residence time and elimination half-life values for d-p-Br MPH were significantly longer than those for d-MPH and d-p-OCH3 MPH, and clearance of the bromo derivative was substantially lower than the latter two compounds. Tissue distribution studies of the three d-threo enantiomers revealed that para-substitution of d-MPH had a profound effect on the distribution pattern of these drugs. The highest concentration of drug was found in the kidney and lung for d-MPH, lung and liver for d-p-Br MPH, and lung and brain for d-p-OCH3 MPH. The bromo derivative was found in the highest concentration in the central nervous system at 30, 120, and 180 min whereas levels of d-MPH were twice as high as d-p-OCH3 MPH at 30 min but slightly lower than the latter at 120 min. Related studies on the lipophilicity, plasma protein binding, and resistance to plasma degradation of these compounds were also conducted. The combined data from these experiments along with the pharmacokinetics and central nervous system distribution of these drugs provide explanations for discrepancies between the in vivo and in vitro activity of these compounds described in previous work.

Fluoxetine versus placebo for the marijuana use of depressed alcoholics.

The aim of this analysis was to evaluate the efficacy of the SSRI antidepressant fluoxetine versus placebo for the marijuana use of depressed alcoholics. There are no previous reports involving and SSRI antidepressant for marijuana abuse. This analysis involved a subsample of 22 depressed alcoholic marijuana users out of a total of 51 depressed alcoholics. The entire sample was involved in a 12-week double-blind, placebo-controlled study evaluating the efficacy of fluoxetine versus placebo in depressed alcoholics. During the course of the trial, the cumulative number of marijuana cigarettes used was almost 20 times as high in the placebo group as in the fluoxetine group. Also, the number of days of marijuana use during the study was five times higher in the placebo group than in the fluoxetine group. These data suggest efficacy for fluoxetine in decreasing marijuana use of depressed alcoholics.

Treatment of bereavement-related major depressive episodes in later life: a controlled study of acute and continuation treatment with nortriptyline and interpersonal psychotherapy.

OBJECTIVE: The authors tested the hypothesis that nortriptyline and interpersonal psychotherapy, alone and in combination, are superior to placebo in achieving remission of bereavement-related major depressive episodes. METHOD: Eighty subjects, aged 50 years and older, with major depressive episodes that began within 6 months before or 12 months after the loss of a spouse or significant other were randomly assigned to a 16-week doubleblind trial of one of four treatment conditions: nortriptyline plus interpersonal psychotherapy (N = 16), nortriptyline alone in a medication clinic (N = 25), placebo plus interpersonal psychotherapy (N = 17), or placebo alone in a medication clinic (N = 22). The protocol required that the acute-phase double-blind treatment be ended after 8 weeks if Hamilton depression scale ratings had not improved by 50%. Remission was defined as a 17-item Hamilton scale score of 7 or lower for 3 consecutive weeks. RESULTS: The rate of remission for nortriptyline plus interpersonal psychotherapy was 69% (N = 11); for medication clinic, nortriptyline, 56% (N = 14); for placebo plus interpersonal psychotherapy, 29% (N = 5); and for medication clinic, placebo, 45% (N = 10). In a generalized logit model, there was a significant effect of nortriptyline over placebo but no interpersonal psychotherapy effect and no nortriptyline-by-interpersonal psychotherapy interaction. Rates of all-cause attrition were lowest in the nortriptyline plus interpersonal psychotherapy group. CONCLUSIONS: Nortriptyline was superior to placebo in achieving remission of bereavement-related major depressive episodes. The combination of medication and psychotherapy was associated with the highest rate of treatment completion. These results support the use of pharmacologic treatment of major depressive episodes in the wake of a serious life stressor such as bereavement.