Roger T. Mulder

A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression

The multi-drug resistance gene ABCB1 (or MDR1) encodes a P-glycoprotein (P-gp) that regulates passage of many substances across the blood–brain barrier. The antidepressant amitriptyline and its metabolites (including nortriptyline) are substrates for P-gp, and in mice lacking P-gp, penetration of amitriptyline, but not fluoxetine, into the brain is enhanced. We reasoned that polymorphic variation of P-gp may contribute to differing responses of patients to antidepressant drugs. A single nucleotide polymorphism (SNP) of ABCB1 (3435C>T) was recently correlated with expression levels and in vivo function of P-gp. We examined this SNP in patients with major depression enrolled in a randomized antidepressant treatment trial of nortriptyline and fluoxetine, and observed a significant association between nortriptyline-induced postural hypotension and 3435C>T (χ2 = 6.78, df = 2, P = 0.034). Our results suggest that homozygosity for 3435T alleles of ABCB1 is a risk factor for occurrence of nortriptyline-induced postural hypotension (OR = 1.37, P = 0.042, 95% CI 1.01–1.86).

Infants in a neonatal intensive care unit: parental response

Objective: To compare the psychosocial functioning of the parents (mother and father) of infants admitted to a neonatal intensive care unit (NICU) with the parents of infants born at term and not admitted to the NICU. Design: Random sample of NICU parents and term non-NICU parents were assessed across a variety of psychiatric and psychosocial measures shortly after the birth of their infant. Setting: Christchurch Women’s Hospital, New Zealand. Labour ward and level III NICU. Participants: A total of 447 parents (242 mothers; 205 fathers) with an infant admitted to a regional NICU during a 12 month period; 189 parents (100 mothers; 89 fathers) with infants born at term and not requiring NICU admission. Main outcome measures: Depression and anxiety symptoms, psychosocial functioning. Results: Overall, levels of anxiety and depression were low in both parent groups. Compared with control parents, a higher percentage of NICU parents had clinically relevant anxiety and were more likely to have had a previous NICU admission and be in a lower family income bracket. Infant prematurity was associated with higher levels of symptomatology in both NICU mothers and fathers. Conclusions: Specific interventions are not needed for most parents who have an infant admitted to the NICU as they appear to adapt relatively successfully. Infant prematurity impacts negatively on the father as well as the mother. Consequently these parents may benefit from increased clinical attention.

A differential response to nortriptyline and fluoxetine in melancholic depression: the importance of age and gender.

Objective: To consider the impact of age and gender on the antidepressant response to nortriptyline and fluoxetine in melancholic depression.

Bipolar II disorder: personality and outcome in two clinical samples

OBJECTIVEnTo compare the personality traits and disorders of patients with bipolar II disorder and major depression and to examine the impact on treatment outcome of a bipolar II diagnosis.nnnMETHODnPatients from two clinical trials, a depressive sample (n = 195, 10% bipolar II) and a bulimic sample (n = 135, 16% bipolar II), were assessed for personality traits using DSM-IV criteria. Patients were randomised to treatments (fluoxetine or nortriptyline for depressive sample; cognitive behaviour therapy for bulimic sample) and followed for 3 years (depressive sample) or 5 years (bulimic sample) to assess the impact on outcome of a bipolar II diagnosis.nnnRESULTSnBipolar II patients were assessed as having more borderline, histrionic and schizotypal personality traits than patients with major depression. A baseline bipolar II diagnosis did not impact negatively on treatment outcome, and less than 5% of bipolar II patients developed bipolar I disorder during follow up.nnnCONCLUSIONSnThe low rate of conversion of bipolar II to bipolar I disorder and the lack of adverse impact of the diagnosis on outcome, questions the need for antimanic or mood stabiliser medication in most bipolar II patients.

Towards an understanding of defense style in terms of temperament and character

The aim was to investigate the relationships between a model of personality based on the concept of defense mechanisms, as articulated by Vaillant, with the psychobiological model of personality, as developed by Cloninger. A total of 128 adults from 11 family pedigrees with at least two alcohol‐dependent members completed the self‐report Defense Style Questionnaire and the Temperament and Character Inventory. Immature defenses were largely explained by low character scores, while neurotic defenses were part temperament and part character. Cluster A, B and C defenses were related to low reward dependence, high novelty‐seeking and high harm avoidance respectively. In a regression analysis, cluster B and C defenses were more related to low character scores than to temperament but, for cluster A defenses, temperament and character both contributed. The results suggest that it is possible to integrate an ego defense model of personality with a psychobiological model of personality, thereby enriching both approaches.

The hypothalamic-pituitary-thyroid axis in major depression

We investigated the capacity of several thyroid‐axis measures to distinguish between depressed and control subjects and determined whether these variables were related to antidepressant treatment response. We studied 105 subjects who fulfilled the DSM‐III‐R criteria for a current major depressive episode and 41 volunteers with no current mental disorder. The following thyroid‐axis variables were measured: difference between T4 levels at 09.00 hours and 13.00 hours; baseline TSH; maximal TSH response to 400 μg TRH (Δmax TSH); and presence of a blunted Δmax TSH. The T4 difference variable alone distinguished between depressed and control subjects. In multivariate analyses, T4 difference and Δmax TSH were independently related to antidepressant‐treatment outcome, and predicted a modest proportion (14%) of the variance in outcome. The relationship between these two variables and treatment outcome was particularly strong in depressed male subjects who were receiving desipramine, for whom they accounted for 36% of the variance in treatment outcome. The T4 difference variable both distinguished between depressed and control subjects and was related to treatment outcome. Although this finding requires replication, it is consistent with other reports of the usefulness of thyroid‐axis indices measured at different times of day in depressed patients.

Melancholia: definitions, risk factors, personality, neuroendocrine markers and differential antidepressant response

Objective: To evaluate the CORE measure of melancholia, against the DSM-IV construct of melancholia. To evaluate the validity of both the CORE and DSM-IV constructs of melancholia against psychosocial risk factors, anxiety and personality disorder comorbidity, neuroendocrine markers and differential antidepressant response to fluoxetine and nortriptyline. Method: One hundred and ninety-five outpatients with major depression were evaluated for melancholia with both the DSM-IV criteria and the CORE evaluation. Both constructs were evaluated for validity against psychosocial risk factors, comorbidity, biological markers and differential antidepressant response. Results: The CORE measure has satisfactory interrater reliability when used dimensionally, but has unacceptably low agreement for making a categorical diagnosis of melancholia. There is remarkably poor agreement (kappa = 0.11) between the CORE and DSM-IV criteria for melancholia. Neither the DSM-IV nor CORE criteria for melancholia identified subgroups of patients with better childhood environments or less anxiety or personality disorder comorbidity. The CORE criteria for melancholia, but not DSM-IV, identified patients with neuroendocrine disturbance. CORE scores also were associated with differential responses to fluoxetine and nortriptyline, but not in anticipated directions. Thus, high CORE scores were associated with a higher recovery rate with fluoxetine than nortriptyline. Conclusion: While the episode specifier of melancholia should be retained in diagnostic systems, the DSM-IV criteria were not validated against any of the variables examined in this study. The CORE construct of melancholia, was validated against neuroendocrine measures, and was associated with a differential antidepressant response. However, the limits imposed by interrater reliability, suggest the CORE measure should be used dimensionally and not to make a categorical diagnosis of melancholia.

An international collaborative database: its use in predicting length of stay for inpatient treatment of anorexia nervosa

Objective: To evaluate childhood experiences (neglect and abuse), temperament and childhood and adolescent psychopathology as risk factors for avoidant and borderline personality disorders in depressed outpatients. Method: One hundred and eighty depressed outpatients were evaluated for personality disorders. Risk factors of childhood abuse, parental care, temperament, conduct disorder symptoms, childhood and adolescent anxiety disorders, depressive episodes, hypomania and alcohol and drug dependence were obtained by questionnaires and interviews. Results: Avoidant personality disorder can be conceptualized as arising from a combination of high harm avoidance (shy, anxious), childhood and adolescent anxiety disorders and parental neglect. Borderline personality disorder can be formulated as arising from a combination of childhood abuse and/or neglect, a borderline temperament (high novelty seeking and high harm avoidance), and childhood and adolescent depression, hypomania, conduct disorder and alcohol and drug dependence. Conclusions: Combinations of risk factors from the three domains of temperament, childhood experiences and childhood and adolescent psychopathology make major contributions to the development of avoidant and borderline personality disorders.

Effects of childhood experiences on cortisol levels in depressed adults

Objective: To evaluate the impact of childhood abuse and parental bonding on cortisol levels in depressed adults. Methods: Mean afternoon cortisol levels were measured in 192 depressed adult patients at the beginning of a treatment trial. Childhood experiences of physical and sexual abuse were ascertained by interview, and perceived parenting by self-report. Results: Maternal affectionless control, childhood sexual and physical abuse were all associated with cortisol levels. Conclusion: Childhood experiences, especially maternal affectionless control, appear to be related to hypothalamic pituitary adrenal axis function in depressed adults.

OPRM1 genotype and naltrexone response in depressed alcohol-dependent patients.

A functional polymorphism rs1799971 (A118G) in the μ-opioid receptor gene (OPRM1) produces an amino acid substitution Asn40Asp, which is believed to influence naltrexone response in nondepressed alcohol-dependent patients. In this study, patients with alcohol dependence and major depression (n=108) received open-label naltrexone and clinical case management for 12 weeks, and were randomized to citalopram or placebo. General linear mixed models examined the effect of the OPRM1 A118G genotype on alcohol outcomes during treatment. There was no evidence of any difference in the percentage of days abstinent, drinks per drinking day or percentage of heavy drinking days between Asp40 carriers and noncarriers during treatment. This study therefore failed to replicate the previous positive findings for this single nucleotide polymorphism in relation to naltrexone response, possibly indicating that the effect is not present in depressed patients.