Depression: Mulder RT

Malhi GS, Adams D, Porter R, Wignall A, Lampe L, O'Connor N, Paton M, Newton LA, Walter G, Taylor A, Berk M, Mulder RT, Anonymous00017, Anonymous00018, Anonymous00019. · CADE Clinic, Department of Psychiatry, Royal North Shore Hospital, University of Sydney, NSW, Australia. · Acta Psychiatr Scand Suppl. · Pubmed #19356154 No free full text.

Abstract: OBJECTIVE: To provide clinically relevant evidence-based recommendations for the management of depression in adults that are informative, easy to assimilate and facilitate clinical decision making. METHOD: A comprehensive literature review of over 500 articles was undertaken using electronic database search engines (e.g. MEDLINE, PsychINFO and Cochrane reviews). In addition articles, book chapters and other literature known to the authors were reviewed. The findings were then formulated into a set of recommendations that were developed by a multidisciplinary team of clinicians who routinely deal with mood disorders. The recommendations then underwent consultative review by a broader advisory panel that included experts in the field, clinical staff and patient representatives. RESULTS: The clinical practice recommendations for depression (Depression CPR) summarize evidence-based treatments and provide a synopsis of recommendations relating to each phase of the illness. They are designed for clinical use and have therefore been presented succinctly in an innovative and engaging manner that is clear and informative. CONCLUSION: These up-to-date recommendations provide an evidence-based framework that incorporates clinical wisdom and consideration of individual factors in the management of depression. Further, the novel style and practical approach should promote uptake and implementation.

Mulder RT. · No affiliation provided · Can J Psychiatry. · Pubmed #18286866 No free full text.

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Mulder RT. · No affiliation provided · Chron Respir Dis. · Pubmed #16279742 No free full text.

This publication has no abstract.

Carter FA, Frampton CM, Mulder RT. · Department of Psychological Medicine, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch, New Zealand. · Psychosom Med. · Pubmed #16554400 links to  free full text

Abstract: OBJECTIVE: The objective of this study was to examine the evidence for an association between cesarean section and postpartum depression. METHODS: Medline and PsychInfo databases were searched. All studies on cesarean section that evaluated maternal mood between 10 days and 1 year after delivery were reviewed. Nine methodologically superior studies, including the only randomized, controlled trial (RCT), were analyzed separately. The nine studies that provided adequate summary statistics were combined in a meta-analysis. RESULTS: Of the 24 studies that have examined the association between cesarean section and postpartum depression, five found a significant adverse association, 15 found no significant association, and four found mixed results. With only one exception, methodologically superior studies found either no significant association or mixed evidence for an association between cesarean section and postpartum depression. Meta-analyses of suitable studies failed to find evidence for a significant association between cesarean section and postpartum depression. Possible reasons why different studies have obtained different results are critically evaluated. CONCLUSION: A link between cesarean section and postpartum depression has not been established.

Mulder RT. · Department of Psychological Medicine, Christchurch School of Medicine, PO Box 4345, Christchurch, New Zealand. · Curr Psychiatry Rep. · Pubmed #14738706 No free full text.

Abstract: Research into the relationship between depression and personality disorder is compromised by a number of methodologic factors, including differing concepts of personality disorder, the validity of a personality disorder diagnosis, the effect of mood on diagnosis, and the overlap between some personality disorder symptoms and mood symptoms. Personality pathology is common in patients with personality disorder. Reasons for this include a "scar" effect of chronic low mood on attitudes and behaviors, as well as possible risk factors via certain personality traits. The negative effect of comorbid personality disorder on treatment outcome in depressed patients may be less than previously believed. Possible reasons include treatment bias in non-controlled trials and the increasing use of selective serotonin reuptake inhibitors rather than tricyclic antidepressants. Many personality traits and disorders may be part of the psychopathology of depression and share a common origin.

Porter RJ, Mulder RT. · Department of Psychological Medicine, Christchurch School of Medicine. · N Z Med J. · Pubmed #11913939 No free full text.

Abstract: Both BAD and unipolar depression are common, serious and, in some cases, chronic conditions which often require long term pharmacotherapy. Drug side effects can be severe, contribute to poor compliance and are therefore a factor in maintaining illness and precipitating relapse. Treatment resistance is common. Current evidence suggests that a number of pharmacological agents which are available in other countries (and in some cases have been for many years) may be useful when side effects or treatment resistance occur. In some cases these alternatives are part of recommended algorithms for treatment. In New Zealand, when side effects occur, the options are limited and the problem of treatment resistance is usually approached by using poorly researched combinations of the currently available drugs, thus increasing the likelihood of side effects and adverse drug interactions. The current system is failing to provide appropriate or adequate treatment for people suffering from affective disorders and should be urgently reviewed.

Mulder RT. · Department of Psychological Medicine, Christchurch School of Medicine, New Zealand. · Am J Psychiatry. · Pubmed #11869996 links to  free full text

Abstract: OBJECTIVE: A longstanding belief among many clinicians is that patients with depression and comorbid personality pathology have a worse response to standard depression treatment. This presents potentially significant treatment implications, since personality pathology in depressed patients appears to be common. METHOD: PsycINFO and MEDLINE were systematically searched for studies relating personality to treatment outcome. Over 50 studies were obtained and grouped according to the method used to assess personality pathology. RESULTS: High neuroticism scores generally predicted worse outcome, especially over long-term follow-up. Tridimensional Personality Questionnaire scores did not have a consistent relationship to treatment outcome despite some promising initial findings. Most studies involved patients with comorbid personality disorders; these studies produced conflicting results. Other measures of personality pathology produced an array of findings ranging from a moderately worse outcome to no difference. CONCLUSIONS: Whether or not personality pathology significantly worsens outcome in patients with major depression appears to depend on study design, since the rate of personality pathology varies markedly depending on how it is measured. In addition, depressed patients with personality pathology appear less likely to receive adequate treatment in uncontrolled studies. Finally, studies rarely control for depression characteristics (e.g., chronicity, severity) that may influence outcome and be related to personality pathology. Overall, the best-designed studies reported the least effect of personality pathology on depression treatment outcome. Clinically, this suggests that comorbid personality pathology should not be seen as an impediment to good treatment response.

Porter RJ, Mulder RT, Joyce PR, Luty SE. · Department of Psychological Medicine, Christchurch School of Medicine & Health Sciences, P.O. Box 4345, Christchurch, New Zealand. · J Affect Disord. · Pubmed #15935231 No free full text.

Abstract: BACKGROUND: It has been suggested that the ratio of tryptophan (TRP) and tyrosine (TYR) to other large neutral amino acids may predict response to antidepressant drugs with predominantly serotonergic compared with predominantly noradrenergic activity and that this may be clinically useful. METHOD: 147 subjects with a DSM-III-R diagnosis of major depression underwent a detailed clinical evaluation and prior to treatment had baseline measures of TRP, TYR and other large neutral amino acids (LNAA), prolactin and cortisol. Subjects entered a 6-week randomised treatment trial comparing fluoxetine and nortriptyline. RESULTS: There was no main effect on 6-week outcome of TRP/LNAA ratio or TYR/LNAA ratio and no interaction between these factors and treatment (fluoxetine vs nortriptyline). LIMITATIONS: Alterations in antidepressant dose were allowed therefore possibly reducing the effect of TRP or TYR availability on response. CONCLUSIONS: Previous findings that TRP/LNAA and TYR/LNAA ratios may predict differential response to antidepressants were not replicated and neither was our previous finding of a complex relationship between TRP/LNAA and baseline prolactin in predicting 6-week response.

Joyce PR, Porter RJ, Mulder RT, Luty SE, McKenzie JM, Miller AL, Kennedy MA. · Department of Psychological Medicine, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand. · Psychol Med. · Pubmed #15856721 No free full text.

Abstract: BACKGROUND: Although diurnal variation of mood is a widely recognized symptom of depression, the clinical, neurobiological and psychopharmacological significance of this symptom has not previously been reported. METHOD: A total of 195 depressed out-patients underwent a detailed clinical and neurobiological assessment, and were then randomized to treatment with either fluoxetine or nortriptyline. RESULTS: Of the 195 depressed patients, 62 had a pattern of reversed diurnal variation (i.e. worse in the evening). Those with reversed diurnal variation had a poorer response to a serotonergic anti-depressant, were less likely to have bipolar II disorder, had a higher tryptophan: large neutral amino acid ratio and had different allele frequencies of the polymorphisms in the promoter region of the serotonin transporter. CONCLUSIONS: These findings raise the possibility of serotonergic influence on diurnal variation, and that the symptom of reversed diurnal variation is of relevance to antidepressant prescribing.

Joyce PR, Luty SE, McKenzie JM, Mulder RT, McIntosh VV, Carter FA, Bulik CM, Sullivan PF. · Department of Psychological Medicine, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand. · Aust N Z J Psychiatry. · Pubmed #15209835 No free full text.

Abstract: OBJECTIVE: To 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. METHOD: Patients 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. RESULTS: Bipolar 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. CONCLUSIONS: The 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.

Gendall KA, Joyce PR, Mulder RT, Luty SE. · University Department of Psychological Medicine, Christchurch School of Medicine, Christchurch, New Zealand. · J Psychopharmacol. · Pubmed #14870956 No free full text.

Abstract: We investigated: (i) the status of thyroid hormones and their clinical correlates in patients with major depression; (ii) changes in thyroid hormone status after treatment with fluoxetine versus nortriptyline; and (iii) whether blunted thyrotropin-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) challenge predicts improvement after 6 weeks of fluoxetine versus nortriptyline treatment. Patients with major depression entering a treatment trial were assessed with the Structured Clinical Interview for DSM-III-R and were rated on the Montgomery-Asberg Depression Rating Scale (MADRS). Blood samples were taken for TSH, thyroxine (T4) and free thyroxine (FT4) measurement, and the maximum TSH response (deltamaxTSH) to a TRH challenge test was undertaken. Patients were then randomly assigned to receive fluoxetine or nortriptyline for six weeks. At 6 weeks, patients repeated the thyroid hormone assessment and completed the MADRS. Mean concentrations of TSH, T4, FT4 and deltamaxTSH were within reference ranges. T4 and FT4 levels decreased significantly after treatment in responders, but not in nonresponders. After treatment, deltamaxTSH concentrations decreased significantly in patients who responded to fluoxetine, and increased in patients who responded to nortriptyline. Patients with deltamaxTSH blunting at pretreatment were more likely to be male, to have higher MADRS scores and have a history of alcohol and drug dependence. Patients with a pretreatment deltamaxTSH of < 3.0 microm/ml showed greater improvement on the MADRS when treated with fluoxetine than if treated with nortriptyline. We observed a decrease in T4 and FT4 in responders to treatment with fluoxetine or nortriptyline. Positive relationships between deltamaxTSH blunting and alcohol and drug abuse and severity of depression were found. Patients with blunted deltamaxTSH responded better to fluoxetine than to nortriptyline. It is suggested that a blunted DmaxTSH may reflect a predominantly serotonergic disturbance in this group of patients with major depression.

Roberts RL, Mulder RT, Joyce PR, Luty SE, Kennedy MA. · Department of Pathology, Christchurch School of Medicine & Health Sciences, University of Otago, PO Box 4345, Christchurch, New Zealand. · Hum Psychopharmacol. · Pubmed #14716707 No free full text.

Abstract: The polymorphic enzyme cytochrome P450 CYP2D6 is involved in the metabolism of many antidepressants, including nortriptyline and fluoxetine. Some 7%-10% Caucasians have inactivating mutations in both alleles of the CYP2D6 gene, and are referred to as poor metabolizers (PMs). Several case reports and clinical studies suggest that CYP2D6 PMs are at a greater risk of developing adverse drug reactions (ADRs) on antidepressant medication than extensive metabolizers (EMs). However, few clinical trials have investigated whether CYP2D6 PM genotype is predictive of ADRs during antidepressant treatment. This paper explores the link between CYP2D6 genotype and antidepressant-associated ADRs in outpatients being treated for major depression with either nortriptyline or fluoxetine. Patients were randomized to fluoxetine (n=65) or nortriptyline (n=60) for the 6 week trial. CYP2D6 genotypes predicted that of these patients 115 were EM and the remaining 10 were PMs. ADRs attributed to antidepressant usage were recorded over the 6-week trial. Although the type of ADR was, as expected, different between drugs, the frequency of ADRs experienced did not differ significantly between the two antidepressants or between CYP2D6 PMs and EMs. In addition, the frequency at which PMs discontinued antidepressant medication was not noticeably different from EMs, although with only 10 PMs the study is under powered to detect moderate or small differences. These findings suggest that inability to efficiently metabolize antidepressants that are CYP2D6 substrates does not necessarily lead to increased occurrence of antidepressant-associated ADRs. Thus, for clinicians prescribing antidepressant monotherapy, CYP2D6 polymorphisms are probably not of relevance to antidepressant side effects and therapy.

Joyce PR, Mulder RT, Luty SE, McKenzie JM, Miller AL, Rogers GR, Kennedy MA. · Department of Psychological Medicine, Christchurch School of Medicine and Health Sciences, P.O. Box 4345, Christchurch, New Zealand. · Int J Neuropsychopharmacol. · Pubmed #14604448 No free full text.

Abstract: In 169 depressed patients randomized to treatment with either fluoxetine or nortriptyline, we examined whether polymorphisms of the serotonin transporter and the G protein beta3 subunit influenced response to these antidepressants. For depressed patients under the age of 25 yr the T allele of the G protein beta3 subunit was associated with a markedly poorer response to nortriptyline, while serotonin transporter polymorphisms did not predict antidepressant response. However, in patients 25 yr or older, the G protein beta3 polymorphisms did not predict antidepressant response, while the s,s genotype of the serotonin transporter was associated with a poorer response to both fluoxetine and nortriptyline. These differential pharmacogenetic predictors of antidepressant response by age, may provide clues to understanding the discontinuities in pharmacological responsiveness of child/adolescent and adult depressive disorders.

Mulder RT, Watkins WG, Joyce PR, Luty SE. · Department of Psychological Medicine, Christchurch School of Medicine, PO Box 4345, Christchurch, New Zealand. · J Affect Disord. · Pubmed #12943944 No free full text.

Abstract: BACKGROUND: Multiple lines of evidence suggest continuity from adolescent to adult depression, but treatment response is different in the two groups. There is some consensus that noradrenergic drugs are ineffective in adolescent depression. The aim of this study was to see whether this poor response extended to young adults. METHODS: Patients from two randomised studies on prediction of antidepressant response were used. The subjects were divided into a youth sample (ages 18-24) and an older sample (ages 25 and over). The 6-week percentage response, based on HDRS scores, and the number of patients in remission (i.e., HDRS < or =7) at 6 weeks were compared in subjects who received a serotonergic (clomipramine (mean dose 145 mg) and fluoxetine (mean dose 27 mg)) or a noradrenergic (desipramine (mean dose 200 mg) and nortriptyline (mean dose 100 mg)) antidepressant. RESULTS: There were no significant differences between the two studies, except for a small variation in baseline Hamilton scores. Young adults had a poorer response to noradrenergic antidepressants than they did to serotonergic antidepressants, whereas there was no differential response in the older age group. Young adults had a lower rate of remission on a noradrenergic antidepressant (38% noradrenergic versus 72% serotonergic) but there was no significant difference in remission rates in older adults (65% noradrenergic versus 57% serotonergic) or the sample as a whole (54% noradrenergic versus 62% serotonergic). LIMITATIONS: The age cut-off at 24 is somewhat arbitrary. One study was double-blind while the other was open. There was no placebo control. DISCUSSION: While the response rate to noradrenergic antidepressants in young adults is lower, it is not clear whether this is comparable to adolescents. The reasons for a reduced response may be related to maturation of the noradrenergic system in the brain. Our results suggest that age may be one factor to consider when choosing antidepressants for patients.

Mulder RT, Joyce PR, Frampton C. · Department of Psychological Medicine, Christchurch School of Medicine, PO Box 4345, Christchurch, New Zealand. · J Affect Disord. · Pubmed #12943942 No free full text.

Abstract: BACKGROUND: Studies attempting to identify predictors of antidepressant response in patients with major depression have reported inconsistent results. One explanation may be the different definitions of outcome used. METHODS: 187 depressed subjects were recruited and were randomised to treatment with fluoxetine and nortriptyline. At baseline and 6 weeks, subjects completed Hamilton Depression Rating Scale HDRS-17 and 27, Montgomery Asberg Depression Rating Scale (MADRS), the Hopkins Symptom Checklist (SCL-90) and the Social Adjustment Scale (SAS) as well as the Clinical Global Impression Scale (CGI). Relationships among outcome measures were assessed. Receiver Operator Characteristic (ROC curves) were used to show the diagnostic ability of the MADRS and HDRS in predicting the clinician's rating. RESULTS: All outcome measures were moderately to highly correlated. All measures were significantly related to the clinician's global impression, but the strongest associations were with the MADRS score. Using ROC curves we showed that a score of 8 on the HDRS or 14 on the MADRS was the optimal compromise between sensitivity and specificity in dividing this sample into responders and non-responders. A 60% reduction in HDRS and MADRS scores rather than a 50% reduction appeared the most valid division between responders and non-responders. LIMITATIONS: We relied on clinician judgement as the validating criterion. The results only apply to a sample of moderately depressed outpatients. CONCLUSIONS: The MADRS score seemed to most accurately reflect a clinician's impression of change. Dividing a sample into responders and non-responders can be approached empirically.

Jordan J, Joyce PR, Carter FA, Horn J, McIntosh VV, Luty SE, McKenzie JM, Mulder RT, Bulik CM. · Department of Psychological Medicine, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch, New Zealand. · Int J Eat Disord. · Pubmed #12898557 No free full text.

Abstract: OBJECTIVE: This study considered whether the prevalence and type of anxiety and psychoactive substance use disorder (PSUD) diagnoses differ between women with spectrum anorexia nervosa (AN) (N=40) and women with major depressive disorder (N = 58) participating in outpatient clinical trials. METHOD: Anxiety and PSUD diagnoses (according to criteria in the 3rd Rev. ed. of the Diagnostic and Statistical Manual of Mental Disorders) were assessed using structured clinical interviews. Comparisons were made between AN subtypes (restricting or binge eating/purging) and by history of depression within the AN sample. RESULTS: A high prevalence of obsessive-compulsive disorder (OCD) was found in women with AN. However, social phobia, simple phobia, and PSUD were significantly elevated in both women with depression and women with AN. Prevalences were similar for anxiety and PSUD diagnoses between AN subtypes. DISCUSSION: Women with anorexia or depression were comparable in all respects, except for the elevated OCD prevalence in AN, emphasizing the need to use clinical comparison groups to avoid inadvertently attributing elevated prevalences of comorbid conditions to specific disorders.

Joyce PR, Mulder RT, Luty SE, McKenzie JM, Rae AM. · Department of Psychological Medicine, Christchurch School of Medicine & Health Sciences, PO Box 4345, Christchurch, New Zealand. · Acta Psychiatr Scand. · Pubmed #12807373 No free full text.

Abstract: OBJECTIVE: To consider the impact of age and gender on the antidepressant response to nortriptyline and fluoxetine in melancholic depression. METHOD: Of 191 depressed patients, 113 met study criteria for melancholia. All patients were randomized to receive either fluoxetine or nortriptyline. Response rates, defined as an improvement of 60% or more on the Montgomery Asberg Depression Rating Scale over 6 weeks of antidepressant treatment on an intention to treat basis, were examined by age, and by age and gender. RESULTS: Melancholic depressed patients 40 years or older, especially men, had a markedly superior response to nortriptyline compared with fluoxetine. Conversely, melancholic depressed patients, age 18-24 years, especially women, had a markedly superior response to fluoxetine. CONCLUSION: Age and gender appear to be critical variables in understanding differential antidepressant responses to tricyclic antidepressants and selective serotonin reuptake inhibitors in melancholic depression.

Mulder RT, Joyce PR, Luty SE. · Department of Psychological Medicine, Christchurch School of Medicine, Christchurch, New Zealand. · J Clin Psychiatry. · Pubmed #12716266 No free full text.

Abstract: BACKGROUND: Many clinicians believe that depressed patients with comorbid personality disorder(s) may respond differently to standard treatments than patients with depression alone. Personality disorders appear to be common among patients with depression, suggesting potentially significant treatment implications for a large group of patients. METHOD: Subjects with DSM-III-R major depression were recruited for a study looking at prediction of antidepressant response. All patients were assessed using the Structured Clinical Interviews for DSM-III-R Axis I and Axis II, as well as rated on the Hamilton Rating Scale for Depression and the Montgomery-Asberg Depression Rating Scale (MADRS). Patients were then randomly assigned to treatment with fluoxetine or nortriptyline and reassessed at 6 weeks. The major outcome measure was percentage reduction in MADRS scores. RESULTS: Of the 183 patients who completed the personality disorder assessment, 45% had at least 1 comorbid personality disorder. Subjects with comorbid personality disorders were slightly younger, more depressed at baseline, had poorer social adjustment, more general psychopathology, and more chronic depression. Despite these differences, the presence of a comorbid personality disorder did not adversely affect overall outcome at 6 weeks, but there was an interaction between having a comorbid personality disorder and drug type. The major effect was that patients with a cluster B personality disorder did relatively poorly on nortriptyline compared with fluoxetine treatment. CONCLUSION: The finding that the presence of a comorbid personality disorder does not affect overall treatment response is similar to that reported by some recent studies. The finding that patients with cluster B personality disorders respond poorly to nortriptyline is also consistent with a small literature on borderline personality disorder.

Mulder RT, Porter RJ, Joyce PR. · Department of Psychological Medicine, Christchurch School of Medicine, Christchurch, New Zealand. · J Psychopharmacol. · Pubmed #12680745 No free full text.

Abstract: Depression may be associated with a hypofunction of central serotonergic systems. The prolactin response to fenfluramine, an indicator of serotonergic activity, has been reported to be blunted in depressed patients compared to controls. It has also been suggested that blunting is more likely in melancholic depression. Baseline cortisol, prolactin and tryptophan availability have also been suggested to affect this response. Forty-eight men and 61 women with a major depressive episode, and who were drug free, and 20 healthy control men underwent clinical evaluation and fenfluramine challenge with dl-fenfluramine 1 mg/kg. When baseline variables were covaried, there was no difference in prolactin response to fenfluramine between males with depression and age-matched controls. Amongst all the depressed patients, body mass index showed a significant association with prolactin response to fenfluramine. There was an interaction between baseline cortisol and DSM-III-R melancholic subtype of depression whereby non-melancholic patients appeared more likely to increase prolactin response to fenfluramine in response to higher cortisol levels. Prolactin response to fenfluramine was not blunted in major depression and there was no difference between melancholic and non-melancholic depression. However, the relationship between prolactin response to fenfluramine and baseline cortisol levels appeared to differ between these two subtypes of depression.

Joyce PR, Mulder RT, Luty SE, McKenzie JM, Sullivan PF, Cloninger RC. · Department of Psychological Medicine, Christchurch School of Medicine, Christchurch, New Zealand. · Compr Psychiatry. · Pubmed #12524634 No free full text.

Abstract: Among 183 depressed patients participating in a randomized long-term treatment trial of fluoxetine and nortriptyline, 30 patients had borderline personality disorder (BPD), 53 had other personality disorders (OPD), and 100 had no personality disorders (NPD). The borderline depressed patients had earlier age of onset of their depressions, more chronic depressions, more alcohol and cannabis comorbidity, and were more likely to have histories of suicide attempts and of self-mutilation. On self-report, patients with BPD and OPD reported more phobic symptoms, greater interpersonal sensitivity, and more paranoid ideation. Uniquely, BPD patients were more angry than OPD patients. BPD patients had high novelty seeking, high harm avoidance, low self-directedness, and low cooperativeness. Depressed patients with BPD did poorly in the short term if treated with nortriptyline rather than fluoxetine. After 6 months, those with BPD had a favorable outcome in regard to depressive symptoms, social adjustment, and even improvement in the character measure of self-directedness. Those with the poorest outcome were those with OPD.

Porter RJ, Mulder RT, Joyce PR. · Department of Psychological Medicine, Christchurch School of Medicine and Health Sciences, P.O. Box 4345, Christchurch, New Zealand. · Psychopharmacology (Berl). · Pubmed #12439628 No free full text.

Abstract: RATIONALE: Depression may be associated with a hypofunction of central serotonin (5HT) systems. The prolactin response to fenfluramine (PRF) is an indicator of 5HT activity. It has been suggested that the PRF may predict response to different forms of treatment. Baseline cortisol, prolactin, and L-tryptophan ( L-TRP) availability may affect PRF and may also influence response to treatment. METHOD: In this study, 46 males and 58 females with a DSM-III-R diagnosis of major depression underwent a detailed clinical evaluation and prior to treatment had baseline measures of prolactin, cortisol, L-TRP, and other large neutral amino acids (LNAAs) taken and underwent a fenfluramine challenge. The subjects with major depression entered a 6-week double-blind treatment trial comparing clomipramine and desipramine. RESULTS: There was no effect on the 6-week outcome of treatment (clomipramine versus desipramine), PRF or baseline cortisol and no interactions between these factors. However, there was a significant effect of baseline prolactin (BLP) and a significant interaction between TRP/LNAA ratio and BLP. Post-hoc analysis revealed that at low TRP/LNAA values, outcome improved as prolactin levels increased while at high TRP/LNAA values the opposite was the case. CONCLUSION: The PRF did not predict 6-week outcome. BLP and TRP/LNAA ratio measurement is easy and may be useful clinically. We hypothesise that failure to upregulate post-synaptic 5HT receptors in response to low 5HT availability predicts a poor response to antidepressant treatment.

Roberts RL, Joyce PR, Mulder RT, Begg EJ, Kennedy MA. · Department of Pathology, Christchurch School of Medicine, Christchurch, New Zealand. · Pharmacogenomics J. · Pubmed #12082591 links to  free full text

Abstract: 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 (chi(2) = 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).

Joyce PR, Mulder RT, Luty SE, Sullivan PF, McKenzie JM, Abbott RM, Stevens IF. · Department of Psychological Medicine, Christchurch School of Medicine and Health Sciences, New Zealand. · Aust N Z J Psychiatry. · Pubmed #12060188 No free full text.

Abstract: OBJECTIVE: The first objective of this paper was to describe the pattern of remission, response and recovery in patients with major depression who were randomised for treatment with fluoxetine ornortriptyline. The second objective was to report on the demographic and diagnostic predictors of the response and recovery in these depressed patients. METHOD: One hundred and ninety-five patients with major depression were recruited for this outpatient study. After a detailed clinical and neurobiological evaluation patients were randomized to receive either fluoxetine or nortiptyline as an initial antidepressant treatment. RESULTS: Of the 195 depressed patients randomised to treatment,154 completed an adequate 6-week trial of either fluoxetine or nortriptyline as their initial antidepressant. Of the 41 patients who did not complete an adequate trial the dropout rate was higher on those randomized to nortriptyline (p = 0.02). There was also an important interaction of drug and gender in determining dropouts in that women did not complete an adequate trial with nortriptyline and men did not complete an adequate trial with fluoxetine (p = 0.002).Of the 154 patients who completed an adequate 6-week antidepressant trial there were no significant differences in 6-week measures of depression severity or of percentage improvement. However, if we use an intention to treat analysis and dichotomise outcomes into response,remission or recovery; then recovery rates were significantly higher with fluoxetine than nortriptyline (p = 0.005).Using an intention to treat analysis fluoxetine was superior tonortriptyline in women, in those less than 25-years old, and in those with atypical depression. Independent of drug, those with chronic depressions had a poorer outcome. CONCLUSION: In this sample of depressed patients randomized tonortriptyline or fluoxetine the change in depressive symptoms over 6 weeks were comparable between fluoxetine and nortriptyline. However,when we look at the more clinically important variable of recovery then fluoxetine was superior to nortriptyline. Predictors of a poorer response to nortriptyline were gender, young age and atypical depression.The results challenge traditional beliefs that selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressant have comparable efficacy.

Luty SE, Joyce PR, Mulder RT. · Department of Psychological Medicine, Christchurch School of Medicine, New Zealand. · J Psychopharmacol. · Pubmed #11769819 No free full text.

Abstract: The Social Adjustment Scale (SAS) was used to assess social functioning sequentially over 13 weeks in a group of 188 depressed outpatients randomized to either the noradrenergic antidepressant, nortriptyline, or the selective serotonin reuptake inhibitor, fluoxetine. Over the period of 13 weeks, there were no differences in total SAS scores between the nortriptyline and the fluoxetine group. In comparing the SAS subscale scores, which may measure different areas of motivation and behaviour (drive), there were differences between the two groups in only two subscales. At 13 weeks, the group randomized to fluoxetine were more impaired in marital role (p = 0.026) whereas, at 6 weeks, the group randomized to nortriptyline were more impaired in friction scores (p = 0.012). These results do not support the concept of specific augmentation of drive-related behaviour by noradrenergic medication. This challenges the earlier findings relating to drive enhancement and social adjustment using such medication.

Inder WJ, Prickett TC, Mulder RT, Donald RA, Joyce PR. · Department of Endocrinology, Christchurch Hospital and Christchurch School of Medicine, New Zealand. · Psychopharmacology (Berl). · Pubmed #11465636 No free full text.

Abstract: RATIONALE: Subjects with depression may exhibit activation of the hypothalamic-pituitary-adrenal (HPA) axis, but little is known about the response of basal hormone levels to antidepressant therapy. OBJECTIVES: To determine whether treatment of depression with standard antidepressant medications resulted in reductions in basal activity of afternoon cortisol, ACTH and AVP. A secondary aim was to examine whether there was any difference in hormonal response between an SSRI (fluoxetine) and a tricyclic antidepressant (nortriptyline). METHODS: Forty-three subjects with a DSM-IV diagnosis of depression (Hamilton score 18.9+/-0.6 at baseline) had five basal venous blood samples drawn at 15-min intervals between 1400 and 1500 hours for cortisol, ACTH and AVP, before and 6 weeks after randomisation to treatment with fluoxetine (n=27) or nortriptyline (n=16). RESULTS: Both medications resulted in a similar improvement in depression as determined by Hamilton score. In the group as a whole, ACTH levels showed a significant decrease over the 6 weeks (4.1+/-0.4 pmol/l at baseline versus 3.3+/-0.3 at 6 weeks, P<0.05), while cortisol and AVP levels were unchanged. Further analysis revealed that the fall in plasma ACTH occurred predominantly in the subgroup treated with fluoxetine (drug x time interaction by ANOVA, P=0.035). There was a significant relationship between cortisol and ACTH at baseline (r=0.48, P=0.002), that weakened considerably after treatment (r=0.22, P=0.16). The subgroup with baseline hypercortisolemia [mean cortisol >276 nmol/l (10 microg/dl), n=18] demonstrated a reduction in both cortisol and ACTH following treatment, but also showed a loss of the relationship between the two. CONCLUSIONS: It is postulated that the initial recovery of the HPA axis during the treatment of depression with fluoxetine is mediated via restoration of glucocorticoid negative feedback on ACTH levels.