Background. Conflicting results have been reported in previous association studies of the seroton... more Background. Conflicting results have been reported in previous association studies of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR), seasonal affective disorder (SAD) and seasonality (seasonal variations in mood and behaviour). The aim of this study was to test for association in new case-control and population-based materials, and to perform a combined analysis of all published studies of 5-HTTLPR and SAD.
Objective: Neurocognitive deficits are demonstrated in major depressive disorder (MDD) and most l... more Objective: Neurocognitive deficits are demonstrated in major depressive disorder (MDD) and most likely contribute to the functional impairment experienced by affected individuals. We systematically reviewed the evidence on neurocognitive deficits and their relationship(s) to psychosocial functioning in MDD.
Major depressive disorder (MDD) is associated with staggering personal and economic costs, a majo... more Major depressive disorder (MDD) is associated with staggering personal and economic costs, a major proportion of which stem from impaired psychosocial and occupational functioning. Few studies have examined the impact of depression-related cognitive dysfunction on work functioning. We examined the association between neurocognitive and work functioning in employed patients with MDD. Employed adult outpatients (n=36) with MDD of at least moderate severity (≥23 on the Montgomery Asberg Depression Rating Scale, MADRS) and subjective cognitive complaints completed neurocognitive tests (CNS Vital Signs computerized battery) and validated self-reports of their work functioning (LEAPS, HPQ) before and after 8 weeks of open-label treatment with flexibly-dosed desvenlafaxine 50-100mg/day. Relationships between neurocognitive tests and functional measures were examined using bivariate correlational and multiple regression analyses, as appropriate. An ANCOVA model examined whether significant change in neurocognitive performance, defined as improvement of ≥1SD in the Neurocognition Index (NCI) from baseline to post-treatment, was associated with improved outcomes. Patients showed significant improvements in depressive symptom, neurocognitive, and work functioning measures following treatment with desvenlafaxine (e.g., MADRS response=77% and MADRS remission=49%). There were no significant correlations between changes in NCI or cognitive domain subscales and changes in MADRS, LEAPS, or HPQ scores. However, patients demonstrating significant improvement in NCI scores (n=11, 29%) had significantly greater improvement in clinical and work functioning outcomes compared to those without NCI improvement. The limitations of this study include small sample size, lack of a placebo control group, and lack of a healthy comparison group. Our sample also had more years of education and higher premorbid intelligence than the general population. There were no significant correlations between changes in neurocognitive and work functioning measures in this study. However, meaningful improvement in neurocognitive functioning with desvenlafaxine was associated with greater improvement in both mood and occupational outcomes. This suggests that addressing cognitive dysfunction may improve clinical and occupational outcomes in employed patients with MDD. However, the relationship between neurocognitive and work functioning in MDD is complex and requires further study.
Occupational impairment accounts for much of the burden and economic costs associated with major ... more Occupational impairment accounts for much of the burden and economic costs associated with major depressive disorder (MDD). Many studies have documented neurocognitive deficits in MDD, and depression-associated cognitive dysfunction would be expected to have significant effects on occupational functioning. We systematically reviewed the literature for studies on neurocognition and occupational functioning in MDD. Electronic databases (e.g., MEDLINE, PsychInfo and Cochrane Clinical Trials) were searched using appropriate terms and bibliographies of relevant publications were scanned for additional citations. Two reviewers independently reviewed papers for inclusion and data extraction,
Major depressive disorder (MDD) is associated with significant impairment in quality of life and ... more Major depressive disorder (MDD) is associated with significant impairment in quality of life and psychosocial functioning, including social and occupational/role functioning. Evaluation of clinical effectiveness of treatments for depression must include improvement in these important functional outcomes. However, clinical trials for depression have primarily focused on reduction in symptoms, as measured by symptom severity scales such as the HDRS and MADRS or by standard definitions of response and remission.
Canadian journal of psychiatry. Revue canadienne de psychiatrie, 2009
To describe clinical characteristics, course, and outcome during a 1-year period after the first ... more To describe clinical characteristics, course, and outcome during a 1-year period after the first manic episode in patients with bipolar disorder (BD). This paper describes the project design, demographics, clinical outcomes, and predictors at 6 months to 1 year of follow-up of the first 53 recruited subjects with first-episode mania from the Systematic Treatment Optimization Program for Early Mania. Survival analysis for recurrence of mood episodes showed that 46.7% of patients survived without a mood episode during 1-year of follow-up, and the mean time-to-mood event was 7.9 months. Earlier age of onset was the only variable that significantly predicted recurrence of mood episodes. When examined separately, the survival rates were 76% for a manic episode and 58.7% for a depressive episode. These results suggest that recurrences are common after the first manic episode with more than one-half of the patients experiencing a mood event within 12 months. Aggressive treatment strategies...
TO THE EDITOR: Endogenous opioids have been related to anxiety disorders, and the opioid antagoni... more TO THE EDITOR: Endogenous opioids have been related to anxiety disorders, and the opioid antagonist naltrexone has been reported to precipitate phobic behavior (1). We report a case of panic attacks precipitated by the administration of the opioid antagonist naltrexone.
Background: The brain regions involved in the pathophysiology of bipolar disorder have not been d... more Background: The brain regions involved in the pathophysiology of bipolar disorder have not been definitively determined. Previous studies have suggested possible involvement of the hippocampus and of prefrontal regions. Proton magnetic resonance spectroscopic imaging ( 1 H-MRSI) allows measurement of N-acetylaspartate (NAA, marker of neuronal integrity), choline-containing compounds (CHO), and creatineϩphosphocreatine (CRE) in multiple brain regions. The objective of this study was to assess possible NAA reductions in hippocampus and prefrontal regions in patients with bipolar disorder. Methods: We studied 17 patients with bipolar disorder and 17 age-and gender-matched healthy subjects on a 1.5-T nuclear magnetic resonance (NMR) machine. With 1 H-MRSI we measured ratios of areas under the metabolite peaks of the proton spectra (i.e., NAA/CRE, NAA/ CHO, CHO/CRE) for multiple cortical and subcortical regions. Results: Patients showed significant reductions of NAA/ CRE bilaterally in the hippocampus. There were no significant changes in CHO/CRE or in NAA ratios in any other area sampled. Conclusions: This study shows that patients with bipolar disorder have a regional reduction of NAA relative signals, suggesting neuronal damage or malfunction of the hippocampus. As suggested by other studies, neuronal pathology in the hippocampus may be involved in the pathophysiology of bipolar disorder and in susceptibility to psychosis. Biol Psychiatry 2003;53:906 -913
The effect of pretreatment with odansetron on prolactin (PRL) release induced by electroconvulsiv... more The effect of pretreatment with odansetron on prolactin (PRL) release induced by electroconvulsive therapy (ECT) was examined in 16 depressive patients in a double-blind, placebo-controlled crossover study. Ten patients were pretreated with 4 mg and the other six with 8 mg of ondansetron. The order of administration of study medication (ondansetron and placebo) was counterbalanced. The failure of ondansetron to attenuate ECT-induced PRL release suggested that serotonin3 receptors are not involved in mediating this response.
A substantial proportion of the disease burden of major depressive disorder (MDD) results from im... more A substantial proportion of the disease burden of major depressive disorder (MDD) results from impairments in occupational functioning, including disability and reduced productivity. Accumulating evidence suggests that antidepressants can improve functional as well as symptomatic outcomes in patients with MDD. We examined the treatment effects of newer antidepressants on occupational impairment in MDD, based on a systematic review and meta-analysis of randomized controlled trials (RCTs). We searched MEDLINE, EMBASE, and ClinicalTrials.gov for the period 1 January 1992 to 15 June 2015 to identify RCTs of newer antidepressants (excluding tricyclic antidepressants and monoamine oxidase inhibitors), with or without a placebo condition, that included a validated measure of occupational functioning in patients with MDD. Abstracts were scanned for eligibility by two independent reviewers and investigators of unpublished studies were contacted to obtain data. Study data were extracted and double-entered for accuracy. We selected the Sheehan Disability Scale Work/School subscale (SDS-Work) for the meta-analysis because it was the most consistently used assessment of occupational impairment. Analysis employed a random-effects model. The systematic review initially identified 42 RCTs but only 28 (67 %) had data on occupational outcomes that were published or obtained from investigators. The SDS-Work subscale was used in 25 of 28 trials; five other assessments of occupational functioning were used in seven trials. Data were synthesized from 17 placebo-controlled studies (n = 7031) that used the SDS-Work subscale. Antidepressants (n = 4722) were significantly superior to placebo (n = 2309) in improving SDS-Work scores at 8 weeks, with a mean difference of 0.73 [95 % confidence interval (CI) 0.60-0.86] and a standardized mean difference of 0.28 (95 % CI 0.23-0.33), representing small effects. Few included trials reported on the employment status of their samples, and most trials were of short-term treatment duration (8-12 weeks). Several RCTs that collected data on occupational outcomes were also excluded from the review and meta-analysis because their data were unpublished and unobtainable. Our meta-analysis suggests that newer antidepressants have a small, positive impact on occupational impairment in the short-term, but the clinical significance of this impact is questionable. To improve assessment of this important outcome, future research studies should use more comprehensive measures of occupational functioning, productivity and impairment, and longer treatment durations.
Prolactin (PRL) plasma levels rise severalfold following spontaneous or electrically induced seiz... more Prolactin (PRL) plasma levels rise severalfold following spontaneous or electrically induced seizures. To assess the role of dopamine in this neuroendocrine response, we studied the effect of electroconvulsive therapy (ECT) on plasma PRL after maximal dopamine receptor blockade induced by intravenous metoclopramide. Six patients undergoing ECT received metoclopramide or placebo, in counterbalanced order, 30 min prior to application of the electrical stimulus. Blood samples were obtained at - 15 min, immediately before, and at 15 min intervals for 1 h after the treatment. Under placebo conditions, PRL plasma levels increased nearly sevenfold in response to ECT. The administration of metoclopramide produced a large increase in PRL plasma levels, with no further increase in PRL concentrations after ECT. The data suggest that the PRL plasma rise after ECT involves dopamine as it is not seen when the dopaminergic inhibitory tone, exerted by the hypothalamus on the pituitary lactotroph, h...
Canadian Journal of Psychiatry Revue Canadienne De Psychiatrie, Dec 1, 2014
Lam RW, Kennedy SH, McIntyre RS, et al. Cognitive dysfunction in major depressive disorder: effec... more Lam RW, Kennedy SH, McIntyre RS, et al. Cognitive dysfunction in major depressive disorder: effects on psychosocial functioning and implications for treatment. Can J Psychiatry. 2014;59(12):639-648. . Summary of primary articles evaluating the associations between psychosocial functioning and cognition, and between antidepressant treatment and cognitive outcomes in MDD (listed in chronological order).
Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worl... more Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers ("biomarkers") of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD. CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with ...
Background. Conflicting results have been reported in previous association studies of the seroton... more Background. Conflicting results have been reported in previous association studies of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR), seasonal affective disorder (SAD) and seasonality (seasonal variations in mood and behaviour). The aim of this study was to test for association in new case-control and population-based materials, and to perform a combined analysis of all published studies of 5-HTTLPR and SAD.
Objective: Neurocognitive deficits are demonstrated in major depressive disorder (MDD) and most l... more Objective: Neurocognitive deficits are demonstrated in major depressive disorder (MDD) and most likely contribute to the functional impairment experienced by affected individuals. We systematically reviewed the evidence on neurocognitive deficits and their relationship(s) to psychosocial functioning in MDD.
Major depressive disorder (MDD) is associated with staggering personal and economic costs, a majo... more Major depressive disorder (MDD) is associated with staggering personal and economic costs, a major proportion of which stem from impaired psychosocial and occupational functioning. Few studies have examined the impact of depression-related cognitive dysfunction on work functioning. We examined the association between neurocognitive and work functioning in employed patients with MDD. Employed adult outpatients (n=36) with MDD of at least moderate severity (≥23 on the Montgomery Asberg Depression Rating Scale, MADRS) and subjective cognitive complaints completed neurocognitive tests (CNS Vital Signs computerized battery) and validated self-reports of their work functioning (LEAPS, HPQ) before and after 8 weeks of open-label treatment with flexibly-dosed desvenlafaxine 50-100mg/day. Relationships between neurocognitive tests and functional measures were examined using bivariate correlational and multiple regression analyses, as appropriate. An ANCOVA model examined whether significant change in neurocognitive performance, defined as improvement of ≥1SD in the Neurocognition Index (NCI) from baseline to post-treatment, was associated with improved outcomes. Patients showed significant improvements in depressive symptom, neurocognitive, and work functioning measures following treatment with desvenlafaxine (e.g., MADRS response=77% and MADRS remission=49%). There were no significant correlations between changes in NCI or cognitive domain subscales and changes in MADRS, LEAPS, or HPQ scores. However, patients demonstrating significant improvement in NCI scores (n=11, 29%) had significantly greater improvement in clinical and work functioning outcomes compared to those without NCI improvement. The limitations of this study include small sample size, lack of a placebo control group, and lack of a healthy comparison group. Our sample also had more years of education and higher premorbid intelligence than the general population. There were no significant correlations between changes in neurocognitive and work functioning measures in this study. However, meaningful improvement in neurocognitive functioning with desvenlafaxine was associated with greater improvement in both mood and occupational outcomes. This suggests that addressing cognitive dysfunction may improve clinical and occupational outcomes in employed patients with MDD. However, the relationship between neurocognitive and work functioning in MDD is complex and requires further study.
Occupational impairment accounts for much of the burden and economic costs associated with major ... more Occupational impairment accounts for much of the burden and economic costs associated with major depressive disorder (MDD). Many studies have documented neurocognitive deficits in MDD, and depression-associated cognitive dysfunction would be expected to have significant effects on occupational functioning. We systematically reviewed the literature for studies on neurocognition and occupational functioning in MDD. Electronic databases (e.g., MEDLINE, PsychInfo and Cochrane Clinical Trials) were searched using appropriate terms and bibliographies of relevant publications were scanned for additional citations. Two reviewers independently reviewed papers for inclusion and data extraction,
Major depressive disorder (MDD) is associated with significant impairment in quality of life and ... more Major depressive disorder (MDD) is associated with significant impairment in quality of life and psychosocial functioning, including social and occupational/role functioning. Evaluation of clinical effectiveness of treatments for depression must include improvement in these important functional outcomes. However, clinical trials for depression have primarily focused on reduction in symptoms, as measured by symptom severity scales such as the HDRS and MADRS or by standard definitions of response and remission.
Canadian journal of psychiatry. Revue canadienne de psychiatrie, 2009
To describe clinical characteristics, course, and outcome during a 1-year period after the first ... more To describe clinical characteristics, course, and outcome during a 1-year period after the first manic episode in patients with bipolar disorder (BD). This paper describes the project design, demographics, clinical outcomes, and predictors at 6 months to 1 year of follow-up of the first 53 recruited subjects with first-episode mania from the Systematic Treatment Optimization Program for Early Mania. Survival analysis for recurrence of mood episodes showed that 46.7% of patients survived without a mood episode during 1-year of follow-up, and the mean time-to-mood event was 7.9 months. Earlier age of onset was the only variable that significantly predicted recurrence of mood episodes. When examined separately, the survival rates were 76% for a manic episode and 58.7% for a depressive episode. These results suggest that recurrences are common after the first manic episode with more than one-half of the patients experiencing a mood event within 12 months. Aggressive treatment strategies...
TO THE EDITOR: Endogenous opioids have been related to anxiety disorders, and the opioid antagoni... more TO THE EDITOR: Endogenous opioids have been related to anxiety disorders, and the opioid antagonist naltrexone has been reported to precipitate phobic behavior (1). We report a case of panic attacks precipitated by the administration of the opioid antagonist naltrexone.
Background: The brain regions involved in the pathophysiology of bipolar disorder have not been d... more Background: The brain regions involved in the pathophysiology of bipolar disorder have not been definitively determined. Previous studies have suggested possible involvement of the hippocampus and of prefrontal regions. Proton magnetic resonance spectroscopic imaging ( 1 H-MRSI) allows measurement of N-acetylaspartate (NAA, marker of neuronal integrity), choline-containing compounds (CHO), and creatineϩphosphocreatine (CRE) in multiple brain regions. The objective of this study was to assess possible NAA reductions in hippocampus and prefrontal regions in patients with bipolar disorder. Methods: We studied 17 patients with bipolar disorder and 17 age-and gender-matched healthy subjects on a 1.5-T nuclear magnetic resonance (NMR) machine. With 1 H-MRSI we measured ratios of areas under the metabolite peaks of the proton spectra (i.e., NAA/CRE, NAA/ CHO, CHO/CRE) for multiple cortical and subcortical regions. Results: Patients showed significant reductions of NAA/ CRE bilaterally in the hippocampus. There were no significant changes in CHO/CRE or in NAA ratios in any other area sampled. Conclusions: This study shows that patients with bipolar disorder have a regional reduction of NAA relative signals, suggesting neuronal damage or malfunction of the hippocampus. As suggested by other studies, neuronal pathology in the hippocampus may be involved in the pathophysiology of bipolar disorder and in susceptibility to psychosis. Biol Psychiatry 2003;53:906 -913
The effect of pretreatment with odansetron on prolactin (PRL) release induced by electroconvulsiv... more The effect of pretreatment with odansetron on prolactin (PRL) release induced by electroconvulsive therapy (ECT) was examined in 16 depressive patients in a double-blind, placebo-controlled crossover study. Ten patients were pretreated with 4 mg and the other six with 8 mg of ondansetron. The order of administration of study medication (ondansetron and placebo) was counterbalanced. The failure of ondansetron to attenuate ECT-induced PRL release suggested that serotonin3 receptors are not involved in mediating this response.
A substantial proportion of the disease burden of major depressive disorder (MDD) results from im... more A substantial proportion of the disease burden of major depressive disorder (MDD) results from impairments in occupational functioning, including disability and reduced productivity. Accumulating evidence suggests that antidepressants can improve functional as well as symptomatic outcomes in patients with MDD. We examined the treatment effects of newer antidepressants on occupational impairment in MDD, based on a systematic review and meta-analysis of randomized controlled trials (RCTs). We searched MEDLINE, EMBASE, and ClinicalTrials.gov for the period 1 January 1992 to 15 June 2015 to identify RCTs of newer antidepressants (excluding tricyclic antidepressants and monoamine oxidase inhibitors), with or without a placebo condition, that included a validated measure of occupational functioning in patients with MDD. Abstracts were scanned for eligibility by two independent reviewers and investigators of unpublished studies were contacted to obtain data. Study data were extracted and double-entered for accuracy. We selected the Sheehan Disability Scale Work/School subscale (SDS-Work) for the meta-analysis because it was the most consistently used assessment of occupational impairment. Analysis employed a random-effects model. The systematic review initially identified 42 RCTs but only 28 (67 %) had data on occupational outcomes that were published or obtained from investigators. The SDS-Work subscale was used in 25 of 28 trials; five other assessments of occupational functioning were used in seven trials. Data were synthesized from 17 placebo-controlled studies (n = 7031) that used the SDS-Work subscale. Antidepressants (n = 4722) were significantly superior to placebo (n = 2309) in improving SDS-Work scores at 8 weeks, with a mean difference of 0.73 [95 % confidence interval (CI) 0.60-0.86] and a standardized mean difference of 0.28 (95 % CI 0.23-0.33), representing small effects. Few included trials reported on the employment status of their samples, and most trials were of short-term treatment duration (8-12 weeks). Several RCTs that collected data on occupational outcomes were also excluded from the review and meta-analysis because their data were unpublished and unobtainable. Our meta-analysis suggests that newer antidepressants have a small, positive impact on occupational impairment in the short-term, but the clinical significance of this impact is questionable. To improve assessment of this important outcome, future research studies should use more comprehensive measures of occupational functioning, productivity and impairment, and longer treatment durations.
Prolactin (PRL) plasma levels rise severalfold following spontaneous or electrically induced seiz... more Prolactin (PRL) plasma levels rise severalfold following spontaneous or electrically induced seizures. To assess the role of dopamine in this neuroendocrine response, we studied the effect of electroconvulsive therapy (ECT) on plasma PRL after maximal dopamine receptor blockade induced by intravenous metoclopramide. Six patients undergoing ECT received metoclopramide or placebo, in counterbalanced order, 30 min prior to application of the electrical stimulus. Blood samples were obtained at - 15 min, immediately before, and at 15 min intervals for 1 h after the treatment. Under placebo conditions, PRL plasma levels increased nearly sevenfold in response to ECT. The administration of metoclopramide produced a large increase in PRL plasma levels, with no further increase in PRL concentrations after ECT. The data suggest that the PRL plasma rise after ECT involves dopamine as it is not seen when the dopaminergic inhibitory tone, exerted by the hypothalamus on the pituitary lactotroph, h...
Canadian Journal of Psychiatry Revue Canadienne De Psychiatrie, Dec 1, 2014
Lam RW, Kennedy SH, McIntyre RS, et al. Cognitive dysfunction in major depressive disorder: effec... more Lam RW, Kennedy SH, McIntyre RS, et al. Cognitive dysfunction in major depressive disorder: effects on psychosocial functioning and implications for treatment. Can J Psychiatry. 2014;59(12):639-648. . Summary of primary articles evaluating the associations between psychosocial functioning and cognition, and between antidepressant treatment and cognitive outcomes in MDD (listed in chronological order).
Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worl... more Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers ("biomarkers") of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD. CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with ...
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Papers by Raymond Lam