Managing medical and psychiatric comorbidity in individuals with major depressive disorder and bipolar disorderRoger S. McIntyre, MD, FRCPC
Mood Disorders Psychopharmacology Unit, University Health Network, Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Ontario, CanadaMichael Rosenbluth, MD, FRCPC
Toronto East General Hospital Day Treatment Program, East York, Ontario, Canada, Sunnybrook Health Sciences Centre, Department of Psychiatry, University of Toronto, Toronto, Ontario, CanadaRajamannar Ramasubbu, MD, FRCPC, MSc
Department of Psychiatry and Clinical Neurosciences, University of Calgary, Hotchkiss Brain Institute, Calgary, Alberta, CanadaDavid J. Bond, MD, FRCPC
Mood Disorders Centre, University of British Columbia, Vancouver, British Columbia, CanadaValerie H. Taylor, MD, PhD, FRCPC
Department of Psychiatry, University of Toronto, Toronto, Ontario, CanadaSerge Beaulieu, MD, PhD, FRCPC
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, Québec, CanadaAyal Schaffer, MD, FRCPC
Mood and Anxiety Disorders Program, Sunnybrook Health Sciences Centre, Department of Psychiatry, University of Toronto , Toronto, Ontario, Canada
BACKGROUND: Most individuals with mood disorders experience psychiatric and/or medical comorbidity. Available treatment guidelines for major depressive disorder (MDD) and bipolar disorder (BD) have focused on treating mood disorders in the absence of comorbidity. Treating comorbid conditions in patients with mood disorders requires sufficient decision support to inform appropriate treatment.
METHODS: The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force sought to prepare evidence- and consensus-based recommendations on treating comorbid conditions in patients with MDD and BD by conducting a systematic and qualitative review of extant data. The relative paucity of studies in this area often required a consensus-based approach to selecting and sequencing treatments.
RESULTS: Several principles emerge when managing comorbidity. They include, but are not limited to: establishing the diagnosis, risk assessment, establishing the appropriate setting for treatment, chronic disease management, concurrent or sequential treatment, and measurement-based care.
CONCLUSIONS: Efficacy, effectiveness, and comparative effectiveness research should emphasize treatment and management of conditions comorbid with mood disorders. Clinicians are encouraged to screen and systematically monitor for comorbid conditions in all individuals with mood disorders. The common comorbidity in mood disorders raises fundamental questions about overlapping and discrete pathoetiology.
KEYWORDS: bipolar disorder, major depressive disorder, comorbidity, obesity, anxiety disorders, personality disorders, substance use disorders, attention-deficit/hyperactivity disorder, cardiovascular disease, hypertension, dyslipidemia
ANNALS OF CLINICAL PSYCHIATRY 2012;24(2):163–169
Understudied and priority research vista
Notwithstanding the prevalence, persistence, and hazards posed by comorbidity in MDD and BD, relatively few studies have aimed primarily to characterize treatment response on the basis of stratifying individuals as a function of comorbidity. A chasm exists between the reality of clinical medicine where comorbidity is the rule rather the exception and registration trials that consistently exclude individuals with comorbid conditions. A major criticism of evidence-based guidelines for treating MDD and BD is that they have been formulated based on non-comorbid patients.
The aim of the CANMAT task force recommendations for treating MDD and BD was to provide a preliminary management framework for practitioners and to identify areas that have been studied insufficiently and need empirical evidence.1-7 Levels of evidence were specified based on criteria from the 2009 CANMAT Guidelines for the Treatment of Major Depressive Disorder and Bipolar Disorder and revised to reflect consensus opinions about quantitative reviews8,9 (TABLE 1). The levels of evidence represent the quality of the studies that have been conducted. Recommendations also were graded according to line of treatment based on criteria we used for our previous guidelines (TABLE 2). A first-line treatment represents an optimal balance of efficacy, tolerability, and clinical support. When creating these comorbidity recommendations, there was insufficient evidence for most comorbid conditions and as such, there was an increased emphasis on expert opinion of the CANMAT committee. The CANMAT committee’s opinions were intended to enhance utility for practitioners. Second-line treatments represent those strategies wherein the first-line treatment was deemed to be inefficacious or not appropriate for the patient.
Criteria for level of evidence
||At least 2 RCTs with adequate sample sizes, preferably placebo-controlled, and/or meta-analysis with narrow confidence intervals
||At least 1 RCT with adequate sample size and/or meta-analysis with wide confidence intervals
||Non-randomized, controlled prospective studies or case series or high quality retrospective studies
Criteria for lines of treatmenta
|Line of treatment
||Level 1 or level 2 evidence, plus clinical support
||Level 3 evidence or higher, plus clinical support
||Level 4 evidence or higher, plus clinical support
Developing the task force recommendations was an iterative process wherein manuscripts were circulated among subsection committee members for revision and consensus. The CANMAT comorbidity task force recommendations did not receive any financial support from the pharmaceutical industry or any other external funding body. The potential conflicts of interest of each author are listed in the CANMAT recommendations.1-7
The comorbid conditions selected for these recommendations reflect those conditions most commonly encountered in clinical practice. The task force recommendations are comprised of 6 sections emphasizing the treatment of MDD or BD with comorbidity. The comorbid conditions were: anxiety disorders; substance use disorders; personality disorders; cardiometabolic disorders; attention-deficit/hyperactivity disorder (ADHD); and other medical comorbidity. Several other psychiatric and medical comorbidities were not reviewed simply because our aim was to be relevant yet succinct. Indeed there are many other disorders that are relevant, including, but not limited to, eating disorders, sleep disorders, impulse control disorders, and somatoform disorders.10-14 Providing comprehensive recommendations for the management of MDD and BD comorbid for each of these conditions was not feasible. Therefore, we focused on the management of mood disorders and the most common and disabling comorbid conditions.
As with all guidelines, these CANMAT comorbidity task force recommendations represent a combination of evidence and consensus opinion. Admittedly these recommendations are weighted heavily on consensus and are not intended to be used as an inflexible algorithm for treatment selection and sequencing. Instead, the recommendations are intended to inform clinical practice where the individual needs of each patient are considered separately. Our hope is that creating these recommendations will not only inform treatment decisions, but also will provide the impetus for evaluating disparate interventions for persons with mood disorders and other comorbid conditions.
Comorbidity prevalence in mood disorders
National Comorbidity Survey-Replication (NCS-R) estimated a 16.2% lifetime prevalence of MDD and 6.6% prevalence of MDD in the 12 months before the interview.13 Lifetime prevalence estimates of BD were 1.0% for bipolar I disorder (BD I), 1.1% for bipolar II disorder (BD II), and 2.4% for subthreshold BD (4.4% overall). The 12-month prevalence estimates were 0.6% for BD I, 0.8% for BD II, and 1.4% for subthreshold BD (2.8% overall).13
Comorbidity generally is defined as the joint occurrence of multiple disorders. Feinstein introduced the term “comorbidity” into medicine, and suggested that multiple disorders have distinct pathoetiology.15 Results from community epidemiological surveys and clinical studies indicate that the majority of individuals with MDD or BD will meet criteria for at least 1 other DSM-IV-TR psychiatric disorder.16-21
The majority of community epidemiological respondents with lifetime bipolar spectrum disorders meet comorbidity criteria, with higher comorbidity rates seen in individuals with threshold BD compared with subthreshold BD.22,23 The NCS-R reported that 63.1% to 86.7% of respondents with lifetime BD also met criteria for at least 1 lifetime comorbid anxiety disorder and 35.5% to 60.3% met criteria for at least 1 lifetime comorbid substance use disorder.24 The high rates of psychiatric comorbidity in population-based epidemiological settings offsets the Berkson’s bias (the differential representation of comorbidity in clinical cohorts) in clinical samples but does not sufficiently deal with the artifact of overlapping diagnostic criteria.25,26
The prevalence of psychiatric comorbidity in cohorts using health services is similar. For example, the Stanley Foundation Bipolar Treatment Outcome Network reported that 65% of patients with BD also met DSM-IV criteria for at least 1 comorbid lifetime Axis I disorder.16 The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study reported that 65.2% of patients enrolled had at least 1 comorbid psychiatric disorder (social phobia was the most common comorbid psychiatric disorder, 31.3%); 38.6% of patients had ≥2 comorbid psychiatric disorders. Moreover, the mean number of medical conditions endorsed in the STAR*D cohort was 3.3.27
High rates of medical comorbidity also have been reported in patients with BD. For example, a descriptive study of 4,310 veterans who received at least 1 inpatient or outpatient BD diagnosis reported a high prevalence of comorbid medical conditions including cardiovascular (hypertension), endocrine (hyperlipidemia, diabetes), pulmonary (chronic obstructive pulmonary disease), infectious (hepatitis C), and musculoskeletal (eg, low back pain) conditions. More than one-third of BD patients were diagnosed with ≥3 comorbid medical conditions. Individuals with BD had a greater burden of medical comorbidity at a younger age than the general veteran population.28
Persistence of comorbidity
Another observation pertaining to comorbidity in mood disorders is its stability across time. Results from the 15-year prospective Zurich cohort demonstrated that anxiety comorbid with MDD is more persistent than either syndrome alone.24,25,29 This greater persistence is thought to contribute to the greater functional disability described in comorbid populations.24,25,29
Implications of comorbidity in mood disorders
At the individual level, comorbidity affects evaluation, course, and treatment, as well as social and economic costs of psychiatric disorders.25 A replicated observation is that psychiatric and medical comorbidity is associated with an earlier age of onset, intensified symptomatology, suicidality, poor symptomatic and functional recovery, diminished acute response to pharmacologic and psychosocial treatment, decreased quality of life, a more complex affective disorder presentation, lower rate of recovery, and unfavorable course and outcome.25
For example, individuals with BD and medical comorbidity exhibit a longer duration of lifetime depression and lifetime inpatient depression treatment, higher baseline depression severity scores, higher service utilization for depressive episodes, and increased suicidal behavior.30 Moreover, ADHD in individuals with MDD or BD is associated with more frequent affective episodes, antisocial personality disorder, and substance use disorders.31 Taken together, the composite of comorbidity provides the impetus for careful screening, detection, treatment, and management of co-occurring conditions.
The cost of mood disorders involves not only health care costs for the primary condition, but also costs related to psychiatric and medical comorbidity. Individuals with BD and medical comorbidity incur costs approximately 40% higher than individuals with BD and no medical comorbidity.32 The increased costs incurred by the comorbid BD patient are mediated largely by increased health care utilization and decreased role functioning (eg, occupational impairment).
Several factors contribute to comorbidity in mood disorder patients. Results from epidemiological, clinical, family, and brain volumetric studies indicate that mood and anxiety disorders share pathophysiological and causative factors.33 Evidence suggests that disturbances in reward circuits implicated in affective disorders also subserve other “comorbid” addictive disorders including substance use disorders and excess food intake (ie, food addiction).34-37 For example, excess food intake might be a phenotypic expression of addictive behavior subserved by similar circuits implicated in illicit substance misuse.35
BD linkage studies indicate that panic comorbidity may proxy a genetically distinct BD subtype. Building on reports of a possible genetic link for BD on chromosome 18, significant variation between linkage scores were reported across sets of families when researchers stratified genetic linkage results by proband panic diagnoses.38-40 Families at risk for panic were linked to markers on the long arm of chromosome 18, while families of probands without panic exhibited no evidence of linkage.
Other factors contributing to the co-occurrence of mood and other disorders can be categorized as organizational (eg, economic, access to primary and preventative health care, educational attainment), behavioral, neurobiological, and iatrogenic.41 For example, individuals with mood disorders often have relatively less access to public and private health care systems compared with individuals without a psychiatric disorder. Moreover, a comorbid condition has a lower rate of detection, treatment, and management in an individual with a chronic psychiatric disorder compared with persons with a single medical condition.42
Mood disorders are associated with a host of negative health behaviors including smoking, poor diet, overeating, and a sedentary lifestyle.43 The high prevalence of medical disorders in mood disorder populations is related to an increased rate of merging risk factors (eg, inflammation, oxidative stress) as well as established risk factors (eg, hypertension, diabetes mellitus).44
Implications for diagnoses
The high prevalence of lifetime comorbidity in mood disorder patients has emboldened the perspective that comorbid conditions are not validated as distinct. Discriminant validity has not been established for psychiatric disorders and comorbidity.45 The prevailing system of rule-based classification and diagnostic criteria may inflate the prevalence of comorbidity. For example, the diagnostic criteria for ADHD in adults overlap considerably with criteria for a manic episode, therefore increasing the probability of comorbidity.
Moreover, comorbidity studies often cannot distinguish between homotypic continuity (the same diagnosis at different assessments) and heterotypic continuity (continuity of disorder but a different diagnosis). Homotypic continuity suggests that a disorder has a similar manifestation independent of age at assessment whereas heterotypic continuity suggests a broad-based underlying vulnerability with heterogeneous manifestations at different ages.46,47 An example would be pediatric ADHD as a phenotypic variant of BD. This scenario may be coded as comorbidity when in fact heterotypic continuity may be operating, indicating that comorbidity is imprecise.
The temporal association of the co-occurring conditions may help dissect and unravel the complex relationship between mood disorders and comorbidity. For example, when evaluating alcohol abuse or dependence in patients with BD, researchers determined that individuals with BD who reported alcohol use disorders before BD onset (ie, alcohol first) had characteristics consistent with a less severe form of affective illness compared with “bipolar first patients.” Specifically, these patients had a later age of BD onset, symptomatically recovered more rapidly, spent less time in affective episodes, and had a relatively rapid recovery rate.48 These observations (ie, that the sequence of onset of bipolar and substance use disorders would differentially affect outcome) also were reported for co-occurring cannabis use disorders.49
Principles of treatment
1. Establish the diagnosis. Treating comorbidity in mood disorder populations begins with identifying the mood disorder. Notwithstanding extensive education and public awareness programs pertaining to mood disorders, an estimated 50% of individuals with MDD are not diagnosed, furthermore there remains a high rate of false positives in primary care settings.50 Moreover, deficiencies in BD diagnosis lead to a high rate of false positives, false negatives, and delay in diagnoses. It is estimated that <25% of mood disorder patients receive guideline-concordant care for the mood disorder.51
2. Risk assessment. All individuals with mood disorders need to be assessed for self-harm, suicide ideation, and plan. A thorough inventory of previous suicide or self-harm attempts and ongoing surveillance for factors that heighten risk is essential for each patient. Several psychiatric and medical conditions are associated with increased suicidality in mood disorders.52-56
3. Establish the appropriate treatment setting. The least restrictive setting should be sought when managing comorbidity. The assessment process needs to include symptom severity, functionality, supports, risk assessment, and comorbidity.
4. Chronic disease management. Mood disorders are chronic medical syndromes that have been identified as national health priorities. The routine inclusion of chronic disease management components (eg, decision support) is encouraged for all patients. Integrating treatment and multi-disciplinary professionals services increases the probability for full recovery. Patient psychoeducation and family involvement in the care process is encouraged.57,58
5. Concurrent or sequential treatment. Treatment needs to determine whether the co-occurring condition should be treated concurrently or sequentially. Evidence indicates that integrated treatment of mood disorders and comorbidities concurrently increases the probability of recovery from both conditions (eg, substance use disorders, diabetes mellitus). The sequential treatment of comorbidity would be preferred in some situations, for example, when treating an adult with comorbid BD and ADHD, mood stabilization should be considered before introducing psychostimulants. Determining the sequence of treating comorbid conditions should be based on a hierarchical assessment that gives priority to the level of harmful dysfunction. For example, when treating individuals with symptomatic BD, active illicit substance abuse, and panic disorder, the primary focus should be mood stabilization and abstinence. When these therapeutic objectives are achieved, then attention to panic disorder would be warranted.
6. Measurement-based care. Structured evaluation of symptoms, functioning, and side effects at each visit is encouraged. Measurement-based care has been demonstrated to enhance the quality and consistency of care and increase the probability of remission.27
Individuals with mood disorders are differentially affected by psychiatric and medical comorbidity. The presence of a co-occurring condition in an individual with a mood disorder is associated with a more complex illness presentation, lower rate of recovery, and generally unfavorable course. In many cases, comorbidity may antedate the onset of mood disorders, while in most cases it seems to follow the onset of mood disorders. Evaluating individuals with comorbid conditions introduces a research opportunity to refine disease models by identifying points of pathoetiological commonality. For practitioners, the evidence unequivocally supports recommendations for routine surveillance of comorbid conditions. When comorbidity is present, guideline-concordant care as part of an integrated, coordinated, and continuous care model is recommended for both the mood disorder and the comorbid condition. The CANMAT task force recommendations on the treatment of comorbid conditions is intended to offer decision support and foster further research in the study of these commonly encountered conditions.
Disclosures: Dr. McIntyre is on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Janssen-Ortho, Lundbeck, Merck, Pfizer, and Shire; is on speakers bureaus for AstraZeneca, Eli Lilly and Company, Janssen-Ortho, Lundbeck, Merck, Otsuka, and Pfizer; is involved in CME activities with AstraZeneca, Bristol-Myers Squibb, CME Outfitters, Eli Lilly and Company, Lundbeck, Merck, Otsuka, Pfizer, and the Physicians’ Postgraduate Press; and receives research grants from AstraZeneca, Eli Lilly and Company, Forest, Janssen-Ortho, Lundbeck, Pfizer, Sepracor, and Shire. Dr. Rosenbluth is a speaker for AstraZeneca, Eli Lilly and Company, Janssen, L.P., Lundbeck, Organon, and Wyeth Pharmaceuticals. Dr. Ramasubbu receives grant/research support from AstraZeneca (investigator initiated grant). Dr. Bond is on speaker/advisory boards for , or has received research grants from AstraZeneca, Bristol-Myers Squibb, the Canadian Institutes of Health Research (CIHR), the Canadian Network for Mood and Anxiety Treatments, the Canadian Psychiatric Association, Janssen-Ortho, Otsuka, Pfizer, and the UBC Institute of Mental Health/Coast Capital Depression Research Fund. Dr. Taylor receives grant/research support from Bristol-Myers Squibb and Novartis, is a consultant to Bristol-Myers Squibb and Eli Lilly and Company, and is a speaker for Bristol-Myers Squibb, Eli Lilly and Company, Lundbeck, and Pfizer. Dr. Beaulieu receives grant/research support from AstraZeneca, Biovail, Bristol-Myers Squibb, the CIHR, Eli Lilly and Company, Fonds de recherche du Québec, Janssen-Ortho, Lundbeck, Merck-Frosst, Novartis, the National Alliance for Research on Schizophrenia and Depression, Pfizer Servier, Revue Santé mentale au Québec, and the Stanley Foundation; is a consultant to AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Janssen-Ortho, Lundbeck, Oryx, Schering-Plough Merck, Wyeth Pfizer; and is a speaker for AstraZeneca, Biovail, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Janssen-Ortho, Lundbeck, Organon, Oryx, and Wyeth Pfizer. Dr. Schaffer receives grant/research support from the CIHR and Pfizer Canada; is a consultant to AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, and Lundbeck; and is a speaker for AstraZeneca, Bristol-Myers Squibb, and Eli Lilly and Company.
- Schaffer A, McIntosh D, Goldstein BI, et al. The CANMAT task force recommendations for the management of patients with mood disorders and comorbid anxiety disorders. Ann Clin Psychiatry. 2012;24:6–22.
- Bond DJ, Hadjipavlou G, Lam RW, et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and comorbid attention-deficit/hyperactivity disorder. Ann Clin Psychiatry. 2012;24:23–37.
- Beaulieu S, Saury S, Sareen J, et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and comorbid substance use disorders. Ann Clin Psychiatry. 2012;24:38–55.
- Rosenbluth M, MacQueen G, McIntyre RS, et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and comorbid personality disorders. Ann Clin Psychiatry. 2012;24:56–68.
- McIntyre RS, Alsuwaidan M, Goldstein BI, et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and comorbid metabolic disorders. Ann Clin Psychiatry. 2012;24:69–81.
- Ramasubbu R, Beaulieu S, Taylor VH, et al. The CANMAT task force recommendations for the management of patients with mood disorders and comorbid medical conditions: diagnostic, assessment, and treatment principles. Ann Clin Psychiatry. 2012;24:82–90.
- Ramasubbu R, Taylor VH, Samaan Z, et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and select comorbid medical conditions. Ann Clin Psychiatry. 2012;24:91–109.
- Yatham LN, Kennedy SH, Schaffer A, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar Disord. 2009;11:225–255.
- Kennedy SH, Lam RW, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults.Introduction. J Affect Disord. 2009;117:S1–S2.
- McElroy SL, Frye MA, Hellemann G, et al. Prevalence and correlates of eating disorders in 875 patients with bipolar disorder. J Affect Disord. 2011;128:191–198.
- Harvey AG, Schmidt DA, Scarnà A, et al. Sleep-related functioning in euthymic patients with bipolar disorder, patients with insomnia, and subjects without sleep problems. Am J Psychiatry. 2005;162:50–57.
- Martín-Merino E, Ruigómez A, Johansson S, et al. Study of a cohort of patients newly diagnosed with depression in general practice: prevalence, incidence, comorbidity, and treatment patterns. Prim Care Companion J Clin Psychiatry. 2010; 12:PCC.08m00764.
- Kessler RC, Merikangas KR, Wang PS. Prevalence comorbidity, and service utilization for mood disorders in the United States at the beginning of the twenty-first century. Annu Rev Clin Psychol. 2007;3:137–158.
- Mergl R, Seidscheck I, Allgaier AK, et al. Depressive, anxiety, and somatoform disorders in primary care: prevalence and recognition. Depress Anxiety. 2007;24:185–195.
- McIntyre RS, Keck PE Jr. Comorbidity in bipolar disorder: clinical and research opportunities. Bipolar Disord. 2006;8:645–647.
- McElroy SL, Altshuler LL, Suppes T, et al. Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. Am J Psychiatry. 2001;158:420–426.
- McElroy SL, Pope HG Jr, Keck PE Jr, et al. Are impulse-control disorders related to bipolar disorder? Compr Psychiatry. 1996;37:229–240.
- Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289:3095–3105.
- Kessler RC, Rubinow DR, Holmes C, et al. The epidemiology of DSM-III-R bipolar I disorder in a general population survey. Psychol Med. 1997;27:1079–1089.
- Stinson FS, Grant BF, Dawson DA, et al. Comorbidity between DSM-IV alcohol and specific drug use disorders in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Drug Alcohol Depend. 2005;80:105–116.
- Simon NM, Otto MW, Wisniewski SR, et al. Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2004;161:2222–2229.
- Angst J, Cui L, Swendsen J, et al. Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication. Am J Psychiatry. 2010;167:1194–1201.
- Judd LL, Schettler PJ, Akiskal H, et al. Prevalence and clinical significance of subsyndromal manic symptoms, including irritability and psychomotor agitation, during bipolar major depressive episodes. J Affect Disord. 2012;138:440–448.
- Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2007;64:543–552.
- Merikangas KR, Kalaydjian A. Magnitude and impact of comorbidity of mental disorders from epidemiologic surveys. Curr Opin Psychiatry. 2007;20:353–358.
- Feinstein AR, Walter SD, Horwitz RI. An analysis of Berkson’s bias in case-control studies. J Chronic Dis. 1986;39:495–504.
- Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28–40.
- Kilbourne AM, Cornelius JR, Han X, et al. Burden of general medical conditions among individuals with bipolar disorder. Bipolar Disord. 2004;6:368–373.
- Merikangas KR, Zhang H, Avenevoli S, et al. Longitudinal trajectories of depression and anxiety in a prospective community study: the Zurich Cohort Study. Arch Gen Psychiatry. 2003;60:993–1000.
- Thompson WK, Kupfer DJ, Fagiolini A, et al. Prevalence and clinical correlates of medical comorbidities in patients with bipolar I disorder: analysis of acute-phase data from a randomized controlled trial. J Clin Psychiatry. 2006;67:783–788.
- McIntyre RS, Kennedy SH, Soczynska JK, et al. Attention-deficit/hyperactivity disorder in adults with bipolar disorder or major depressive disorder: results from the international mood disorders collaborative project. Prim Care Companion J Clin Psychiatry. 2010; 12: pii: PCC.09m00861.
- Simon GE, Unützer J. Health care utilization and costs among patients treated for bipolar disorder in an insured population. Psychiatr Serv. 1999;50:1303–1308.
- Krishnan V, Nestler EJ. Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry. 2010;167:1305–1320.
- Volkow ND, Wang GJ, Telang F, et al. Inverse association between BMI and prefrontal metabolic activity in healthy adults. Obesity (Silver Spring). 2009;17:60–65.
- Volkow ND, Wise RA. How can drug addiction help us understand obesity? Nat Neurosci. 2005;8:555–560.
- Volkow N, Li TK. The neuroscience of addiction. Nat Neurosci. 2005;8:1429–1430.
- McIntyre RS, McElroy SL, Konarski JZ, et al. Substance use disorders and overweight/obesity in bipolar I disorder: preliminary evidence for competing addictions. J Clin Psychiatry. 2007;68:1352–1357.
- MacKinnon DF, Zandi PP, Cooper J, et al. Comorbid bipolar disorder and panic disorder in families with a high prevalence of bipolar disorder. Am J Psychiatry. 2002;159:30–35.
- MacKinnon DF, Xu J, McMahon FJ, et al. Bipolar disorder and panic disorder in families: an analysis of chromosome 18 data. Am J Psychiatry. 1998;155:829–831.
- MacKinnon DF, McMahon FJ, Simpson SG, et al. Panic disorder with familial bipolar disorder. Biol Psychiatry. 1997;42:90–95.
- McIntyre RS. Overview of managing medical comorbidities in patients with severe mental illness. J Clin Psychiatry. 2009;70:e17.
- Redelmeier DA, Tan SH, Booth GL. The treatment of unrelated disorders in patients with chronic medical diseases. N Engl J Med. 1998;338:1516–1520.
- Kupfer DJ. The increasing medical burden in bipolar disorder. JAMA. 2005;293:2528–2530.
- McIntyre RS, Soczynska JK, Beyer JL, et al. Medical comorbidity in bipolar disorder: re-prioritizing unmet needs. Curr Opin Psychiatry. 2007;20:406–416.
- Jablensky A, Kendell RE. Criteria for assessing a classification in psychiatry. In: Mai M Gaebel W, López-Ibor JJ, et al., eds. Psychiatric diagnosis and classification. New York, NY: John Wiley & Sons, Ltd.; 2002:1-24.
- Costello EJ, Mustillo S, Erkanli A, et al. Prevalence and development of psychiatric disorders in childhood and adolescence. Arch Gen Psychiatry. 2003;60:837–844.
- Ferdinand RF, Dieleman G, Ormel J, et al. Homotypic versus heterotypic continuity of anxiety symptoms in young adolescents: evidence for distinctions between DSM-IV subtypes. J Abnorm Child Psychol. 2007;35:325–333.
- Strakowski SM, DelBello MP, Fleck DE, et al. Effects of co-occurring alcohol abuse on the course of bipolar disorder following a first hospitalization for mania. Arch Gen Psychiatry. 2005;62:851–858.
- Strakowski SM, DelBello MP, Fleck DE, et al. Effects of co-occurring cannabis use disorders on the course of bipolar disorder after a first hospitalization for mania. Arch Gen Psychiatry. 2007;64:57–64.
- Mitchell AJ, Vaze A, Rao S. Clinical diagnosis of depression in primary care: a meta-analysis. Lancet. 2009;374:609–619.
- Hirschfeld RM, Calabrese JR, Weissman MM, et al. Screening for bipolar disorder in the community. J Clin Psychiatry. 2003;64:53–59.
- Norton PJ, Temple SR, Pettit JW. Suicidal ideation and anxiety disorders: elevated risk or artifact of comorbid depression? J Behav Ther Exp Psychiatry. 2008;39:515–525.
- Frye MA, Salloum IM. Bipolar disorder and comorbid alcoholism: prevalence rate and treatment considerations. Bipolar Disord. 2006;8:677–685.
- Dilsaver SC, Akiskal HS, Akiskal KK, et al. Dose-response relationship between number of comorbid anxiety disorders in adolescent bipolar/unipolar disorders, and psychosis, suicidality, substance abuse and familiality. J Affect Disord. 2006;96:249–258.
- Goldberg JF, Singer TM, Garno JL. Suicidality and substance abuse in affective disorders. J Clin Psychiatry. 2001;62:35–43.
- Waller SJ, Lyons JS, Costantini-Ferrando MF. Impact of comorbid affective and alcohol use disorders on suicidal ideation and attempts. J Clin Psychol. 1999;55:585–595.
- Katon WJ. Clinical and health services relationships between major depression depressive symptoms, and general medical illness. Biol Psychiatry. 2003;54:216–226.
- Von Korff M, Katon W, Unützer J, et al. Improving depression care: barriers, solutions, and research needs. J Fam Pract. 2001;50:E1.
CORRESPONDENCE Roger S. McIntyre, MD, FRCPC, Mood Disorders Psychopharmacology Unit University Health Network, Departments of Psychiatry and Pharmacology University of Toronto, 399 Bathurst Street, MP9-325, Toronto, ON, M5T 2S8 Canada E-MAIL firstname.lastname@example.org
Annals of Clinical Psychiatry ©2012 Quadrant HealthCom Inc.