Skip to main content Accessibility help
×
Home
Hostname: page-component-79b67bcb76-bzjh5 Total loading time: 0.634 Render date: 2021-05-14T21:20:35.769Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "metricsAbstractViews": false, "figures": false, "newCiteModal": false, "newCitedByModal": true, "newEcommerce": true }

Guidelines for the recognition and management of mixed depression

Published online by Cambridge University Press:  28 February 2017

Stephen M. Stahl
Affiliation:
Department of Psychiatry, University of California, San Diego, California, USA Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom Neuroscience Education Institute, Carlsbad, California, USA
Debbi A. Morrissette
Affiliation:
Neuroscience Education Institute, Carlsbad, California, USA
Gianni Faedda
Affiliation:
Lucio Bini Mood Disorders Center, New York, New York, USA Centro Lucio Bini, Rome, Italy
Maurizio Fava
Affiliation:
Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA
Joseph F. Goldberg
Affiliation:
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Paul E. Keck
Affiliation:
Research Institute at the Lindner Center of HOPE, Mason, Ohio, USA
Yena Lee
Affiliation:
Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
Gin Malhi
Affiliation:
Department of Psychiatry, University of Sydney, Sydney, Australia
Ciro Marangoni
Affiliation:
Centro Lucio Bini, Rome, Italy
Susan L. McElroy
Affiliation:
Research Institute at the Lindner Center of HOPE, Mason, Ohio, USA
Michael Ostacher
Affiliation:
VA Palo Alto Health Care System, Palo Alto, California, USA Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Stanford, California, USA
Joshua D. Rosenblat
Affiliation:
Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
Eva Solé
Affiliation:
Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
Trisha Suppes
Affiliation:
VA Palo Alto Health Care System, Palo Alto, California, USA Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Stanford, California, USA
Minoru Takeshima
Affiliation:
Psychiatry Clinic, Sainen, Kanazawa City, Ishikawa Prefecture, Japan
Michael E. Thase
Affiliation:
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, and the Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA
Eduard Vieta
Affiliation:
Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
Allan Young
Affiliation:
Department of Psychological Medicine, Kings College, London, United Kingdom
Mark Zimmerman
Affiliation:
Department of Psychiatry, Rhode Island Hospital, Providence, Rhode Island, USA
Roger S. McIntyre
Affiliation:
Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
Corresponding
E-mail address:
Rights & Permissions[Opens in a new window]

Abstract

A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM–5 codified a new nosological entity, the “mixed features specifier,” referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM–IV definition of “mixed states” wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

Type
Guidelines
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright
© Cambridge University Press 2017

Introduction

The recent addition of the mixed features specifier in the latest edition of the Diagnostic and Statistical Manual (DSM–5) codifies a new nosological entity characterized by subthreshold hypomanic or manic symptoms occurring during depressive episodes of either major depressive disorder (MDD) or bipolar I or bipolar II disorder. 1 The introduction of the DSM–5 mixed features specifier also reflects a growing consensus that mood disorders may be conceptualized along a spectrum ranging from pure unipolar depression, through an admixture of varying degrees and presentations of depressive and manic symptoms, to pure mania (Figure 1).Reference Benazzi 2 Reference Solé, Garriga, Valentí and Vieta 6 Perhaps one of the greatest challenges in recognizing the existence of mixed depression or depressive mixed states (DMX) is the question of how to optimize treatment for patients with depression who exhibit concomitant subthreshold features of hypomania or mania. Although there are several guidelines available that provide recommendations for the treatment of unipolar depression, for bipolar depression, and for bipolar mania, there is currently only one treatment guideline that has provided decision support for individuals presenting with a major depressive episode with mixed features (i.e., the Florida Best Practice Psychotherapeutic Medication Guidelines for Adults [2015], available for download at http://www.medicaidmentalhealth.org/_assets/file/Guidelines/Web_2015-Psychotherapeutic%20Medication%20Guidelines%20for%20Adults_Final_Approved1.pdf).Reference Cerullo and Strakowski 7 Reference Fountoulakis, Grunze and Vieta 19 In fact, any treatment guidelines developed prior to the release of the DSM–5 that mention “mixed states” are based on the previous DSM–IV diagnostic criteria that refer to co-occurring full-blown, threshold-level depression with full-blown, threshold-level mania (mixed mania) and simply lump mixed states together with bipolar mania in terms of treatment recommendations.Reference Grunze and Azorin 20

Since the release of the DSM–5 in 2013, it has been suggested that clinicians follow existing guidelines written for the treatment of MDD or bipolar disorder (BD) without any particular reference to individuals presenting with depressive episodes with mixed (DMX) features. However, not only is DMX different in its clinical presentation compared to an MDE, it is not pathognomonic of either MDD or BD. Toward the aim of filling the gaps between updated diagnostic criteria, the latest research findings, and optimal clinical practice, we have gathered together a panel of experts on mood disorders to develop a set of guidelines for the recognition and treatment of DMX.

The guideline recommendations throughout this article are made in reference to DSM–5 rather than DSM–IV descriptions and criteria. However, the diagnostic criteria warranting a DSM–5 major depressive episode (MDE) with mixed features diagnosis exclude “overlapping symptoms” of irritability, distractibility, insomnia, and psychomotor agitation as defining of the opposite polarity due to the presence of these symptoms in both mania and depression. The exclusion of overlapping symptoms increases the specificity of the diagnosis at the expense of sensitivity and possibly face validity insofar as most individuals presenting with an MDE and mixed features do present with “overlapping symptoms.”Reference Takeshima and Oka 21 Reference Sani, Vohringer and Napoletano 31 The potential of DMX being misdiagnosed and treated as pure unipolar depression is far greater than if unipolar depression is misdiagnosed and mistreated as DMX).

Overview and Key Points

  • Not all patients with depression (as part of bipolar disorder or major depressive disorder) should be prescribed an antidepressant.

  • All patients who receive antidepressants for an MDE should be monitored for signs of abnormal behavioral activation or psychomotor acceleration.

  • The use of antidepressants in MDE patients with mixed features may not alleviate depressive symptoms and may pose a potential hazard for exacerbating subthreshold mania symptoms that accompany depression.

  • For an individual presenting with a depressive episode with mixed features, in addition to antidepressant medication, alternative psychotropic agents (e.g., lithium, anticonvulsant mood stabilizers, atypical antipsychotics) with demonstrated efficacy in treating depressive symptoms as part of MDE may be considered.

  • You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask! Ask every patient. Every time.

Assessment

DSM–5 diagnostic criteria for a major depressive episode 1 (consider an itemized depression screener such as the Quick Inventory Depressive Symptomatology–Self Report or Clinically Useful Depression Outcome Scale)

  • EITHER depressed mood OR anhedonia/loss of interest AND four (or more) of the following symptoms:

    1. Weight/appetite changes

    2. Sleep disturbances

    3. Psychomotor agitation or retardation

    4. Fatigue

    5. Worthlessness or guilt

    6. Executive dysfunction

    7. Suicidal ideation or thoughts of death

  • May be part of unipolar depression, bipolar II depression, or bipolar I depression

DSM–5 diagnostic criteria for the mixed features specifier 1

  • Full criteria for a major depressive episode and at least three of the following (hypo)manic symptoms during the majority of days of the current or most recent depressive episode:

    1. Elevated, expansive mood

    2. Inflated self-esteem or grandiosity

    3. More talkative than usual or pressure to keep talking

    4. Flight of ideas or subjective experience that thoughts are racing

    5. Increase in energy or goal-directed activity

    6. Increased or excessive involvement in activities that have a high potential for painful consequences

    7. Decreased need for sleep (to be contrasted with insomnia)

  • May be part of unipolar depression, bipolar II depression, or bipolar I depression

Non DSM–5 diagnostic criteria for mixed depression (overlapping symptoms) Reference Benazzi 2 , Reference Takeshima and Oka 21 Reference Malhi, Lampe and Coulston 23 , Reference Faedda, Marangoni and Reginaldi 25 , Reference Perugi, Angst and Azorin 29

  • Controversy exists as to whether the symptoms of DMX are fully captured by the DSM–5 diagnostic criteria, as well as the extent to which DMX symptoms can be differentiated from comorbid disorders or other conditions, including borderline personality disorder, posttraumatic stress disorder, substance use disorders, and attention deficit hyperactivity disorderReference Perugi, Angst and Azorin 29 , Reference Goldberg 32

  • Alternative diagnostic criteria have been proposed and focus on the most common symptoms seen in patients with DMX, including:

    1. Irritability

    2. Anxiety

    3. Distractibility

    4. Psychomotor agitation

    5. Racing/crowded thoughts

    6. Initial and middle insomnia

    7. Indecisiveness

    8. Anger

    9. Increased talkativeness

    10. Emotional lability/tearfulness

    11. Inner tension

    12. Rumination

    13. Initial or middle insomnia

    14. Impulsivity

    15. Risky behaviors

Differential Diagnosis

  • The prognosis for depression with cooccurring subthreshold hypomania (DMX) is much worse than for pure unipolar depression or bipolar depression without mixed featuresReference Goldberg, Perlis and Bowden 26 , Reference Angst, Cui and Swendsen 40

  • A significant minority (about 13–20%) of individuals with unipolar DMX will eventually meet diagnostic criteria for bipolar I or bipolar II disorder

  • In order to avoid treatments that could worsen symptoms of hypo/mania in MDE patients with mixed features (e.g., antidepressant monotherapy), to prevent the development of resistance to appropriate treatments, and to avert treatment-emergent affective switch (TEAS), it is essential that DMX be distinguished from pure unipolar depression as early as possibleReference Angst, Cui and Swendsen 40 Reference Post, Leverich and Altshuler 45

  • A key differential diagnostic issue is unipolar depression with borderline personality disorder versus DMX. Most of the correlates listed below are also correlates of unipolar depression with borderline personality disorder

  • MDD with active substance use disorders could inflate rates of false-positive detection of hypo/mania symptoms and requires a careful longitudinal historyReference Goldberg, Garno, Callahan, Kearns, Kerner and Ackerman 46

  • DMX has been associated with:

    1. Family history of bipolar spectrum disorders

    2. Suicidality

    3. Antidepressant-induced mania

    4. Rapid cycling

    5. Young age of onset

    6. Long duration of illness

    7. Poor prognosis

    8. Severe depression

    9. Antidepressant resistance

    10. Females

    11. Comorbid anxiety

    12. Comorbid substance-use disorder (SUD)

    13. Impulse control disorders

  • There are several assessment tools available to aid in the recognition of subthreshold hypomanic symptoms, including:

    1. Bipolar Depression Rating Scale (BDRS)Reference Galvao, Sportiche and Lambert 47

      1. ʘ Clinician-administered assessment of current symptoms

    2. Hypomania Interview Guide (HIG)Reference Williams, Terman, Link, Amira and Rosenthal 48 , Reference Benazzi 49

      1. ʘ Clinician-administered assessment of current symptoms

    3. Mini International Neuropsychiatric Interview (M.I.N.I.)Reference Hergueta and Weiller 50

      1. ʘ Patient self-report assessing current (hypo)manic symptoms

    4. Clinically Useful Depression Outcome Scale with DSM–5 Mixed (CUDOS–M)Reference Zimmerman, Chelminski, Young, Dalrymple and Martinez 51

      1. ʘ Patient self-report assessing current (hypo)manic symptoms

    5. Hypomania Checklist (HCL–32)Reference Prieto, Youngstrom and Ozerdem 33 , Reference Altinbas, Ozerdem and Prieto 52

      1. ʘ Patient self-report that screens for lifetime (hypo)manic symptoms—this does not assess mixed episodes, and has not been suggested to do so

    6. Mood Disorder Questionnaire (MDQ)Reference Hirschfeld, Williams and Spitzer 53

      1. ʘ Patient self-report that screens for lifetime (hypo)manic symptoms

    7. Altman Mania Rating ScaleReference Altman, Hedeker, Peterson and Davis 54

      1. ʘ Patient self-report assessing current (hypo)manic symptoms

  • Patient self-report that screens for “bipolar spectrum disorder” (which includes bipolar I and bipolar II), and the “probabilistic” approach may help to identify patients who are more likely to have a bipolar spectrum disorder rather than pure unipolar depression (Figure 2)

    1. The same factors that indicate bipolarity are also evident in patients with DMX

  • Rule out comorbid conditions that phenotypically overlap with mixed features and/or secondary causes of (hypo)mania, but keep in mind that some secondary causes (e.g., substance use) could be more frequent among individuals with bipolar than unipolar disorder

    1. Drug and/or alcohol misuse

      1. ʘ If comorbid, the mood state will generally precede and significantly outlast the state induced by intoxication or withdrawal, and a diagnosis of bipolar disorder can be made

    2. Certain medications

      1. ʘ e.g., L-dopa and corticosteroids, stimulants

    3. Organic conditions

      1. ʘ Most likely in older patients

    4. Caffeine use

    5. Infections (HIV, syphilis, other)

    6. Multiple sclerosis

    7. Traumatic brain injury (TBI), brain lesion(s) involving subcortical or cortical areas

    8. Thyroid disease

    9. Disruptive behavior disorders (CD, ODD)

    10. Cyclothymic temperament, novelty seeking, narcissistic and borderline personality disorders

    11. Agitated or anxious depression

      1. ʘ It has been proposed that agitated depression (a major depressive episode with psychomotor agitation) is a form of mixed depression because it often occurs along with other symptoms of hypomaniaReference Koukopoulos and Sani 22 , Reference Olgiati, Serretti and Colombo 27 , Reference Akiskal, Benazzi, Perugi and Rihmer 55

Baseline Medical History and Laboratory Parameters 11 , Reference Ng, Mammen and Wilting 56

  • Medical history

  • Smoking history

  • Cardiometabolic family history

  • Waist circumference and/or BMI

  • Blood pressure

  • Complete blood count (CBC)

  • Electrolytes, urea, and creatinine (EUC)

  • Urine toxicology for substance use

  • Fasting glucose

  • Fasting lipid profile (TC, vLDL, LDL, HDL, TG)

  • Liver enzymes

  • Hepatitis A, B, C; syphilis testing in patients deemed at risk

  • Estimated glomerular filtration rate

  • Platelets

  • Thyroid-stimulating hormone

  • Serum bilirubin

  • Electrocardiogram (>40 years or if indicated)

  • Prolactin (if relevant)

  • Pregnancy test (if relevant)

  • Contraceptive use (if relevant)

Treatment

Initial treatment

Patients failing to respond to monotherapy and continuing to experience subthreshold symptoms or relapses

Maintenance treatment 11 , Reference Yatham, Kennedy and Parikh 17 , Reference Fountoulakis, Kasper and Andreassen 71 , Reference Grunze 74 , Reference Muneer 106

  • In an individual patient, if one of the recommended acute treatments led to prompt remission from the most recent mixed depressive episode, this may be considered evidence in favor of its long-term use as monotherapy

  • The preferred strategy is for continuous rather than intermittent treatment with oral medication to prevent new episodes

  • Without active acceptance of the need for long-term treatment, adherence may be poor; consider offering enhanced psychological and social support

  • Consistent outpatient follow-up is necessary

  • Long-term treatment is indefinite for the prevention of new episodes and to achieve adequate inter-episode control of residual or chronic mood symptoms

  • Because of the high risk of relapse and the apparent progression to more frequent episodes, long-term treatment with appropriate medication is advocated from as early in the illness course as is acceptable to a patient and his or her family

  • Remain vigilant to conversion to bipolar disorder of patients whose index episode is diagnosed as unipolar DMX

  • In the absence of convincing evidence in favor of long-term treatment with antidepressants, the usual policy should be eventual discontinuation, although a small minority of patients have a robust initial antidepressant response and appear to do well on long-term combination treatment that includes an antidepressantReference Goldberg, Perlis and Ghaemi 89

Safety monitoringReference Ng, Mammen and Wilting 56

  • Suicide is the main serious safety concern in this population, and an individualized approach is necessary depending on clinical variables, social support, and preexisting suicide risk factors

  • Take all possible steps to protect and improve the physical health of patients in your care through active screening and treatment of risk factors or declared disease

  • Higher morbidity and mortality have been reported in bipolar patients, even before treatment with psychotropic agents was initiated. It is of growing concern that many of the long-term treatments that appear to be required for mixed depression may add to the burden of physical disease

  • In addition to baseline laboratory measurements, patients should be monitored continually for the development of adverse events specific to the treatment(s) utilized

  • The risk of tardive dyskinesia is significantly increased with the use of antipsychotics and should be monitored for regularly

Discontinuation of treatmentsReference Connolly and Thase 9 , 11 , Reference Nivoli, Murru and Goikolea 15

  • Following discontinuation of medicines, the risk of relapse remains, even after years of sustained remission; accordingly, if considered, it should be accompanied by an informed assessment of the potential costs and dangers

  • Discontinuation of any long-term medication should normally be tapered over at least two weeks and preferably longer. Early relapse to mania in bipolar disorder patients is a risk of abrupt lithium discontinuation. Clinical monitoring during treatment withdrawal is desirable

  • When a patient has accepted treatment for several years and remains very well, he or she should be strongly advised to continue indefinitely, as the risk of relapse remains high

Children and adolescentsReference Grunze, Vieta and Goodwin 12 , Reference Woo, Lee and Jeong 16 , Reference Yatham, Kennedy and Parikh 17 , Reference Axelson, Goldstein and Goldstein 34 , Reference Rihmer and Gonda 43 , Reference Ng, Mammen and Wilting 56 , Reference Benazzi 61 , Reference Rihmer and Akiskal 70 , Reference Dilsaver, Benazzi and Akiskal 107 , Reference Dilsaver, Benazzi, Rihmer, Akiskal and Akiskal 108

Women of child-bearing potential 11 , Reference Yatham, Kennedy and Parikh 17 , Reference Ng, Mammen and Wilting 56

  • The postpartum period is a time of very high risk of relapse or recurrence into severe illness in women with mood disorders. Vigilance and close monitoring during the perinatal period is essential, and effective prophylactic treatment should be considered

  • In pregnancy, there is a risk of teratogenicity from a number of medications used in all phases of treatment. Higher teratogenic risks appear to be associated with certain anticonvulsants (notably, valproate and carbamazepine). Lithium has also been associated with teratogenicity, although prospective studies suggest that the risk is lower than originally described. The lowest risks appear to be associated with the antipsychotics. However, risks for new compounds are usually unknown and always justify caution

  • Many psychotropics can cause symptoms in neonates (including discontinuation effects from, e.g., antipsychotics, SSRIs). Neonates should be monitored for possible adverse effects following birth. Long-term effects on cognitive development have been reported with exposure to valproate in pregnancy

  • However, optimization of maternal mental health remains a key determinant of pregnancy outcomes; thus, effective treatment of the mother must be carefully weighed against potential risks to the neonateReference Cohen, Wang, Nonacs, Viguera, Lemon and Freeman 112

  • Discontinuation or switching medications risks destabilizing mood and precipitating relapse. Any risk putatively associated with the use of medications should be considered in the context of the relatively high age-related background risk for congenital malformations and spontaneous abortion in the general population

  • If a mother takes medication and breastfeeds, the infant should be monitored for possible adverse effects

  • Medications with a high risk in pregnancy such as valproate or carbamazepine should not be used routinely if there is a significant likelihood of pregnancy

Enhanced careReference Connolly and Thase 9 , 11 , Reference Grunze, Vieta and Goodwin 12 , Reference Faedda, Marangoni and Reginaldi 25

  • Make use of evidence to address poor insight, the seriousness of the illness, reluctance to give up the experience of hypo(mania), the risk of relapse, and the benefit of therapeutic engagement

  • While respecting patient preferences, education about the illness should emphasize the long-term need for medicines

  • Help the patient, family members, and significant others recognize the signs and symptoms of mixed depressive episodes for early treatment; family psychoeducation may improve treatment outcomes

  • Psychosocial interventions enhance care, which can increase adherence and reduce the risk of relapse

  • A large and comprehensive program of psychoeducation may be superior to an equivalent time spent in nonspecific talking therapy

  • Interpersonal and family therapy as well as cognitive behavioral therapy may be beneficial

  • Group psychoeducation may also be more effective than cognitive behavioral therapy for some patients

  • Internet-based psychosocial interventions may be helpful and hold promise, particularly with respect to accessibility

  • A consistent long-term flexible alliance among the patient, the patient’s family, and one effective clinician is the ideal arrangement for outpatient care in patients whose condition has been effectively stabilized. Patients’ relatives should feel comfortable contacting the clinician to report escalations of symptoms or other emergencies

  • Known tolerability of available medicines should guide prescribing:

    1. Inform patients about possible side effects and monitor their possible emergence

    2. Make side effect reduction a priority by lowering the dose, by employing different scheduling (e.g., prescribing all sedative medicines at bed time), or by using alternative formulations

    3. Some patients with mixed depression may require or tolerate lower doses of mood-stabilizing drugs than those used for threshold-level mania

Disclosures

Stephen M. Stahl has served as a consultant to Acadia, Allergan, Arbor Pharmaceuticals, Avanir, Axovant, Axsome, Biogen Celgene, Forest, Forum, Genomind, Innovative Science Solications, Jazz, Lundbeck, Merck, Otsuka, PamLabs, Pierre Fabre, Reviva, Servier, Shire, Spout, Sunovion, Takeda, Teva, Tonix, and Vanda; and he is board member of Genomind. He has served on speakers bureaus for Forum, Lundbeck, Otsuka, Servier, Sunovion, and Takeda. He has received research and/or grant support from Arcadia, Actavis, Alkermes, Arbor Pharmaceuticals, Avanir, Axovant, Biogen, Celegen, Eli Lilly, Forest, Forum, Jazz, Lundbeck, Merck, Otsuka, Reviva, Servier, Shire, Sprout, Sunovion, Takeda, Teva, Tonix and Vanda.

Debbi Morrissette has nothing to disclose.

Gianni Faedda has the following disclosure. Manhattan Behavioral Medicine: owner and principal investigator in clinical trials site.

Maurizio Fava has the following disclosures. Research Support: Abbott Laboratories, Acadia Pharmaceuticals, Alkermes Inc., American Cyanamid, Aspect Medical Systems, AstraZeneca, Avanir Pharmaceuticals, AXSOME Therapeutics, BioResearch, Braincells Inc., Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Cerecor, Clintara LLC, Covance, Covidien, Eli Lilly and Company, EnVivo Pharmaceuticals Inc., Euthymics Bioscience Inc., Forest Pharmaceuticals Inc., FORUM Pharmaceuticals, Ganeden Biotech Inc., GlaxoSmithKline, Harvard Clinical Research Institute, Hoffman-LaRoche, Icon Clinical Research, i3 lnnovus/lngenix, Janssen R&D LLC, Jed Foundation, Johnson & Johnson Pharmaceutical Research & Development, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Lundbeck Inc., MedAvante, Methylation Sciences Inc., National Alliance for Research on Schizophrenia and Depression (NARSAD), National Center for Complementary and Alternative Medicine (NCCAM), National Coordinating Center for Integrated Medicine (NiiCM), National Institute of Drug Abuse (NIDA), National Institute of Mental Health (NIMH), Neuralstem Inc., NeuroRx, Novartis AG, Organon Pharmaceuticals, PamLab LLC, Pfizer Inc., Pharmacia & Upjohn Company LLC, Pharmaceutical Research Associates Inc., Pharmavite® LLC, PharmoRx Therapeutics, Photothera, Reckitt Benckiser, RCT Logic LLC (formerly Clinical Trials Solutions LLC), Roche Pharmaceuticals, Sanofi-Aventis US LLC, Shire, Solvay Pharmaceuticals Inc., Stanley Medical Research Institute (SMRI), Synthelabo, Takeda Pharmaceuticals, Tal Medical, VistaGen, Wyeth-Ayerst Laboratories Advisory Board. Consultant: Abbott Laboratories, Acadia, Affectis Pharmaceuticals AG, Alkermes Inc., Amarin Pharma Inc., Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Avanir Pharmaceuticals, AXSOME Therapeutics, Bayer AG, Best Practice Project Management Inc., Biogen, BioMarin Pharmaceuticals Inc., Biovail Corporation, BrainCells Inc., Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon Inc., Cerecor, CNS Response Inc., Compellis Pharmaceuticals, Cypress Pharmaceutical Inc., DiagnoSearch Life Sciences (P) Ltd ., Dinippon Sumitomo Pharma Co. Inc., Dov Pharmaceuticals Inc., Edgemont Pharmaceuticals Inc., Eisai Inc., Eli Lilly and Company, EnVivo Pharmaceuticals Inc., ePharmaSolutions, EPIX Pharmaceuticals Inc., Euthymics Bioscience Inc., Fabre-Kramer Pharmaceuticals Inc., Forest Pharmaceuticals Inc., Forum Pharmaceuticals, GenOmind LLC, GlaxoSmithKline, Grunenthal GmbH, lndivior, i3 lnnovus/lngenis, Intracellular, Janssen Pharmaceutica, Jazz Pharmaceuticals Inc., Johnson & Johnson Pharmaceutical Research & Development LLC, Knoll Pharmaceuticals Corp., Labopharm Inc., Lorex Pharmaceuticals, Lundbeck Inc., MedAvante Inc., Merck & Co. Inc., MSI Methylation Sciences Inc., Naurex Inc., Nestlé Health Sciences, Neuralstem Inc., Neuronetics Inc., NextWave Pharmaceuticals, Novartis AG, Nutrition 21, Orexigen Therapeutics Inc., Organon Pharmaceuticals, Osmotica, Otsuka Pharmaceuticals, Pamlab LLC, Pfizer Inc., PharmaStar, Pharmavite® LLC, PharmoRx Therapeutics, Precision Human Biolaboratory, Prexa Pharmaceuticals Inc., PPD, Puretech Ventures, PsychoGenics, Psylin Neurosciences Inc., RCT Logic LLC (formerly Clinical Trials Solutions LLC), Rexahn Pharmaceuticals Inc., Ridge Diagnostics Inc., Roche, Sanofi-Aventis US LLC, Sepracor Inc., Servier Laboratories, Schering-Plough Corporation, Shenox Pharmaceuticals, Solvay Pharmaceuticals Inc., Somaxon Pharmaceuticals Inc., Somerset Pharmaceuticals Inc., Sunovion Pharmaceuticals, Supernus Pharmaceuticals Inc., Synthelabo, Taisho Pharmaceutical Company, Takeda Pharmaceutical Company Limited, Tai Medical Inc., Tetragenex Pharmaceuticals Inc., TransForm Pharmaceuticals Inc., Transcept Pharmaceuticals Inc., Vanda Pharmaceuticals Inc., VistaGen. Speaking/Publishing: Adamed Co., Advanced Meeting Partners, American Psychiatric Association, American Society of Clinical Psychopharmacology, AstraZeneca, Belvoir Media Group, Boehringer lngelheim GmbH, Bristol-Myers Squibb, Cephalon Inc., CME Institute/Physicians Postgraduate Press Inc., Eli Lilly and Company, Forest Pharmaceuticals Inc., GlaxoSmithKline, lmedex LLC, MGH Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier, Novartis AG, Organon Pharmaceuticals, Pfizer Inc., PharmaStar, United BioSource Corp., Wyeth-Ayerst Laboratories. Stock/Other Financial Options: Equity Holdings: Compellis, PsyBrain Inc. Royalty/Patent, other income: patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development LLC (PPD), and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MOD), licensed by MGH to Biohaven. Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation–Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolters Kluwer; World Scientific Publishing Co. Pte. Ltd.

Joseph Goldberg has the following disclosures. Merck: speakers bureau, speaker’s fee. Sunovion: speakers bureau and consultant, speaker’s fee and consulting fee. Supernus: speakers bureau and consultant, speaker’s fee and consulting fee. Medscape: consultant consulting fee. WebMD: consultant, consulting fee. Otsuka: speakers bureau and consultant, speaker’s fee and consulting fee. Vanda Pharmaceuticals: speakers bureau, speaker’s fee. WebMD: consultant, consulting fee.

Paul Keck has the following disclosures. Otsuke: advisory board, personal fees. Shire: advisory board, personal fees.

Yena Lee has nothing to disclose.

Gin Malhi reports grants from NHMRC, personal fees from Astrazeneca, personal fees from Lundbeck, personal fees from Janssen-Cilag, personal fees from Servier, other from Melbourne University, personal fees from Elsevier, grants from Ramsay Research and Teaching Fund, grants from American Foundation for Suicide Prevention, grants from Australian Rotary Health, outside the submitted work.

Ciro Marangoni has nothing to disclose.

Susan McElroy reports personal fees from Bracket, personal fees from F. Hoffmann-La Roche Ltd., personal fees from MedAvante, personal fees from Mitsubishi Tanabe Pharma America, grants and personal fees from Myriad, grants and personal fees from Naurex, grants and personal fees from Novo Nordisk, grants and personal fees from Shire, grants and personal fees from Sunovion, grants from Alkermes, grants from Forest, grants from Marriott Foundation, grants from National Institute of Mental Health, grants from Takeda Pharmaceutical Company Ltd., outside the submitted work.

Roger McIntyre has the following disclosures. Advisory Boards: Lundbeck, Pfizer, AstraZeneca, Elli-Lilly, JanssenOrtho, Purdue, Johnson & Johnson, Moksha8, Sunovion, Mitsubishi, Takeda, Forest, Otsuka, Bristol-Myers Squibb. Speakers Fees: Lundbeck, Pfizer, AstraZeneca, Elli-Lilly, JanssenOrtho, Purdue, Johnson & Johnson, Moksha8, Sunovion, Mitsubishi, Takeda, Forest, Otsuka, Bristol-Myers Squibb. Research Grants: Lundbeck, JanssenOrtho, Shire, Purdue, AstraZeneca, Pfizer, Otsuka. Others: Allergan: research grants, patents. Shire: speaker’s fees, profit-sharing agreements. Shire: advisory boards, speaker’s fees, equity ownerships. Shire: research profit-sharing agreements

Michael Ostacher reports personal fees from Otsuka, personal fees from Eli Lilly, personal fees from Johnson & Johnson, personal fees from Supernus Pharmaceuticals, personal fees from Sunovion Pharmaceuticals, personal fees from Lundbeck, personal fees from Acadia Pharmaceuticals, grants from Palo Alto Health Sciences, outside the submitted work.

Joshua Rosenblat has nothing to disclose.

Eva Solé has nothing to disclose.

Trisha Suppes reports grants from the National Institute of Mental Health, grants from the VA Cooperative Studies Program, grants from Pathways Genomics, grants from Stanley Medical Research Institute, personal fees from Medscape Education, personal fees from Global Medical Education, personal fees from CMEology, personal fees from Jones and Bartlett, personal fees from UpToDate, grants and personal fees from Sunovion Pharmaceuticals Inc., grants from Elan Pharma International Limited, personal fees from H. Lundbeck A/S, personal fees from AstraZeneca, personal fees from Merck & Co., outside the submitted work.

Minoru Takeshima reports personal fees from Astellas, Eli Lilly, GlaxoSmithKline, Meiji Seika Pharma, Otsuka, Sumitomo Dainippon Pharma, and Yoshitomi, outside the submitted work.

Michael Thase has the following disclosures. Alkermes: personal fees, consultant. AstraZeneca: consultant, personal fees. Bristol-Myers Squibb Company: personal fees, consultant. Eli Lilly & Company: grant, consultant, personal fees. Forest Laboratories: grant, consultant, personal fees. Gerson Lehman Group: consultant, grant, personal fees. GlaxoSmithKline: consultant, personal fees. Guidepoint Global: consultant, personal fees. H. Lundbeck A/S: consultant, personal fees. MedAvante: consultant; equity holdings, personal fees. Merck and Company: consultant, personal fees. Neuronetics Inc.: consultant, personal fees. Ortho-McNeil Pharmaceuticals: consultant, personal fees. Otsuka: consultant grant and personal fees. Pfizer: consultant, personal fees. Roche: consultant, personal fees. Shire US Inc.: consultant, personal fees. Sunovion Pharmaceuticals Inc.: consultant, personal fees. Takeda: consultant, personal fees. American Psychiatric Foundation: royalties. Guilford Publications: royalties. Herald House: royalties. W.W. Norton & Company Inc.: royalties. Peloton Advantage: other spouse’s employment (salary). Cerecor Inc.: consultant, personal fees. Moksha8: consultant, personal fees. Pamlab LLC (Nestlé): consultant, personal fees. Allergan: consultant, personal fees. Trius Therapeutical Inc.: consultant, personal fees. Fabre-Kramer Pharmaceuticals Inc.: consultant, personal fees.

Eduard Vieta has the following disclosures. Ab-Biotics: grant and personal fees. Acatis grant and personal fees. Allergen: grant and personal fees. AstraZeneca: grant and personal fees. Bristol-Myers Squibb: grant and personal fees. Ferrer: grant and personal fees. Forest Research Institute: grant and personal fees. Gedeon Richter: grant and personal fees. Glaxo-Smith Kline: grant and personal fees. Janssen: grant and personal fees. Lundbeck: grant and personal fees. Otsuka: grant and personal fees. Pfizer: grant and personal fees. Roche: grant and personal fees. Sanofi-Aventis: grant and personal fees. Servier: grant and personal fees. Sunovion: grant and personal fees. Takeda: grant and personal fees. Telefónica: grant and personal fees. The Brain and Behaviour Foundation: grant. The Spanish Ministry of Science and Innovation (CIBERSAM), grant. The Stanley Medical Research Institute, grant.

Allan Young has the following disclosures. Sunovion: personal fees. Lundbeck: personal fees. Eli Lilly: personal fees. AstraZeneca: personal fees. Livanova: personal fees. Jansen: grant.

Mark Zimmerman has nothing to disclose.

Figure 1 Mood disorders spectrum and DSM–5 diagnosis. Mood disorders can be conceptualized as existing along a spectrum that spans from pure unipolar depression with no intra- or inter-episode symptoms of (hypo)mania all the way to threshold level mania.

Figure 2 The probabilistic approach to differential diagnosis. Numerous factors, including early age at onset of first depressive episode, seasonality, antidepressant-induced (hypo)mania, and impulsivity, while not diagnostic of bipolar depression, are less common in pure unipolar depression compared to bipolar spectrum disorders. Moreover, the presence of psychotic features and extensive family history of psychopathology are additional probabilistic factors for BD. Patterns of comorbidity can also be evaluated as substance-use disorders, and several medical disorders (e.g., migraine and metabolic disturbances) are more common in BD when compared to MDD. Although the presence of any of these probabilistic qualities is not pathognomic, accumulation of these factors should alert clinicians to the possibility that their patient may lie along the bipolar spectrum, either with mixed depression or with bipolar depression.

Figure 3 Bipolar spectrum-based first-line monotherapy treatment recommendations.

Figure 4 Treatment algorithm for major depressive episode without mixed features.

Figure 5 Treatment algorithm for major depressive episode with mixed features (DMX).

Figure 6 Relative tolerability of atypical antipsychotics.

Table 1 Recommendations for acute pharmacological treatment of mixed depression a

Table 2 Dosing recommendations for pharmacotherapy of mixed depression

Table 3 Notable side effects associated with mood stabilizers

Table 4 Longitudinal monitoring according to treatment

References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.Google ScholarPubMed
2. Benazzi, F. Reviewing the diagnostic validity and utility of mixed depression (depressive mixed states). Eur Psychiatry. 2008; 23(1): 4048; Epub ahead of print Aug 30, 2007.CrossRefGoogle Scholar
3. Hu, J, Mansur, R, McIntyre, RS. Mixed specifier for bipolar mania and depression: highlights of DSM–5 changes and implications for diagnosis and treatment in primary care. Prim Care Companion CNS Disord. 2014; 16(2): pii: PCC.13r01599. Epub ahead of print Apr 17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116292/. Accessed January 29, 2017.Google ScholarPubMed
4. Sato, T, Bottlender, R, Sievers, M, Schröter, A, Kleindienst, N, Möller, HJ. Evaluating the inter-episode stability of depressive mixed states. J Affect Disord. 2004; 81(2): 103113.CrossRefGoogle ScholarPubMed
5. Vieta, E, Valentí, M. Mixed states in DSM–5: implications for clinical care, education, and research. J Affect Disord. 2013; 148(1): 2836; Epub ahead of print Apr 2. http://www.jad-journal.com/article/S0165-0327(13)00232-2/pdf. Accessed January 29, 2017.CrossRefGoogle ScholarPubMed
6. Solé, E, Garriga, M, Valentí, M, Vieta, E. Mixed features in bipolar disorder. CNS Spectr. 2017: 17; Epub ahead of print.Google ScholarPubMed
7. Cerullo, MA, Strakowski, SM. A systematic review of the evidence for the treatment of acute depression in bipolar I disorder. CNS Spectr. 2013; 18(4): 199208; Epub ahead of print Mar 18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3688656/. Accessed January 29, 2017.CrossRefGoogle ScholarPubMed
8. Cleare, A, Pariante, CM, Young, AH, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol. 2015. 29(5): 459525; Epub ahead of print May 12. http://journals.sagepub.com/doi/pdf/10.1177/0269881115581093. Accessed January 29, 2017.Google Scholar
9. Connolly, KR, Thase, ME. The clinical management of bipolar disorder: a review of evidence-based guidelines. Prim Care Companion CNS Disord. 2011; 13(4): pii: PCC.10r01097. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219517/. Accessed January 29, 2017.Google ScholarPubMed
10. Fountoulakis, KN, Kontis, D, Gonda, X, Siamouli, M, Yatham, LN. Treatment of mixed bipolar states. Int J Neuropsychopharmacol. 2012; 15(7): 10151026; Epub ahead of print Jan 5. https://academic.oup.com/ijnp/article-lookup/doi/10.1017/S1461145711001817. Accessed January 29, 2017.CrossRefGoogle ScholarPubMed
11. Goodwin GM, Consensus Group of the British Association for Psychopharmacology. Evidence-based guidelines for treating bipolar disorder: revised second edition. Recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2009; 23(4): 346388; Epub ahead of print Mar 27. http://journals.sagepub.com/doi/pdf/10.1177/0269881109102919. Accessed January 29, 2017.CrossRefGoogle ScholarPubMed
12. Grunze, H, Vieta, E, Goodwin, GM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: update 2010 on the treatment of acute bipolar depression. World J Biol Psychiatry. 2010; 11(2): 81109.CrossRefGoogle Scholar
13. McIntyre, RS, Yoon, J. Efficacy of antimanic treatments in mixed states. Bipolar Disord. 2012; 14(Suppl. 2): 2236.CrossRefGoogle ScholarPubMed
14. Musetti, L, Del Grande, C, Marazziti, D, Dell’Osso, L. Treatment of bipolar depression. CNS Spectr. 2013; 18(4): 177187; Epub ahead of print Feb 8.CrossRefGoogle ScholarPubMed
15. Nivoli, AM, Murru, A, Goikolea, JM, et al. New treatment guidelines for acute bipolar mania: a critical review. J Affect Disord. 2012; 140(2): 125141; Epub ahead of print Nov 17, 2011.CrossRefGoogle Scholar
16. Woo, YS, Lee, JG, Jeong, JH, et al. Korean Medication Algorithm Project for Bipolar Disorder, third revision. Neuropsychiatr Dis Treat. 2015; 11: 493506; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348143/. Accessed January 29, 2017.Google ScholarPubMed
17. Yatham, LN, Kennedy, SH, Parikh, SV, 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 2013. Bipolar Disord. 2013; 15(1): 144; Epub ahead of print Dec 12, 2012.CrossRefGoogle ScholarPubMed
18. 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(3): 225255.CrossRefGoogle ScholarPubMed
19. Fountoulakis, KN, Grunze, H, Vieta, E, et al. The International College of Neuro-Psychopharmacology (CINP) treatment guidelines for bipolar disorder in adults (CINP–BD–2017), part 3: the clinical guidelines. Int J Neuropsychopharmacol. 2016: pii: pyw109. Epub ahead of print. https://academic.oup.com/ijnp/article-lookup/doi/10.1093/ijnp/pyw109. Accessed January 29, 2017.Google Scholar
20. Grunze, H, Azorin, JM. Clinical decision making in the treatment of mixed states. World J Biol Psychiatry. 2014; 15(5): 355368; Epub ahead of print May 14.CrossRefGoogle Scholar
21. Takeshima, M, Oka, T. DSM–5-defined “mixed features” and Benazzi’s mixed depression: which is practically useful to discriminate bipolar disorder from unipolar depression in patients with depression? Psychiatry Clin Neurosci. 2015; 69(2): 109116; Epub ahead of print Jul 14, 2014. http://onlinelibrary.wiley.com/doi/10.1111/pcn.12213/full. Accessed January 29, 2017.CrossRefGoogle Scholar
22. Koukopoulos, A, Sani, G. DSM–5 criteria for depression with mixed features: a farewell to mixed depression. Acta Psychiatr Scand. 2014; 129(1): 416; Epub ahead of print Apr 19, 2013.CrossRefGoogle Scholar
23. Malhi, GS, Lampe, L, Coulston, CM, et al. Mixed state discrimination: a DSM problem that wont go away? J Affect Disord. 2014; 158: 810; Epub ahead of print Jan 28.Google Scholar
24. Benazzi, F, Akiskal, HS. Psychometric delineation of the most discriminant symptoms of depressive mixed states. Psychiatry Res. 2006; 141(1): 8188; Epub ahead of print Nov 28, 2005.CrossRefGoogle Scholar
25. Faedda, GL, Marangoni, C, Reginaldi, D. Depressive mixed states: a reappraisal of Koukopoulos’ criteria. J Affect Disord. 2015; 176: 1823; Epub ahead of print Feb 4.CrossRefGoogle Scholar
26. Goldberg, JF, Perlis, RH, Bowden, CL, et al. Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP–BD. Am J Psychiatry. 2009; 166(2): 173181; Epub ahead of print Jan 2. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2008.08050746. Accessed January 29, 2017.CrossRefGoogle Scholar
27. Olgiati, P, Serretti, A, Colombo, C. Retrospective analysis of psychomotor agitation, hypomanic symptoms, and suicidal ideation in unipolar depression. Depress Anxiety. 2006; 23(7): 389397.CrossRefGoogle ScholarPubMed
28. Maj, M. “Mixed” depression: drawbacks of DSM–5 (and other) polythetic diagnostic criteria. J Clin Psychiatry. 2015; 76(3): e381e382; http://www.psychiatrist.com/jcp/article/Pages/2015/v76n03/v76n0324.aspx. Accessed January 29, 2017.CrossRefGoogle ScholarPubMed
29. Perugi, G, Angst, J, Azorin, JM, et al. Mixed features in patients with a major depressive episode: the BRIDGE–II–MIX study. J Clin Psychiatry. 2015; 76(3): e351e358.CrossRefGoogle ScholarPubMed
30. Sani, G, Napoletano, F, Vohringer, PA, et al. Mixed depression: clinical features and predictors of its onset associated with antidepressant use. Psychother Psychosom.. 2014; 83(4): 213221; Epub ahead of print Jun 19.CrossRefGoogle ScholarPubMed
31. Sani, G, Vohringer, PA, Napoletano, F, et al. Koukopoulos’ diagnostic criteria for mixed depression: a validation study. J Affect Disord. 2014; 164: 1418; Epub ahead of print Apr 12.CrossRefGoogle Scholar
32. Goldberg, JF. Mixed depression: a farewell to differential diagnosis? J Clin Psychiatry. 2015; 76(3): e378e380; http://www.psychiatrist.com/jcp/article/Pages/2015/v76n03/v76n0323.aspx. Accessed January 30, 2017.CrossRefGoogle Scholar
33. Prieto, ML, Youngstrom, EA, Ozerdem, A, et al. Different patterns of manic/hypomanic symptoms in depression: a pilot modification of the Hypomania Checklist–32 to assess mixed depression. J Affect Disord. 2015; 172: 355360.CrossRefGoogle Scholar
34. Axelson, D, Goldstein, B, Goldstein, T, et al. Diagnostic precursors to bipolar disorder in offspring of parents with bipolar disorder: a longitudinal study. Am J Psychiatry. 2015; 172(7): 638646; Epub ahead of print Mar 3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489996/. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
35. Akiskal, HS, Benazzi, F. Family history validation of the bipolar nature of depressive mixed states. J Affect Disord. 2003; 73(1–2): 113122.CrossRefGoogle ScholarPubMed
36. Brietzke, E, Moreira, CLRL, Duarte, SVB, et al. Impact of comorbid migraine on the clinical course of bipolar disorder. Compr Psychiatry. 2012; 53(6): 809812; Epub ahead of print Nov 20, 2011.CrossRefGoogle Scholar
37. Oedegaard, KJ, Fasmer, OB. Is migraine in unipolar depressed patients a bipolar spectrum trait? J Affect Disord. 2005; 84(2–3): 233242.CrossRefGoogle ScholarPubMed
38. Ortiz, A, Cervantes, P, Zlotnik, G, et al. Cross-prevalence of migraine and bipolar disorder. Bipolar Disord. 2010; 12(4): 397403.CrossRefGoogle ScholarPubMed
39. Jerrell, JM, McIntyre, RS, Tripathi, A. A cohort study of the prevalence and impact of comorbid medical conditions in pediatric bipolar disorder. J Clin Psychiatry. 2010; 71(11): 15181525; Epub ahead of print Jun 15. http://www.psychiatrist.com/JCP/article/Pages/2010/v71n11/v71n1115.aspx. Accessed January 30, 2017.CrossRefGoogle Scholar
40. 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(10): 11941201; Epub ahead of print Aug 16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145248/pdf/nihms249007.pdf. Accessed January 30, 2017.CrossRefGoogle Scholar
41. Dudek, D, Siwek, M, Zielinska, D, Jaeschke, R, Rybakowski, J. Diagnostic conversions from major depressive disorder into bipolar disorder in an outpatient setting: results of a retrospective chart review. J Affect Disord. 2013; 144(1–2): 112115; Epub ahead of print Aug 5, 2012.CrossRefGoogle Scholar
42. Sharma, V, Khan, M, Smith, A. A closer look at treatment-resistant depression: is it due to a bipolar diathesis? J Affect Disord. 2005; 84(2–3): 251257.CrossRefGoogle Scholar
43. Rihmer, Z, Gonda, X. Antidepressant-resistant depression and antidepressant-associated suicidal behaviour: the role of underlying bipolarity. Depress Res Treat. 2011; 2011: 906462. Epub ahead of print Apr 3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096313/pdf/DRT2011-906462.pdf. Accessed January 30, 2017.Google Scholar
44. Amsterdam, JD, Shults, J. Does tachyphylaxis occur after repeated antidepressant exposure in patients with bipolar II major depressive episode? J Affect Disord. 2009; 115(1–2): 234240; Epub ahead of print Aug 9, 2008.CrossRefGoogle Scholar
45. Post, RM, Leverich, GS, Altshuler, LL, et al. Relationship of prior antidepressant exposure to long-term prospective outcome in bipolar I disorder outpatients. J Clin Psychiatry. 2012; 73(7): 924930; Epub ahead of print Mar 20.CrossRefGoogle Scholar
46. Goldberg, JF, Garno, JL, Callahan, AM, Kearns, DL, Kerner, B, Ackerman, SH. Overdiagnosis of bipolar disorder among substance use disorder inpatients with mood instability. J Clin Psychiatry. 2008; 69(11): 17511757; Epub ahead of print Aug 12, 2008.CrossRefGoogle ScholarPubMed
47. Galvao, F, Sportiche, S, Lambert, J, et al. Clinical differences between unipolar and bipolar depression: interest of BDRS (Bipolar Depression Rating Scale). Compr Psychiatry. 2013; 54(6): 605610; Epub ahead of print Jan 31.CrossRefGoogle Scholar
48. Williams, JB, Terman, M, Link, MJ, Amira, L, Rosenthal, NE. Hypomania interview guide (including hyperthymia): retrospective assessment version (HIGH–R). Depress Anxiety. 1999; 9(2): 92100.3.0.CO;2-1>CrossRefGoogle Scholar
49. Benazzi, F. Depressive mixed state: dimensional versus categorical definitions. Prog Neuropsychopharmacol Biol Psychiatry. 2003; 27(1): 129134.CrossRefGoogle ScholarPubMed
50. Hergueta, T, Weiller, E. Evaluating depressive symptoms in hypomanic and manic episodes using a structured diagnostic tool: validation of a new Mini International Neuropsychiatric Interview (M.I.N.I.) module for the DSM–5 “With Mixed Features” specifier. Int J Bipolar Disord. 2013; 1: 21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230688/. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
51. Zimmerman, M, Chelminski, I, Young, D, Dalrymple, K, Martinez, JH. A clinically useful self-report measure of the DSM–5 mixed features specifier of major depressive disorder. J Affect Disord. 2014; 168: 357362; Epub ahead of print Jul 22.CrossRefGoogle ScholarPubMed
52. Altinbas, K, Ozerdem, A, Prieto, ML, et al. A multinational study to pilot the modified Hypomania Checklist (mHCL) in the assessment of mixed depression. J Affect Disord. 2014; 152–154: 478482.CrossRefGoogle Scholar
53. Hirschfeld, RM, Williams, JB, Spitzer, RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry. 2000; 157(11): 18731875; http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.157.11.1873. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
54. Altman, EG, Hedeker, D, Peterson, JL, Davis, JM. The Altman Self-Rating Mania Scale. Biol Psychiatry. 1997; 42(10): 948955.CrossRefGoogle ScholarPubMed
55. Akiskal, HS, Benazzi, F, Perugi, G, Rihmer, Z. Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant–suicide controversy. J Affect Disord. 2005; 85(3): 245258.CrossRefGoogle ScholarPubMed
56. Ng, F, Mammen, OK, Wilting, I, et al. The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments. Bipolar Disord. 2009; 11(6): 559595; http://onlinelibrary.wiley.com/doi/10.1111/j.1399-5618.2009.00737.x/full. Accessed January 30, 2017.CrossRefGoogle Scholar
57. Akiskal, HS, Benazzi, F. Psychopathologic correlates of suicidal ideation in major depressive outpatients: is it all due to unrecognized (bipolar) depressive mixed states? Psychopathology. 2005; 38(5): 273280.CrossRefGoogle ScholarPubMed
58. Angst, J, Azorin, JM, Bowden, CL, et al. Prevalence and characteristics of undiagnosed bipolar disorders in patients with a major depressive episode: the BRIDGE Study. Arch Gen Psychiatry. 2011; 68(8): 791798; http://jamanetwork.com/journals/jamapsychiatry/fullarticle/1107421. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
59. Balazs, J, Benazzi, F, Rihmer, Z, Rihmer, A, Akiskal, KK, Akiskal, HS. The close link between suicide attempts and mixed (bipolar) depression: implications for suicide prevention. J Affect Disord. 2006; 91(2–3): 133138; Epub ahead of print Feb 3.CrossRefGoogle ScholarPubMed
60. Benazzi, F, Berk, M, Frye, MA, Wang, W, Barraco, A, Tohen, M. Olanzapine/fluoxetine combination for the treatment of mixed depression in bipolar I disorder: a post-hoc analysis. J Clin Psychiatry. 2009; 70(10): 14241431; http://www.psychiatrist.com/JCP/article/Pages/2009/v70n10/v70n1011.aspx. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
61. Benazzi, F. Bipolar disorder: focus on bipolar II disorder and mixed depression. Lancet. 2007; 369(9565): 935945.CrossRefGoogle ScholarPubMed
62. Bjorklund, L, Horsdal, HT, Mors, O, Ostergaard, SD, Gasse, C. Trends in the psychopharmacological treatment of bipolar disorder: a nationwide register-based study. Acta Neuropsychiatr. 2016; 28(2): 7584; Epub ahead of print Sep 11, 2015.CrossRefGoogle ScholarPubMed
63. Gijsman, HJ, Geddes, JR, Rendell, JM, Nolen, WA, Goodwin, GM. Antidepressants for bipolar depression: a systematic review of randomized, controlled trials. Am J Psychiatry. 2004; 161(9): 15371547; https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0021171/. Accessed January 30, 2017.CrossRefGoogle Scholar
64. Frye, MA, Helleman, G, McElroy, SL, et al. Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression. Am J Psychiatry . 2009; 166(2): 164172; Epub ahead of print Nov 17, 2008. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2008.08030322. Accessed January 30, 2017.CrossRefGoogle Scholar
65. Möller, HJ, Grunze, H, Broich, K. Do recent efficacy data on the drug treatment of acute bipolar depression support the position that drugs other than antidepressants are the treatment of choice? A conceptual review. Eur Arch Psychiatry Clin Neurosci. 2006; 256(1): 116; Epub ahead of print Aug 4, 2005.CrossRefGoogle Scholar
66. Nierenberg, AA. An analysis of the efficacy of treatments for bipolar depression. J Clin Psychiatry. 2008; 69(Suppl. 5): 48.Google ScholarPubMed
67. Pacchiarotti, I, Bond, DJ, Baldessarini, RJ, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013; 170(11): 12491262; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091043/. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
68. Pae, CU, Vohringer, PA, Holtzman, NS, et al. Mixed depression: a study of its phenomenology and relation to treatment response. J Affect Disord. 2012; 136(3): 10591061; Epub ahead of print Dec 14, 2011.CrossRefGoogle ScholarPubMed
69. Patel, R, Reiss, P, Shetty, H, et al. Do antidepressants increase the risk of mania and bipolar disorder in people with depression? A retrospective electronic case register cohort study. BMJ Open. 2015; 5(12): e008341. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679886/pdf/bmjopen-2015-008341.pdf. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
70. Rihmer, Z, Akiskal, H. Do antidepressants t(h)reat(en) depressives? Toward a clinically judicious formulation of the antidepressant–suicidality FDA advisory in light of declining national suicide statistics from many countries. J Affect Disord. 2006; 94(1–3): 313; Epub ahead of print May 19.CrossRefGoogle Scholar
71. Fountoulakis, KN, Kasper, S, Andreassen, O, et al. Efficacy of pharmacotherapy in bipolar disorder: a report by the WPA section on pharmacopsychiatry. Eur Arch Psychiatry Clin Neurosci. 2012; 262(Suppl 1.): 148.CrossRefGoogle ScholarPubMed
72. Sidor, MM, Macqueen, GM. Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry. 2011; 72(2): 156167; Epub ahead of print Oct 5, 2010. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0031744/. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
73. Tundo, A, Calabrese, JR, Proietti, L, de Filippis, R. Short-term antidepressant treatment of bipolar depression: are ISBD recommendations useful in clinical practice? J Affect Disord. 2015; 171: 155160; Epub ahead of print Sep 28, 2014.CrossRefGoogle Scholar
74. Grunze, H. The role of polypharmacy in bipolar disorder treatment guidelines. In: Ritsner MS, ed. Polypharmacy in Psychiatry Practice Vol. II: Use of Polypharmacy in the “Real World.” New York: Springer Science; 2013: P. 275287.Google Scholar
75. Heijnen, WT, De Fruyt, J, Wierdsma, AI, Sienaert, P, Birkenhager, TK. Efficacy of tranylcypromine in bipolar depression: a systematic review. J Clin Psychopharmacol. 2015; 35(6): 700705.CrossRefGoogle Scholar
76. Berk, M, Tiller, JW, Zhao, J, Yatham, LN, Malhi, GS, Weiller, E. Effects of asenapine in bipolar I patients meeting proxy criteria for moderate to severe mixed major depressive episodes: a post-hoc analysis. J Clin Psychiatry. 2015; 76(6): 728734; http://www.psychiatrist.com/jcp/article/Pages/2015/v76n06/v76n0607.aspx. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
77. McIntyre, RS, Tohen, M, Berk, M, Zhao, J, Weiller, E. DSM–5 mixed specifier for manic episodes: evaluating the effect of depressive features on severity and treatment outcome using asenapine clinical trial data. J Affect Disord. 2013; 150(2): 378383; Epub ahead of print May 25.CrossRefGoogle ScholarPubMed
78. McIntyre, RS, Cucchiaro, J, Pikalov, A, Kroger, H, Loebel, A. Lurasidone in the treatment of bipolar depression with mixed (subsyndromal hypomanic) features: post hoc analysis of a randomized placebo-controlled trial. J Clin Psychiatry. 2015; 76(4): 398405; http://www.psychiatrist.com/jcp/article/Pages/2015/v76n04/v76n0402.aspx. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
79. Suppes, T, Silva, R, Cucchiaro, J, et al. Lurasidone for the treatment of major depressive disorder with mixed features: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2016; 173(4): 400407; Epub ahead of print Nov 10, 2015.CrossRefGoogle Scholar
80. Tohen, M, Kanba, S, McIntyre, RS, Fujikoshi, S, Katagiri, H. Efficacy of olanzapine monotherapy in the treatment of bipolar depression with mixed features. J Affect Disord. 2014; 164: 5762; Epub ahead of print Jul 3.CrossRefGoogle Scholar
81. Suppes, T, Ketter, TA, Gwizdowski, IS, et al. First controlled treatment trial of bipolar II hypomania with mixed symptoms: quetiapine versus placebo. J Affect Disord. 2013; 150(1): 3743; Epub ahead of print Mar 19.CrossRefGoogle ScholarPubMed
82. Patkar, A, Gilmer, W, Pae, CU, et al. A 6-week randomized double-blind placebo-controlled trial of ziprasidone for the acute depressive mixed state. PLoS One. 2012; 7(4): e34757. Epub ahead of print Apr 24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335844/. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
83. Lombardo, I, Sachs, G, Kolluri, S, Kremer, C, Yang, R. Two 6-week, randomized, double-blind, placebo-controlled studies of ziprasidone in outpatients with bipolar I depression: did baseline characteristics impact trial outcome? J Clin Psychopharmacol. 2012; 32(4): 470478.CrossRefGoogle Scholar
84. Takeshima, M. Treating mixed mania/hypomania: a review and synthesis of the evidence. CNS Spectr. 2016: 19; Epub ahead of print.Google Scholar
85. Kelly, T, Lieberman, DZ. The utility of low-dose aripiprazole for the treatment of bipolar II and bipolar NOS depression. J Clin Psychopharmacol. 2017; 37(1): 99101.CrossRefGoogle ScholarPubMed
86. Stahl, SM. Prescriber’s Guide: Stahl’s Essential Psychopharmacology, 5th ed. New York: Cambridge University Press; 2014.Google Scholar
87. Swann, AC, Bowden, CL, Morris, D, et al. Depression during mania: treatment response to lithium or divalproex. Arch Gen Psychiatry. 1997; 54(1): 3742.CrossRefGoogle Scholar
88. Magiria, S. Evidence-based combination therapy for bipolar disorder. In: Ritsner MS, ed. Polypharmacy in Psychiatry Practice Vol. II: Use of Polypharmacy in the “Real World.” New York, NY: Springer Science; 2013: P. 159177.Google Scholar
89. Goldberg, JF, Perlis, RH, Ghaemi, SN, et al. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP–BD. Am J Psychiatry. 2007; 164(9): 13481355; http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2007.05122032. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
90. Ei-Mallakh, RS, Karippot, A. Antidepressant-associated chronic irritable dysphoria (acid) in bipolar disorder: a case series. J Affect Disord. 2005; 84(2–3): 267272.CrossRefGoogle ScholarPubMed
91. Altshuler, LL, Post, RM, Hellemann, G, et al. Impact of antidepressant continuation after acute positive or partial treatment response for bipolar depression: a blinded, randomized study. J Clin Psychiatry. 2009; 70(4): 450457; Epub ahead of print Apr 7.CrossRefGoogle ScholarPubMed
92. Bauer, M, Berman, S, Stamm, T, et al. Levothyroxine effects on depressive symptoms and limbic glucose metabolism in bipolar disorder: a randomized, placebo-controlled positron emission tomography study. Mol Psychiatry. 2016; 21(2): 229236; Epub ahead of print Jan 20, 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790155/. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
93. Stamm, TJ, Lewitzka, U, Sauer, C, et al. Supraphysiologic doses of levothyroxine as adjunctive therapy in bipolar depression: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2014; 75(2): 162168.CrossRefGoogle Scholar
94. Fernandes, BS, Dean, OM, Dodd, S, Malhi, GS, Berk, M. N-acetylcysteine in depressive symptoms and functionality: a systematic review and meta-analysis. J Clin Psychiatry. 2016; 77(4): e457e466.CrossRefGoogle Scholar
95. Berk, M, Dean, O, Cotton, SM, et al. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. J Affect Disord. 2011; 135(1–3): 389394; Epub ahead of print Jun 29.CrossRefGoogle Scholar
96. Sarris, J, Mischoulon, D, Schweitzer, I. Omega-3 for bipolar disorder: meta-analyses of use in mania and bipolar depression. J Clin Psychiatry. 2012; 73(1): 8186; Epub ahead of print Aug 9, 2011.CrossRefGoogle ScholarPubMed
97. Geoffroy, PA, Etain, B, Franchi, JA, Bellivier, F, Ritter, P. Melatonin and melatonin agonists as adjunctive treatments in bipolar disorders. Curr Pharm Des. 2015; 21(23): 33523358.CrossRefGoogle ScholarPubMed
98. Faridhosseini, F, Sadeghi, R, Farid, L, Pourgholami, M. Celecoxib: a new augmentation strategy for depressive mood episodes. A systematic review and meta-analysis of randomized placebo-controlled trials. Hum Psychopharmacol. 2014; 29(3): 216223; Epub ahead of print Mar 16.CrossRefGoogle ScholarPubMed
99. Corp, SA, Gitlin, MJ, Altshuler, LL. A review of the use of stimulants and stimulant alternatives in treating bipolar depression and major depressive disorder. J Clin Psychiatry. 2014; 75(9): 10101018.CrossRefGoogle Scholar
100. Goss, AJ, Kaser, M, Costafreda, SG, Sahakian, BJ, Fu, CH. Modafinil augmentation therapy in unipolar and bipolar depression: a systematic review and meta-analysis of randomized controlled trials. J Clin Psychiatry. 2013; 74(11): 11011107; https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0061792/. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
101. Taylor, MJ, Wilder, H, Bhagwagar, Z, Geddes, J. Inositol for depressive disorders. Cochrane Database Syst Rev. 2004; 2: CD004049.Google Scholar
102. Mukai, T, Kishi, T, Matsuda, Y, Iwata, N. A meta-analysis of inositol for depression and anxiety disorders. Hum Psychopharmacol. 2014; 29(1): 5563; Epub ahead of print Dec 3, 2013.CrossRefGoogle ScholarPubMed
103. Kraus, C, Rabl, U, Vanicek, T, et al. Administration of ketamine for unipolar and bipolar depression. Int J Psychiatry Clin Pract. 2017: 112; Epub ahead of print.Google Scholar
104. McCloud, TL, Caddy, C, Jochim, J, et al. Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults. Cochrane Database Syst Rev. 2015; 9: CD011611. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011611.pub2/abstract. Accessed January 30, 2017.Google Scholar
105. Dell’Osso, B, Ketter, TA. Assessing efficacy/effectiveness and safety/tolerability profiles of adjunctive pramipexole in bipolar depression: acute versus long-term data. Int Clin Psychopharmacol. 2013; 28(6): 297304.CrossRefGoogle ScholarPubMed
106. Muneer, A. Pharmacotherapy of bipolar disorder with quetiapine: a recent literature review and an update. Clin Psychopharmacol Neurosci. 2015; 13(1): 2535; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423161/pdf/cpn-13-25.pdf. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
107. Dilsaver, SC, Benazzi, F, Akiskal, HS. Mixed states: the most common outpatient presentation of bipolar depressed adolescents? Psychopathology. 2005; 38(5): 268272; Epub ahead of print Sep 21.CrossRefGoogle Scholar
108. Dilsaver, SC, Benazzi, F, Rihmer, Z, Akiskal, KK, Akiskal, HS. Gender, suicidality and bipolar mixed states in adolescents. J Affect Disord. 2005; 87(1): 1116.CrossRefGoogle ScholarPubMed
109. Thapar, A, Collishaw, S, Pine, DS, Thapar, AK. Depression in adolescence. Lancet. 2012; 379(9820): 10561067; Epub ahead of print Feb 2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488279/pdf/nihms415614.pdf. Accessed January 30, 2017.CrossRefGoogle ScholarPubMed
110. Singh, MK, Ketter, T, Chang, KD. Distinguishing bipolar disorder from other psychiatric disorders in children. Curr Psychiatry Rep. 2014; 16(12): 516.CrossRefGoogle ScholarPubMed
111. Cipriani, A, Zhou, X, Del Giovane, C, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. Lancet. 2016; 388(10047): 881890; Epub ahead of print Jun 8.CrossRefGoogle ScholarPubMed
112. Cohen, LS, Wang, B, Nonacs, R, Viguera, AC, Lemon, EL, Freeman, MP. Treatment of mood disorders during pregnancy and postpartum. Psychiatr Clin North Am. 2010; 33(2): 273293.CrossRefGoogle ScholarPubMed
You have Access
Open access