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Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020
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Image courtesy of Substance Abuse and Mental Health Services Administration (SAMHSA).[1]
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
Depression is a common psychiatric disorder. In the United States, the lifetime prevalence of depression is from 15% to 20%. Women are more commonly affected.[1]
Suicide is a major complication of depression and a leading cause of death in the United States. Worldwide, major depressive disorder (MDD) is the leading cause of years lived with disability (YLDs) in 56 countries and the second leading cause in another 56 countries.[2]
Image courtesy of Adrian Preda, MD. Data from Czeisler MÉ et al.[3]
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
The rates of mental health issues, including depression, have been significantly higher in 2020 than in 2019. Increases of 11% in suicidal ideation, 13% in substance misuse, 26% in trauma- and stressor related disorders (TSRDs), and 33% in anxiety and depressive symptoms were reported in a large sample of adults (≥18 years) surveyed in April-June 2020 as compared with April-June 2019.[3]
Young adults aged 18-24 years appeared to be at higher risk for mental health issues than other age groups, reporting higher rates of symptoms of anxiety or depression, COVID-19–related TSRDs, starting or escalating substance use to cope with COVID-19–associated stress, and serious suicidal ideation in the previous 30 days.[3] The prevalence of mental health issues progressively decreased with age.
General factors related to COVID-19 that increase the risk of mental health issues include social isolation, financial distress, job insecurity, and direct health issues. Examples of factors seen in specific populations include the following:
Military - Prolonged quarantine post deployment, with limited ability to reconnect socially with families and friends
Students - Absences of school structure and support
Image courtesy of Adrian Preda, MD. Data from Czeisler MÉ et al.[3]
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
In the context of COVID-related stress, the rates of anxiety and depression almost tripled, from 8% in 2019 to 26% in 2020 for anxiety and from 7% in 2019 to 24% in 2020 for depression; the rate of suicidal ideation more than doubled, from 4% in 2019 to 10% in 2020.[3] Specific populations, especially young adults, Hispanic persons, black persons, essential workers, unpaid caregivers for adults, and those receiving treatment for preexisting psychiatric conditions are at higher risk for mental health issues.
Image courtesy of Wikimedia Commons.
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
According to the Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association (APA), a diagnosis of clinical depression requires the presence of depressed mood, a loss of pleasure and interest, decreased energy (or, alternatively, a sense of aimless restlessness), sleep or appetite disturbances, and feelings of worthlessness, hopelessness, or guilt for a period of at least 2 weeks. The symptoms must lead to significant distress and impair the patient's ability to function. These symptoms are consistent with MDD only if they cannot be attributed to other psychiatric or medical conditions.
There were no major changes in the diagnostic criteria for MDD from the preceding edition of the APA manual, DSM-IV-TR, to the most recent edition, DSM-5.[4] The only revision worth mentioning in the present context is that in DSM-5, the presence of manic symptoms that are insufficient to meet the criteria for mania is now allowed within a depressive episode and leads to the use of the specifier "with mixed features."
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Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
The patient history is of particular importance in evaluation for suspected MDD. The patient should be asked about recent stressful life events, consumption of illicit drugs, alcohol abuse, current medical conditions, and prescribed medications. Whereas a family history of depression and substance abuse increases the likelihood of MDD, a family history of bipolar disorder or schizophrenia is associated with both unipolar and bipolar depression. It is important to assess the overall severity of depressive symptoms because symptom severity correlates with suicide risk. A focused severity assessment for hopelessness, suicidal ideation, and psychotic symptoms is recommended; these symptoms independently increase the risk for suicide.
Image courtesy of Dreamstime | Melcor (right).
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
A 22-year-old woman presents to her primary care physician with a complaint of "feeling down" for the preceding 2 months. She has had no clear stressors. She states that her mood changes were associated with a decrease in her levels of interest and enjoyment. As a result, for the past 6 weeks, the patient has been spending almost all her time off from work by herself, and she has stopped seeing her friends. This is a significant change from her baseline level of social activity, in which she typically went out to eat or spend time with friends two or three times a week. The patient works as an executive assistant. Although she has been able to maintain her work performance, she now needs to "push herself" to do things that previously were "really easy." Further questions reveal that she feels tired most of the time and has difficulty concentrating on the task at hand. The patient states that for the past few weeks, she has been "obsessing" about her mood not getting better; often, her worries interfere with her ability to fall asleep at night. She also states that for the past 2 weeks, she has been waking up around 6 AM, about 1 hour earlier than her customary time, and has been unable to fall back asleep. She continues to enjoy food; in fact, she has been eating more "for comfort," and this has resulted in a slight (~2 lb) weight gain over the preceding 2 months.
Image courtesy of Dreamstime | Melcor (left).
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
The patient denies a past history of hypomania, mania, or psychosis. She reports social drinking and social use of cannabis, which she has continued sporadically for the past 2 months. She has had "many" brief (days-long) periods of "feeling down" in the past; these usually occurred in the context of psychosocial stressors and always spontaneously remitted.
Which of the following is the most likely diagnosis?
MDD
Generalized anxiety disorder (GAD)
Dysthymia (also referred to as dysthymic disorder or persistent depressive disorder)
Bipolar depression
Obsessive-compulsive disorder (OCD)
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
Answer: A. MDD.
This patient's history is consistent with a diagnosis of MDD, single episode, mild. Although the patient states that she "obsesses" about her mood, her thoughts do not qualify as ego-dystonic obsessions; rather, they are ruminations (ie, ego-syntonic thoughts) centered on her distress, consistent with a diagnosis of depression. Accordingly, a diagnosis of OCD is ruled out. Although the patient appears to worry for a significant amount of time, her worries are secondary to her being depressed; consequently, an independent diagnosis of GAD is not warranted. Bipolar depression cannot be conclusively ruled out, because mania may occur at a later date in patients who first present with depression; however, insofar as there is no evidence for previous episodes of hypomania or mania, a diagnosis of bipolar depression is not warranted at this time. Finally, although the patient mentions having experienced periods of "feeling down" in the past, the episodic nature of these experiences and their reported remission make a diagnosis of dysthymia unlikely.
Image courtesy of Dreamstime | Legger.
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
The patient is diagnosed with MDD, first episode, mild. After discussion of the risks and benefits of starting a trial of cognitive behavioral therapy as compared with those of starting antidepressant therapy, the patient opts to begin taking a selective serotonin reuptake inhibitor (SSRI). Accordingly, escitalopram is started at a dosage of 10 mg/day.
Which of the following statements about this therapy is not true?
The chance of response to this first trial is about 50-60%
Around 50% of depressed patients will experience a remission within 6 months of an index case of depression, and perhaps more than 75% will remit by 2 years
If gastrointestinal side effects occur, they will remit within 2 weeks
It is safe for the patient to discontinue escitalopram abruptly because there is no discontinuance syndrome
Image courtesy of Medscape.
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
Answer: D. It is safe for the patient to discontinue escitalopram abruptly because there is no discontinuance syndrome.
In fact, a discontinuance syndrome can follow abrupt cessation of SSRI therapy, with symptoms that include dizziness, vertigo, ataxia, nausea, sleep disturbances, flulike symptoms, paresthesia, and "brain zaps," as well as mood changes ranging from anxiety to agitation and irritability. Discontinuance symptoms are more frequent with the SSRIs that have shorter half-lives and inactive metabolites, such as paroxetine, sertraline, and fluvoxamine. The incidence of discontinuance syndrome is highest with paroxetine, followed by fluvoxamine and sertraline. Withdrawal symptoms are less common with citalopram and fluoxetine.
Image courtesy of Wikimedia Commons.
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
A 32-year-old man reports experiencing sadness and anhedonia for the preceding 4 weeks in the context of increased stress at work. He reports being so worried about his upcoming work review that he has lost his appetite and is unable to sleep at night. He used to love cooking extravagant meals but over the last few weeks he stopped cooking, as "it feels like a chore" and "everything tastes bland anyway," and he has lost about 15 lb. He feels tired most of the time, to the point where he lacks the energy and drive to complete his work projects. The patient's past psychiatric history is significant for three prior depressive episodes, the first of which occurred at the age of 24 years. He states that his depression and his anxiety go "hand in hand." In addition to anxiety, he also experiences significant irritability and low frustration tolerance during his depressive episodes. During an episode, the patient is "very sensitive" to how others see or treat him. He reports no past history of hypomania, mania, or psychosis. He states that he binge-drinks over weekends, but he denies ever using illicit drugs.
Which of the following is the most likely diagnosis?
GAD
Dysthymia (also referred to as dysthymic disorder or persistent depressive disorder)
Bipolar depression
Unipolar depression
OCD
Image courtesy of Wikimedia Commons.
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
Answer: D. Unipolar depression.
This diagnosis is consistent with an episodic course of depressive symptoms with functional impairment. Although the patient complains of anxiety, he makes it clear that his anxiety goes "hand in hand" with his depressive symptoms; thus, a diagnosis of GAD does not apply. The episodic course of his depression is not consistent with dysthymia. Bipolar depression cannot be conclusively ruled out, in that manic episodes can occur after one or more episodes of depression; however, in view of the absence of prior episodes of hypomania or mania, a diagnosis of bipolar depression is not warranted here. The index of suspicion for OCD is low in this case: Although the patient's worries about work might have an obsessional quality, there is no evidence that his thoughts are unwanted and intrusive—two required characteristics of obsessive thoughts.
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
The patient has undergone three prior trials of SSRI therapy, involving citalopram, escitalopram, and paroxetine. For the past 3 months, he has been taking venlafaxine 225 mg/day. He reports that his past antidepressant trials have been at a therapeutic dosage for a minimum of 8 weeks and that all of the trials resulted in partial response but no remission.
Which of the following aspects of this presentation is/are consistent with treatment-resistant depression (TRD)?
History of treatment with at least two antidepressants
History of past antidepressant trials of adequate dosage and duration
Failure to achieve remission
All of the above
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
Answer: D. All of the above.
TRD is defined as MDD that fails to respond to at least two antidepressant trials that are of adequate dosage and duration; the two antidepressants may belong either to the same class or to different classes.[5] Trials involving inadequate dosage or duration can give rise to pseudoresistance, as opposed to true resistance.[6] TRD is a diagnosis of exclusion. Misdiagnosis is a frequent factor leading to an inadequate response.[7]
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
The patient reports a history of multiple tumultuous short-term relationships. He describes himself as "workaholic," "type A," "competitive," and always worrying about his professional performance. He describes his childhood as uneventful and reports no history of trauma. Although the patient denies a formal family psychiatric history, he states that his father used to drink excessively and was married and divorced multiple times.
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
From 25% to 50% of cases of TRD are associated with bipolar disorder; this is by far the most common individual cause of TRD. The remaining 50-75% are associated with noncompliance, poor or rapid metabolism, or misdiagnosis.[8]
Image courtesy of Wikimedia Commons.
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
Which of the following laboratory tests is/are specific for a diagnosis of TRD?
Thyroid function tests (TFTs)
Complete blood count (CBC)
Vitamin D level
None of the above
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
Answer: D. None of the above.
Depression is a clinical diagnosis. TFTs can rule out cases of hypothyroidism manifesting as depression, and a CBC is helpful in ruling out anemia as a cause of decreased energy; however, neither TFTs nor a CBC would confirm a diagnosis of TRD. Low vitamin D levels have been associated with mood disorders in general[9] but not specifically with depression.
Data from Akiskal[9] and Calabrese et al.[10] Image courtesy of Dreamstime | Victoria L Almgren.
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
The patient in this case presents a number of bipolarity predictors, including reactive and labile mood, irritability, biographical instability, and comorbid anxiety.[10,11]
Image courtesy of Wikimedia Commons.
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
In view of the patient's diagnosis of TRD and the high number of bipolarity predictors he exhibits, what would you recommend as the most appropriate next step in management?
Titrate venlafaxine downward
Start lamotrigine
Start an atypical neuroleptic
All of the above
Image courtesy of Wikimedia Commons.
Major Depressive Disorder: Disabling and Dangerous
Adrian Preda, MD | October 8, 2020 | Contributor Information
Answer: D. All of the above.
Antidepressant monotherapy, with an SSRI as the first line of therapy, is the recommended treatment for uncomplicated depression. Sequential antidepressant trials are recommended for the treatment of residual depression.[12] However, antidepressants can exacerbate the underlying mood lability in a patient with TRD and a high bipolarity index (such as the patient described in the preceding slides). Accordingly, discontinuance of venlafaxine is recommended in this case. Lamotrigine is approved by the US Food and Drug Administration (FDA) for the treatment of bipolar disorder and has been shown to be effective against bipolar depression. In addition, three atypical antipsychotic drugs are approved for use in this setting: aripiprazole, for maintenance treatment of bipolar disorder and adjunctive treatment of MDD; quetiapine, for the treatment of bipolar depression; and brexipiprazole, as adjunctive therapy for MDD. The combination of olanzapine plus fluoxetine has received an indication for TRD.[13]
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Major depressive disorder has significant potential morbidity and mortality, contributing to suicide, incidence and adverse outcomes of medical illness, disruption in interpersonal relationships, substance abuse, and lost work time.Medscape Drugs & Diseases, Aug 2020
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Contributor Information
Author
Adrian Preda, MD
Professor of Clinical Psychiatry, Psychiatry & Human Behavior
Department of Psychiatry and Human Behavior
University of California, Irvine, School of Medicine
Disclosure: Adrian Preda, MD, has disclosed no relevant financial relationships.
Editors
Olivia Wong, DO
Section Editor
Medscape Drugs & Diseases
New York, New York
Disclosure: Olivia Wong, DO, has disclosed no relevant financial relationships.
John Heinegg, RN
Section Editor
Medscape Drugs & Diseases
New York, New York
Disclosure: John Heinegg, RN, has disclosed no relevant financial relationships.
Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015 Aug 22;386(9995):743-800. PMID: 26063472
Czeisler MÉ et al. Mental health, substance use, and suicidal ideation during the COVID-19 pandemic—United States, June 24-30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:1049-57. PMID: 32790653
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: DSM-5. Arlington, VA: American Psychiatric Association; 2013.
McIntyre RS et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014 Mar;156:1-7. PMID: 24314926
Souery D et al. Treatment-resistant depression. J Clin Psychiatry. 2006;67 Suppl 6:16-22. PMID: 16848672
Sackeim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 16):10-7. PMID: 11480879
Sharma V et al. A closer look at treatment resistant depression: is it due to a bipolar diathesis? J Affect Disord. 2005;84(2-3):251-7. PMID: 15708423
Shaffer JA et al. Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials. Psychosom Med. 2014 Apr;76(3):190-6. PMID: 24632894
Akiskal HS. The dark side of bipolarity: detecting bipolar depression in its pleomorphic expressions. J Affect Disord. 2005 Feb;84(2-3):107-15. PMID: 15708407
Calabrese JR et al. Predictors of bipolar disorder risk among patients currently treated for major depression. MedGenMed. 2006 Aug 15;8(3):38. PMID: 17406171
Warden D et al. The STAR*D Project results: a comprehensive review of findings. Curr Psychiatry Rep. 2007;9(6):449-59. PMID: 18221624
Han C et al. Second-generation antipsychotics in the treatment of major depressive disorder: current evidence. Expert Rev Neurother. 2013 Jul;13(7):851-70. PMID: 23898855
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