Psychiatric Comorbidity in Major Depressive Disorder

CHAPTER 7

Psychiatric Comorbidity in Major Depressive Disorder JUNGJIN KIM, MD • THOMAS L. SCHWARTZ, MD

INTRODUCTION Major depressive disorder (MDD) frequently co-occurs with other psychiatric disorders, but these comorbidities are often underrecognized and undertreated because they are either overpowered symptomatically or disguised by MDD symptomatology.1,2 In comparison to patients with only MDD, patients with cooccurring psychiatric disorders tend to have greater severity of illness and poorer longitudinal courses and outcomes. Additionally, these patients have higher healthcare utilization rates and greater impairment of psychosocial functioning, adding to the overall economic and social burden of MDD. Clinicians are, thus, encouraged to be diligent in screening for these co-occurring disorders as the resultant assessment may influence the clinical outcome narrowly and the public healthcare burden broadly. To that end, this chapter provides a synthesized overview of the epidemiological data of MDD’s most frequent comorbidities: anxiety disorders, attention-deficit hyperactivity disorder (ADHD), substance use disorder (SUD), psychotic disorders, and personality disorders. In conclusion, the authors will provide practical assessment and treatment strategies in the management of comorbid MDD and these psychiatric disorders. The goal is to improve the readers’ awareness of these co-occurrences and confidence to treat more effectively when these clinical challenges occur in day-to-day practice.

ANXIETY DISORDERS Anxiety disorders are probably the most frequently encountered comorbid psychiatric conditions when treating patients with MDD. A lifetime prevalence study in the Netherlands (n ¼ 1783) has shown that 75% of those with MDD suffered from concomitant anxiety disorder whereas 79% of those with anxiety disorders had MDD.3 A larger, international study (24 countries, Major Depressive Disorder. https://doi.org/10.1016/B978-0-323-58131-8.00007-0 Copyright © 2020 Elsevier Inc. All rights reserved.

n ¼ 74,045) corroborated this finding: 45.7% of individuals with MDD had a lifetime diagnosis of one or more anxiety disorder.4 Twelve-month prevalence studies yield similar results. The National Comorbidity Survey Replication (NCS-R) of nationally representative sample in the United States (US), 65.2% of respondents with 12month MDD had at least one other disorder and more than half of them (56.5%) were anxiety disorders.5 Another epidemiological study in the Netherlands (n ¼ 7076) showed that the rate of comorbid mood and anxiety disorders is 3.5%, higher than the rate of pure mood disorder (3.1%) but lower than that of having a pure anxiety disorder (7.7%).6 Of those with mood disorder, 60.5% had comorbid mental health problems with anxiety topping the list at 54.3%. The approximate prevalence of MDD and each of the five anxiety disorders pooled from these epidemiological studies is shown in Table 7.1. In addition to high rates of co-occurrence, patients with comorbid MDD and anxiety disorders tend to have poorer response to treatment than to the individual disorders.7 These patients tend to have a more persistent and chronic course of MDD symptoms, greater overall symptom severity, increased functional impairment, and a lower quality of life.1,7,8 Given the high rate of comorbidity and the associated clinical consequences, a thorough and systematic evaluation is needed at the time of initial psychiatric evaluation. This usually occurs when a psychiatric review of systems (discussed later in this chapter) is conducted. The Canadian Network for Mood and Anxiety Treatment (CANMAT) task force has published useful guiding principles for managing comorbid psychiatric conditions.9 These are (1) establishing accurate diagnoses, (2) diligent risk assessment, (3) establishing appropriate treatment settings, (4) addressing chronic disease management, (5) consideration for concurrent or

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TABLE 7.1

Approximate MDD þ Anxiety Disorders’ Lifetime Prevalence. MDD þ GAD

58%

MDD þ PD

55%

MDD þ OCD

37%

MDD þ SAD

37%

MDD þ PTSD

48%

sequential treatment, based on hierarchical assessment, and (6) use of measurement-based care. These general principles are useful when managing not only comorbid MDD and anxiety disorders but also other psychiatric disorders. Some of these skills will be discussed in the latter half of this chapter. The diagnosis of both MDD and a co-occurring anxiety disorder is based on the DSM-5 criteria for the individual disorders. However, anxiety disorders and MDD have several overlapping symptoms, making the diagnosis at times complex. Common to both diagnoses include the following symptoms: irritability, psychomotor activation, difficulty with concentration, fatigue, and insomnia. What is not typical for anxiety disorders, however, is a pervasive depressed or sad affect, remarkable loss of interest, and a preoccupation with thoughts of death. Specifically interviewing for these later symptoms may be helpful and pivotal during assessment. It is also important to establish whether the observed anxiety and depressive symptoms are due to MDD with anxious distress (a DSM-5 specifier for MDD) or MDD co-occurring with a premorbid, separate anxiety disorder. Anxiety symptoms in MDD with anxious distress are usually restricted and only occur during depressive episodes and resolve with effective MDD treatment. Presence of a separate anxiety disorder is likely to persist even longer and needs to be treated even when the MDD symptoms remit. The anxious subgroup of patients in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial indeed tended to have lower rates of antidepressant response and remission compared to the nonanxious subgroup.10 There are two other clinical and diagnostic conventions to consider if a clinician wishes to determine if a truly comorbid anxiety disorder is present with MDD. If the anxiety symptoms meet DSM-5 criteria and predate MDD, then it is felt to be that two separate disorders exist. In addition, if after a successful MDD treatment remission, anxiety symptoms meeting the

DSM-5 criteria continue, then the disorders are considered separate and distinct. The psychopharmacologic treatment of choice with the broadest coverage for all five anxiety disorders and MDD are the serotonergic antidepressants: selective serotonin reuptake inhibitors (SSRIs) and the selective serotonin-norepinephrine reuptake inhibitors (SNRIs). The agents that have dual approval for both MDD and anxiety disorders by the US Food and Drug Administration (FDA) are laid out in Table 7.2. The agent selection should be guided by patient preference and risk profile and the agent needs to be titrated throughout the effective therapeutic range. For rapid symptom relief for certain anxiety disordersdfor example, generalized anxiety disorder (GAD), social anxiety disorder (SAD), or panic disorder (PD)d without a history of substance misuse, an addition of a long-acting benzodiazepine may be considered. Psychotherapy can be combined with pharmacotherapy to optimize outcome. Cognitive-behavioral therapy (CBT), acceptance and commitment therapy (ACT), and psychodynamic therapy are evidence-based treatment options for both MDD and anxiety disorders.11,12

ATTENTION-DEFICIT HYPERACTIVITY DISORDER ADHD is a neurodevelopmental disorder of childhood onset associated with significant cognitive, academic, occupational, and social impairment. Approximately 7% of school-aged children meet the criteria for ADHD.13 ADHD frequently persists into adulthood: up to 36% of adults with ADHD had been diagnosed with ADHD as children.14 The adult ADHD prevalence rate is estimated to be 4.4%.15 The prevalence of MDD comorbid with ADHD ranges from 9% to 50% across a number of different studies.15e17 The National Comorbidity Survey (NCSRS), for instance, reported prevalence rates of MDD in individuals diagnosed with ADHD at 18.6% compared to just 7.8% in those without ADHD.15 Individuals with comorbid MDD and ADHD are at higher risk, compared to those with ADHD alone, for poorer academic or occupational performance, mental health utilization rates, suicide risk, and social/vocational outcomes.16e18 Oftentimes, ADHD impairs occupational and interpersonal function, which in turn leads to commensurate financial and social stress that predispose an individual with ADHD to development of MDD. Therefore, a low threshold of suspicion for comorbid depression should exist when managing patients with ADHD.

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Psychiatric Comorbidity in Major Depressive Disorder

TABLE 7.2

Pharmacologic Agents That Have FDA Dual Approval for MDD þ Anxiety Disorders. MDD

GAD

Panic

OCD

SAD

PTSD

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS) Fluoxetine

X

X

X

Sertraline

X

X

X

X

X

Paroxetine

X

X

X

X

X

X

Fluvoxamine

X

Citalopram

X

Escitalopram

X

X

SELECTIVE SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS) Venlafaxine

X

Desvenlafaxine

X

Duloxetine

X

Levomilnacipran

X

X

X

X

X

SSRI-PLUS AGENTS Vilazodone

X

Vortioxetine

X

TRICYCLIC ANTIDEPRESSANTS (TCAS) Imipramine

X

Amitriptyline

X

Clomipramine

X

Doxepin

X

X

MONOAMINE OXIDASE INHIBITORS (MAOIS) Selegiline

X

Phenelzine

X

Tranylcypromine

X

Diagnosing a comorbid depressive episode in an ADHD patient can be complicated by overlapping symptomsdinattention, distractibility, restlessness, or psychomotor activation. In addition, the consequences of untreated ADHD often result in recurrent social stressors, multiple adjustment disorders with resultant disappointments and demoralization that may mimic MDD. However, both the ADHD symptoms and its adverse psychosocial sequelae should dissipate with adequate treatment of ADHD with pharmacotherapy. Persistent depressed or sad affect and preoccupation with suicidal ideas are not typical in patients with only ADHD and may thus serve as a symptomatic clue to the presence of comorbid MDD. McIntosh et al. (2009)19 have compiled an expert consensus of practical assessment strategies that start with a 3-question screen

(“have you ever been diagnosed with ADHD? Do you have a family history of ADHD? Did you have any difficulty in school e did you daydream or have difficulty paying attention? did you get your homework done on time, were you disruptive?”), followed by a functional impairment screen (“Do you currently have substantial difficulties with forgetfulness, attention, impulsivity or restlessness that are interfering with your relationships or your success at work?”). If answers to both of these are positive, then the clinician is encouraged to refine the diagnosis by completing a full diagnostic interview based on the DSM-5 criteria and then to administer the adult ADHD Self-Report Scale (ASRS). A thorough review of the patient’s medical and psychiatric history and collection of data from collateral sources can be of great diagnostic value as well.

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Major Depressive Disorder

TABLE 7.3

Agents With Prominent Noradrenergic Effects That May Be Considered as Off-Label Treatment for ADHD. SNRIs Venlafaxine Desvenlafaxine Duloxetine Levomilnacipran

Noradrenergic and Specific Serotonergic Antidepressants (NaSSA) Mirtazapine

TCAs Desipramine Nortriptyline Protriptyline Imipramine (Metabolites) Amitriptyline (Metabolites)

Norepinephrine dopamine reuptake inhibitor (NDRIs) Bupropion XL

MAOIs Selegiline Isocarboxazid Phenelzine Tranylcypromine

Second-generation antipsychotics (SGAs) Quetiapine

Once the diagnoses of comorbid ADHD and MDD are both established, a sequential treatment strategy based on a hierarchy of greater clinical importance is often appropriate. In this strategy, the clinician treats the more symptomatically severe or functionally impairing disorder firstdthat is, if MDD is the most pressing clinical concern, it is treated first and vice versa. If MDD needs to be addressed first, a trial of antidepressant treatment should be started. If effective, the cognitive impairments associated with MDD should improve together with the affective symptoms. Should the patient still have cognitive difficulties despite improvement in mood symptoms, the cognitive symptoms may then be attributed to a comorbid diagnosis i.e. ADHD that subsequently needs to be treated. When choosing an antidepressant to treat the comorbid ADHD and MDD, the clinician should consider an agent that increases synaptic norepinephrine such as bupropion, (des)venlafaxine, duloxetine, levomilnacipran, and TCAs as these agents work via norepinephrine reuptake inhibition similar to the ADHD-approved atomoxetine.20,21 Atomoxetine has no known antidepressant effect so it should not be a monotherapy approach. Knowing these antidepressants with prominent noradrenergic effects may be helpful in strategizing off-label treatment for ADHD (Table 7.3). Currently, there are no jointly approved medications for MDD and ADHD as there exists for the MDD-anxiety comorbidity. If ADHD is deemed more acute, a trial of long-acting stimulants, guided by riskebenefit discussion and patient preference, is often the next step in management. The use of stimulants to treat MDD may be considered as an off-label option, but there are no definitive data that they are effective as an MDD monotherapy. For patients at risk of substance abuse, nonaddictive alternatives such as the FDA-approved NRI atomoxetine

or alpha 2 agonists (guanfacine or clonidine) are preferred. Once ADHD symptoms improve with these medications, MDD symptoms should be revisited to assess whether further treatment is needed to gain remission of both disorders. Whether treating MDD first or ADHD first, it is often helpful to know how long it takes for each therapeutic option to exert its effect. For example, it can take 2e 6 weeks for antidepressants to become effective,22 while a stimulant titration to an effective dose may take a week.23 Knowing the time course to response may guide the clinician as to which disorder is actually responding to treatment or is most prominent.

SUBSTANCE USE DISORDER SUD is a serious public health concern that commonly co-occurs with MDD. Several epidemiological data confirm the high frequency of co-occurrence. The Epidemiological Catchment Area (ECA) study (n ¼ 20,291) in the 1980’s revealed that the rates of co-occurring alcohol use disorder (AUD) and nonalcohol SUD in patients with MDD were 16.5% and 18.0%, respectively.24 The diagnosis of SUD (either alcohol or drug) almost doubled the risk of having a comorbid MDD when compared to individuals without a history of SUD. The US National Comorbidity Survey (NCS; n ¼ 5877) conducted in the 1990s indicated that individuals with MDD were three times more likely to have a 12-month co-occurrence of SUD and twice as more likely to have a lifetime co-occurrence of SUD compared to the general population.25 The National Study of Alcoholism and Related Conditions (NESARC; n ¼ 43,093) conducted in the early 2000s have yielded even higher rates of co-occurrence with MDD: 3.7 times more likely for AUD and 9.0 times more likely for nonalcohol SUD.26 Putting these results together, the

CHAPTER 7

Psychiatric Comorbidity in Major Depressive Disorder

presence of SUD consistently and remarkably increases the risk of MDD and the converse is also true. Similar to ADHD, SUD often remarkably increases interpersonal stress, social estrangement, and financial distress, making MDD more likely to occur. Regarding different substances of abuse, the lifetime prevalence rates of MDD and AUD (20%e67%), cocaine use disorder (30%e40%), and opioid use disorder (54%) vary.27 Common across these different substances are that the co-occurrence of MDD and SUD leads to greater symptom burden, higher rates of hospitalization and relapse, delayed recovery, and elevated risk of suicide.28e32 Diagnostic refinement regarding these common comorbidities can be made possible through (1) a careful history focusing on the symptom onset chronology of both MDD and SUD and (2) verification of patient history through data from multiple sources (e.g., collateral information from family, physical exam, laboratory tests). Ideally, the patient could be monitored during periods of abstinence from the substance of abuse or during periods of stable affective symptoms for clearer diagnosis. For example, MDD symptoms that follow increases of alcohol daily use or only after a cocaine binge do not strongly support a primary affective disorder but most likely a druginduced depressive state. To do this, knowing the pharmacokinetics of each drug of abuse is essential (e.g., absorption, half-life, etc.). Once the diagnosis of MDD and co-occurring SUD is established, treatment should follow. Three models of treatment exist for addressing co-occurring MDD and SUD: sequential, parallel, and integrated.33 In the sequential treatment, SUD is treated first before targeting the comorbid MDD. In parallel treatment, both disorders are treated simultaneously but by two different clinicians, one for each disorder. For an integrated approach, both disorders are treated by the same clinician/team of clinicians, and there is increasing consensus that integrated treatment most often leads to improved clinical outcomes.34e36 Choice of treatment model often depends on available resources, but regardless of the model, the combination of psychosocial intervention and pharmacotherapy is the cornerstone of treatment.33,37,38 Motivational interviewing (MI),39 CBT,40 and Community Reinforcement Approach (CRA)41 have all shown efficacy for reducing substance misuse and depressive symptoms. Attendance at self-help groups (i.e., Alcoholics Anonymous [AA]) is encouraged and there is some evidence that long-term AA attendance may reduce depressive symptoms.42

95

Regarding pharmacotherapy, adjunctive antidepressant treatment to pharmacotherapy targeting the primary SUD (e.g., buprenorphine, methadone, naltrexone, acamprosate, etc.) may be considered. In several meta-analysis studies, it has been shown that antidepressant treatment may be helpful in improving depressive outcomes in depressed AUD patients but the result was more equivocal for depressed patients with opioid or cocaine use disorder.43,44 It has been proposed that antidepressant treatment may be effective at reducing substance abuse by reducing depressive symptoms but by themselves may not improve substance abuse outcome independent of affective normalization.45 Among antidepressants, TCAs, mirtazapine (NaSSA), and venlafaxine (SNRI) have shown more consistent efficacy than SSRIs. SSRI use is discouraged in patients with MDD and co-occurring early-onset, Babor’s Type B AUD due to its association with worse clinical outcomes.46

PSYCHOTIC DISORDERS Schizophrenia is a severe and chronic mental disorder that affects 1% of the population. Due in part to a striking resemblance of negative symptoms of schizophreniadlack of spontaneous speech or movement, psychomotor retardation, blunted affect, lack of volition, and paucity of social interactionsdwith neurovegetative symptoms in a depressed individual, a comorbid MDD is often missed when treating patients with schizophrenia. It has been suggested that the estimated lifetime prevalence of MDD and schizophrenia is close to 25%,47,48 which is well above the prevalence of MDD in the general population (17%). Schizophrenic patients are already inherently at higher risk of death by suicide, and when combined with depression, these patients are at even greater risk of selfharm.49 In addition, a comorbid schizophrenia and MDD is associated with greater symptom severity and duration, higher frequency of psychotic relapse and rehospitalization, SUD, and diminished quality of life.47,48,50e52 It is therefore important, both clinically and public healthwise, to screen for comorbid MDD when treating schizophrenic patients. Diagnosing MDD in patients with schizophrenia can be challenging due to a long list of differential diagnoses. A systematic way of serially ruling out these possibilities and the patience to carry out this diagnostic investigation over several follow-ups are helpful. Siris and Bench (2007)48 have described a useful list of differential diagnoses and steps to sequentially evaluate this. In this strategy, an organic etiologydincluding

96

Major Depressive Disorder

depressogenic medical problems, medications, substance misuse issuesdis evaluated first, often in collaboration with the primary care physician. Acute psychosocial stressors are also assessed with a close follow-up scheduled. In the follow-up visit, depressive symptoms should have run its course if these were an acute psychological reaction to a proximal psychosocial stressor. Depressive symptoms may also be a marker for early stages of psychotic relapse. Careful screening for covert psychotic symptom emergence, together with antipsychotic adherence evaluation, and, if necessary, dose adjustment, may avert a relapse into a full psychotic decompensation. If the depressive symptoms were not due to an acute psychological stress reaction or a prodromal psychotic relapse, antipsychotic-induced extrapyramidal side effects need to be ruled out. Parkinsonism with bradykinesia and masked facies may mimic MDD. A trial of anticholinergic agents to target bradykinesia may be warranted. In addition, akathisia may present as MDD with anxious distress. A trial of a benzodiazepine or a b-blocker to target akathisia may confirm or dismiss these clinical possibilities. If psychotic symptoms are stable but depressive symptoms persist, a careful antipsychotic dose lowering may be required to rule out the possibility of an antipsychotic-induced dysphoria. Antipsychoticinduced dysphoria, commonly known as neuroleptic dysphoria, is a poorly understood phenomenon that is theorized to result from prefrontal dopamine blockade, causing executive dysfunction and increased negative symptoms from inhibited limbic dopamine neuronal pathways.53 It is equivocal whether a particular antipsychotic is associated with higher or lower incidence of this phenomenon, but using this theory, a lower potency antipsychotic such as quetiapine, iloperidone, clozapine, or olanzapine may theoretically have lower risk of neuroleptic dysphoria. If the psychotic symptoms are stable but the depressive symptoms persist despite above interventions, an adjunctive antidepressant treatment may be considered. SSRIs are usually given initial consideration, though patient preference and riskebenefit considerations should guide the overall selection process. Of note, SSRIs, particularly fluvoxamine, need to be used cautiously with clozapine as they may raise clozapine levels inappropriately via pharmacodynamic drugedrug interaction.54 Tricyclic antidepressants may also be considered but their anticholinergic side effects may be additive to those of concurrent antipsychotic treatment. It should be noted that the evidence base to support the use of adjunctive antidepressant is weak.55,56

A meta-analysis of 82 randomized controlled trials (RCTs; n ¼ 3608)50 examining depression scores for a wide range of antidepressants used in schizophrenics with MDD, did however find a statistically significant modest improvement in depressive symptom outcome (number needed to treat [NNT] ¼ 5) similar to the NNT for individuals diagnosed only with MDD.57 This study was limited by heterogeneity of results, disparate outcome reporting and failure to address multiple confounding factors. Although it is noteworthy that adjunctive antidepressant therapy was safe in combination with antipsychotics in this study, more investigation is needed to establish the efficacy of adjunctive antidepressant treatment for co-occurring schizophrenia and depression. Theoretically, second-generation antipsychotics with known antidepressant effects in MDD/bipolar depression could be preferentially prescribed (e.g., risperidone, olanzapine, quetiapine, aripiprazole, brexpiprazole, lurasidone). Lastly, a concurrent psychosocial intervention, such as CBT for psychosis and vocational rehabilitation, should accompany pharmacotherapy to optimize treatment outcome.58

PERSONALITY DISORDERS Considering the impact of character pathology is important when evaluating patients with MDD. Personality disorders (PDO) are highly prevalent in depressed individuals in both inpatient and outpatient settings. A meta-analysis across 122 studies (n ¼ 24,867) observed the rate of at least one PDO concurrent with MDD at 45%.59 This rate was even higher at 60% for persistent depressive disorder in the same study. The most common PDOs were “cluster C personality disorders” (avoidant, dependent, and obsessive-compulsive) and borderline personality disorder (BPD) as laid out in Table 7.4. The presence of these comorbid personality pathologies, particularly BPD, has been associated with persistent and protracted courses of MDD, higher likelihood of SUD and self-harm behaviors.60 A detailed description of the MDD-PDO interplay and diagnostic assessment is outside the scope of this chapter, but the key to assessing comorbid PDO in depressed patients is the presence of longitudinal symptomatology. Symptoms due to personality pathology are often chronic and enduring whereas symptoms of a pure mood disorder are often limited and episodic. It is not uncommon to take several clinical sessions to link together to arrive at the diagnosis of a PDO. Unfortunately, no medication is remarkably efficacious for PDO per se, but the comorbid depressive episodes may have a better chance of responding to

CHAPTER 7

Psychiatric Comorbidity in Major Depressive Disorder

TABLE 7.4

MDD-PDO Prevalence Rates.59 MDD D Any PDO

45%

MDD D Cluster A PDO

9%

MDD þ Paranoid PDO

7%

MDD þ Schizoid PDO

2%

MDD þ Schizotypal PDO

3%

MDD D Cluster B PDO

19%

MDD þ Antisocial PDO

3%

MDD þ Borderline PDO

14%

MDD þ Histrionic PDO

6%

MDD þ Narcissistic PDO

4%

MDD D Cluster C PDO

30%

MDD þ Avoidant PDO

16%

MDD þ Dependent PDO

10%

MDD þ Obsessive-compulsive PDO

9%

pharmacotherapy with concurrent psychological or psychosocial intervention. Psychosocial treatment is the centerpiece of PDO treatment. Bateman et al. (2015)61 have described the existing evidence-based psychosocial, psychological and pharmacotherapeutic treatment options for a wide range of PDOs. CBT and psychodynamic therapy have been shown to be effective for “cluster C personality disorders” with reports of medium to large positive effect sizes.62,63 No randomized controlled trials of medications have been reported for “cluster C personality disorders.” For BPD, several psychotherapeutic modalitiesddialectical behavioral therapy (DBT),64 mentalization-based therapy (MBT),65 transference-focused therapy (TFT),66 good psychiatric management (GPM),67 and dynamic deconstructive psychotherapy (DDP)68dhave an evidence base to support their use, but these treatments vary widely in their accessibility, time commitment, and cost. It is also unclear how these work when PDO and MDD are comorbid. Drug treatment for BPD should be used cautiously and adjunctively added to psychosocial treatments to target specific symptoms, keeping in mind the risk of intentional overdose.

CONDUCTING A GOOD PSYCHIATRIC REVIEW OF SYSTEMS A good psychiatric review of systems (ROS) can be both useful and critical in identifying patients with

97

comorbid psychiatric disorders. To avoid overlooking a comorbidity, the clinician should assess the patient systematically using a psychiatric ROS, much like the way a nonpsychiatric physician would use a medical ROS. It is often helpful to categorize the psychiatric disorders into eight major clusters: (1) depressive disorders, (2) bipolar disorders, (3) psychotic disorders, (4) anxiety disorders, (5) substance use disorders, (6) personality disorders, (7) ADHD and cognitive disorders, and (8) negative body perception disorders (i.e., eating disorders, somatization disorders). The clinician would then interview regarding each of the disorders with screening questions. A positive response to the screening questions should prompt more thorough follow-up questions guided by the full DSM-5 criteria, and if needed, supplementation with pertinent psychometric scales and collateral information from family and friends, to refine the diagnosis. Useful screening questionnaires adapted from Schwartz (2017)69 are summarized in Table 7.5.

MEASUREMENT-BASED CARE: USE IT! There are several validated rating scales that can supplement the diagnostic interview. Rating scales are completed by the patient or the provider on paper or electronically at each clinical encounter. The same scale should be used consistently so that the clinician can obtain a baseline and follow the trajectory of the symptoms and impairments longitudinally. Abnormal findings should prompt the clinician to make adjustments to the treatment accordingly. The scales vary widely in their sensitivity, specificity, price, and length. For MDD, the Patient Health Questionnaire (PHQ-9), the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), the Beck Depression Inventory (BDI), and the Quick Inventory of Depressive Symptomatology (QIDs) are all valid scales.70,71 For anxiety disorders, Generalized Anxiety Disorder-7 (GAD-7) can be used for GAD, Social Anxiety Questionnaire for Adults (SAQ) or Liebowitz Social Anxiety Scale (LSAS) for SAD, the DSM Severity Measure for Panic Disorder for panic disorder, the PTSD Civilian Checklist (PCL-5) for PTSD, and Obsessive-Compulsive Inventory (OCIR) or Yale-Brown Obsessive-Compulsive Scale (YBOCS) for OCD.71 For ADHD, the Adult ADHD Self-Report Scale (ASRS) is validated and widely used.72 For schizophrenia, the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), and Positive and Negative Syndrome Scale (PANSS) are commonly used.73 For SUD, Alcohol Use Disorders

98

Major Depressive Disorder

TABLE 7.5

Screening Questions for Psychiatric ROS. DEPRESSIVE DISORDERS MDD •

In the last 2 weeks, have you been feeling down, depressed, or hopeless?

•

In the last 2 weeks, have you had little interest or pleasure in doing things?

PDD •

Have you been feeling sad or low more often than not over two or more years continuously?

•

Have you functioned alright despite this?

Premenstrual dysphoric disorder (PMDD) •

Do you typically only get depressed, anxious, or irritable just before and/or during your period?

•

Do you completely recover from these symptoms outside of this timeframe?

MDD with a seasonal pattern •

Do you typically function well all year, and then suffer depression only during the winter months?

BIPOLAR DISORDER •

Have there been times lasting at least 4 days when you felt abnormally high, on top of the world, or overly happy?

•

What about a period lasting at least 4 days when you needed little sleep but were full of energy and never tired despite not sleeping?

PSYCHOTIC DISORDERS •

In your life, have you ever saw or heard things that others cannot or that did not make sense?

•

Have you ever been paranoid or felt people were out to get you, trying to harm you, or following you around?

ANXIETY DISORDERS •

Do you worry, more often than not, continuously about multiple different things for more than 6 months?

•

Do you fear being the center of attention or being scrutinized by others where you feel you will be embarrassed? Do you avoid certain places or events because of this?

•

Do you have panic attacks where you have a sudden rush of physical symptoms such as feeling sweaty, shaky, jittery, and heart beating fast, for no apparent reason?

•

Have you been in a traumatic event like a mugging, assault, natural disaster, car crash, etc., where despite being safe months after, you still had nightmares and recurrent thoughts about the event?

•

Do you have repetitive, intrusive thoughts that are distasteful, bothersome, or disturbing that are hard to dismiss? How about repetitive behaviors like hand washing, checking things, etc., that you feel like cannot stop doing?

SUBSTANCE USE DISORDERS •

Do you drink or use drugs at all? Ever?

•

Have you ever gotten in trouble in relationships, at work, or legally, because you lost control over the amount you used?

ADHD •

Do you often make careless mistakes at home, work, or school because you are not paying attention?

•

Is it hard for you to sit still?

•

What problems do these behaviors cause at school, work or home?

•

How old were you when you began these behaviors?

COGNITIVE DISORDERS •

Do you find yourself losing things more easily? Have you found it difficult to learn new things late?

•

Have you recently noticed any memory problems?

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TABLE 7.5

Screening Questions for Psychiatric ROS.dcont'd EATING DISORDERS •

How do you feel about your weight? What do you make of your body size and how comfortable are you with yourself in this aspect?

•

Do you ever go through short periods of time where you feel compelled to eat tons of food? Have you made yourself throw up after eating?

SOMATIZATION DISORDERS •

In the past several months, have you been persistently bothered by any physical symptoms? How about physical appearance? Or spent a lot of time thinking that you have or will get a serious illness?

Identification Test (AUDIT), and Drug Abuse Screen Test (DAST-10) are helpful and are being increasingly used in primary care settings.74 Alternatively, a clinician may use a single, longer full DSM inventory such as the Psychiatric Diagnostic Screening Questionnaire (PDSQ).75 For PDOs, the Standardized Assessment of Personality-Abbreviated Scale (SAPAS), Personality Diagnostic Questionnaire-4 (PDQ-4), and self-report Iowa Personality Disorder Screen (IPDS) are short and useful.76 Although the use of measurement-based care has been associated with improved outcomes and shorter time to response and remission,77 it is important to note that the use of scales should be thought of as a supplement to, and not a replacement for an empathic, responsive, professional diagnostic interview. Judicious and consistent use of these scales allows for a faster, more focused clinical encounters during which the clinician can use the remaining time for rapportbuilding, informed consent, safety assessment, and use core psychotherapy techniques such as motivational interviewing to improve clinical outcome.

CONCLUDING REMARKS The co-occurrence of MDD and other psychiatric disorders is quite common. The clinical implications generally amount to greater symptom severity and worsened longitudinal course and poorer outcome. Despite the high frequency of co-occurrence and clinical implications, there is yet limited prospective research aimed at identifying overlapping etiologic commonalities and improving treatment outcome. The joint occurrence of MDD and psychiatric disorders remains an underexplored therapeutic frontier that may offer opportunities for refining disease models and improving clinical outcome in this population with clearly unmet treatment needs.

DISCLOSURE Authors have no conflicts of interest to disclose.

REFERENCES 1. Johansson R, Carlbring P, Heedman A, Paxling B, Andersson G. Depression, anxiety and their comorbidity in the Swedish general population: point prevalence and the effect on health-related quality of life. Peer J. 2013;1: e98. 2. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12month DSM-IV disorders in the national comorbidity survey replication. Arch Gen Psychiatr. 2005;62(6):617e627. 3. Lamers F, van Oppen P, Comijs HC, et al. Comorbidity patterns of anxiety and depressive disorders in a large cohort study: The Netherlands Study of Depression and Anxiety (NESDA). J Clin Psychiatry. 2011;72(3):341e348. 4. Kessler RC, Sampson NA, Berglund P, et al. Anxious and non-anxious major depressive disorder in the World Health Organization World Mental Health Surveys. Epidemiol Psychiatr Sci. 2015;24(3):210e226. 5. 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(23):3095e3105. 6. de Graaf R, Bijl RV, Smit F, Vollebergh WA, Spijker J. Risk factors for 12-month comorbidity of mood, anxiety, and substance use disorders: findings from The Netherlands Mental Health Survey and Incidence Study. Am J Psychiatry. 2002;159(4):620e629. 7. Penninx BW, Nolen WA, Lamers F, et al. Two-year course of depressive and anxiety disorders: results from The Netherlands Study of Depression and Anxiety (NESDA). J Affect Disord. 2011;133(1e2):76e85. 8. Kessler R, White LA, Birnbaum H, et al. Comparative and interactive effects of depression relative to other health problems on work performance in the workforce of a large employer. J Occup Environ Med. 2008;50(7): 809e816. 9. McIntyre RS, Rosenbluth M, Ramasubbu R, et al. Managing medical and psychiatric comorbidity in individuals

100

10.

11.

12. 13.

14.

15.

16.

17.

18. 19.

20.

21.

22.

23.

24.

Major Depressive Disorder

with major depressive disorder and bipolar disorder. Ann Clin Psychiatr. 2012;24(2):163e169. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008; 165(3):342e351. Arch JJ, Eifert GH, Davies C, Plumb Vilardaga JC, Rose RD, Craske MG. Randomized clinical trial of cognitive behavioral therapy (CBT) versus acceptance and commitment therapy (ACT) for mixed anxiety disorders. J Consult Clin Psychol. 2012;80(5):750e765. Fonagy P. The effectiveness of psychodynamic psychotherapies: an update. World Psychiatry. 2015;14(2):137e150. Thomas R, Sanders S, Doust J, Beller E, Glasziou P. Prevalence of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Pediatrics. 2015;135(4): e994e1001. Kessler RC, Adler LA, Barkley R, et al. Patterns and predictors of attention-deficit/hyperactivity disorder persistence into adulthood: results from the national comorbidity survey replication. Biol Psychiatry. 2005;57(11):1442e1451. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163(4):716e723. Biederman J, Ball SW, Monuteaux MC, et al. New insights into the comorbidity between ADHD and major depression in adolescent and young adult females. J Am Acad Child Adolesc Psychiatry. 2008;47(4):426e434. Gjervan B, Torgersen T, Nordahl HM, Rasmussen K. Functional impairment and occupational outcome in adults with ADHD. J Atten Disord. 2012;16(7):544e552. Furczyk K, Thome J. Adult ADHD and suicide. Attention deficit and hyperactivity disorders. 2014;6(3):153e158. McIntosh D, Kutcher S, Binder C, Levitt A, Fallu A, Rosenbluth M. Adult ADHD and comorbid depression: a consensus-derived diagnostic algorithm for ADHD. Neuropsychiatr Dis Treat. 2009;5:137e150. Wilens TE, Spencer TJ, Biederman J, et al. A controlled clinical trial of bupropion for attention deficit hyperactivity disorder in adults. Am J Psychiatry. 2001;158(2):282e288. Park P, Caballero J, Omidian H. Use of serotonin norepinephrine reuptake inhibitors in the treatment of attention-deficit hyperactivity disorder in pediatrics. Ann Pharmacother. 2014;48(1):86e92. Lam RW. Onset, time course and trajectories of improvement with antidepressants. Eur Neuropsychopharmacol. 2012;22(suppl 3):S492eS498. Medori R, Ramos-Quiroga JA, Casas M, et al. A randomized, placebo-controlled trial of three fixed dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2008;63(10):981e989. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA. 1990;264(19):2511e2518.

25. Kessler RC, Nelson CB, McGonagle KA, Edlund MJ, Frank RG, Leaf PJ. The epidemiology of co-occurring addictive and mental disorders: implications for prevention and service utilization. Am J Orthopsychiatry. 1996; 66(1):17e31. 26. Hasin DS, Goodwin RD, Stinson FS, Grant BF. Epidemiology of major depressive disorder: results from the national epidemiologic survey on alcoholism and related conditions. Arch Gen Psychiatr. 2005;62(10): 1097e1106. 27. Ross S. Substance abuse and mental illness. In: The American Psychiatric Publishing Textbook of Substance Abuse Treatment. American Psychiatric Publishing; 2014. 28. Hser YI, Grella C, Evans E, Huang YC. Utilization and outcomes of mental health services among patients in drug treatment. J Addict Dis. 2006;25(1):73e85. 29. Cornelius JR, Salloum IM, Mezzich J, et al. Disproportionate suicidality in patients with comorbid major depression and alcoholism. Am J Psychiatry. 1995;152(3): 358e364. 30. Bovasso GB. Cannabis abuse as a risk factor for depressive symptoms. Am J Psychiatry. 2001;158(12):2033e2037. 31. Havard A, Teesson M, Darke S, Ross J. Depression among heroin users: 12-Month outcomes from the Australian Treatment Outcome Study (ATOS). J Subst Abus Treat. 2006;30(4):355e362. 32. Landheim AS, Bakken K, Vaglum P. Impact of comorbid psychiatric disorders on the outcome of substance abusers: a six year prospective follow-up in two Norwegian counties. BMC Psychiatry. 2006;6(1):44. 33. Kim Y, Hack LM, Ahn ES, Kim J. Practical outpatient pharmacotherapy for alcohol use disorder. Drugs Context. 2018; 7:212308. 34. Weiss RD, Griffin ML, Kolodziej ME, et al. A randomized trial of integrated group therapy versus group drug counseling for patients with bipolar disorder and substance dependence. Am J Psychiatry. 2007;164(1):100e107. 35. Mangrum LF, Spence RT, Lopez M. Integrated versus parallel treatment of co-occurring psychiatric and substance use disorders. J Subst Abus Treat. 2006;30(1):79e84. 36. Lydecker KP, Tate SR, Cummins KM, McQuaid J, Granholm E, Brown SA. Clinical outcomes of an integrated treatment for depression and substance use disorders. Psychol Addict Behav. 2010;24(3):453e465. 37. Reus VI, Fochtmann LJ, Bukstein O, et al. The American psychiatric association practice guideline for the pharmacological treatment of patients with alcohol use disorder. Am J Psychiatry. 2018;175(1):86e90. 38. Murthy P, Chand P. Treatment of dual diagnosis disorders. Curr Opin Psychiatr. 2012;25(3):194e200. 39. Satre DD, Leibowitz A, Sterling SA, Lu Y, Travis A, Weisner C. A randomized clinical trial of Motivational Interviewing to reduce alcohol and drug use among patients with depression. J Consult Clin Psychol. 2016;84(7): 571e579. 40. Hides L, Samet S, Lubman DI. Cognitive behaviour therapy (CBT) for the treatment of co-occurring depression

CHAPTER 7

41.

42.

43.

44.

45. 46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

Psychiatric Comorbidity in Major Depressive Disorder

and substance use: current evidence and directions for future research. Drug Alcohol Rev. 2010;29(5):508e517. Higgins ST, Sigmon SC, Wong CJ, et al. Community reinforcement therapy for cocaine-dependent outpatients. Arch Gen Psychiatr. 2003;60(10):1043e1052. Wilcox CE, Pearson MR, Tonigan JS. Effects of long-term AA attendance and spirituality on the course of depressive symptoms in individuals with alcohol use disorder. Psychol Addict Behav. 2015;29(2):382e391. Torrens M, Fonseca F, Mateu G, Farre M. Efficacy of antidepressants in substance use disorders with and without comorbid depression. A systematic review and meta-analysis. Drug Alcohol Depend. 2005;78(1):1e22. Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA. 2004;291(15):1887e1896. Nunes E, Weiss R. Co-occurring addiction and affective disorders. In: Principles of addiction medicine. 4. 2009. Dundon W, Lynch KG, Pettinati HM, Lipkin C. Treatment outcomes in type A and B alcohol dependence 6 months after serotonergic pharmacotherapy. Alcohol Clin Exp Res. 2004;28(7):1065e1073. Buckley PF, Miller BJ, Lehrer DS, Castle DJ. Psychiatric comorbidities and schizophrenia. Schizophr Bull. 2009; 35(2):383e402. Siris SG, Bench C. Depression and schizophrenia. In: Hirsch SR, R WD, eds. Schizophrenia. Malden, MA: Blackwell Publishing Company; 2007:142e167. Popovic D, Benabarre A, Crespo JM, et al. Risk factors for suicide in schizophrenia: systematic review and clinical recommendations. Acta Psychiatr Scand. 2014;130(6): 418e426. Johnson DA. The significance of depression in the prediction of relapse in chronic schizophrenia. Br J Psychiatry. 1988;152:320e323. Mandel MR, Severe JB, Schooler NR, Gelenberg AJ, Mieske M. Development and prediction of postpsychotic depression in neuroleptic-treated schizophrenics. Arch Gen Psychiatr. 1982;39(2):197e203. Sim K, Mahendran R, Siris SG, Heckers S, Chong SA. Subjective quality of life in first episode schizophrenia spectrum disorders with comorbid depression. Psychiatr Res. 2004;129(2):141e147. Awad AG, Voruganti LN. Neuroleptic dysphoria: revisiting the concept 50 years later. Acta Psychiatr Scand Suppl. 2005; (427):6e13. Centorrino F, Baldessarini RJ, Frankenburg FR, Kando J, Volpicelli SA, Flood JG. Serum levels of clozapine and norclozapine in patients treated with selective serotonin reuptake inhibitors. Am J Psychiatry. 1996;153(6): 820e822. Buoli M, Serati M, Ciappolino V, Altamura AC. May selective serotonin reuptake inhibitors (SSRIs) provide some benefit for the treatment of schizophrenia? Expert Opin Pharmacother. 2016;17(10):1375e1385. Helfer B, Samara MT, Huhn M, et al. Efficacy and safety of antidepressants added to antipsychotics for schizophrenia:

57.

58.

59.

60.

61. 62.

63.

64.

65.

66.

67.

68.

69. 70. 71.

101

a systematic review and meta-analysis. Am J Psychiatry. 2016;173(9):876e886. Gibbons RD, Hur K, Brown CH, Davis JM, Mann JJ. Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine. Arch Gen Psychiatr. 2012;69(6):572e579. Turner DT, van der Gaag M, Karyotaki E, Cuijpers P. Psychological interventions for psychosis: a meta-analysis of comparative outcome studies. Am J Psychiatry. 2014; 171(5):523e538. Friborg O, Martinsen EW, Martinussen M, Kaiser S, Overgard KT, Rosenvinge JH. Comorbidity of personality disorders in mood disorders: a meta-analytic review of 122 studies from 1988 to 2010. J Affect Disord. 2014; 152e154:1e11. Yoshimatsu K, Palmer B. Depression in patients with borderline personality disorder. Harv Rev Psychiatry. 2014;22(5):266e273. Bateman AW, Gunderson J, Mulder R. Treatment of personality disorder. Lancet. 2015;385(9969):735e743. Svartberg M, Stiles TC, Seltzer MH. Randomized, controlled trial of the effectiveness of short-term dynamic psychotherapy and cognitive therapy for cluster C personality disorders. Am J Psychiatry. 2004;161(5):810e817. Simon W. Follow-up psychotherapy outcome of patients with dependent, avoidant and obsessive-compulsive personality disorders: a meta-analytic review. Int J Psychiatry Clin Pract. 2009;13(2):153e165. van den Bosch LM, Verheul R, Schippers GM, van den Brink W. Dialectical Behavior Therapy of borderline patients with and without substance use problems. Implementation and long-term effects. Addict Behav. 2002; 27(6):911e923. Bateman A, Fonagy P. Randomized controlled trial of outpatient mentalization-based treatment versus structured clinical management for borderline personality disorder. Am J Psychiatry. 2009;166(12):1355e1364. Clarkin JF, Levy KN, Lenzenweger MF, Kernberg OF. Evaluating three treatments for borderline personality disorder: a multiwave study. Am J Psychiatry. 2007;164(6): 922e928. Gunderson J, Masland S, Choi-Kain L. Good psychiatric management: a review. Curr Opin Psychol. 2018;21: 127e131. Gregory RJ, DeLucia-Deranja E, Mogle JA. Dynamic deconstructive psychotherapy versus optimized community care for borderline personality disorder co-occurring with alcohol use disorders: a 30-month follow-up. J Nerv Ment Dis. 2010;198(4):292e298. Schwartz TL. Practical Psychopharmacology: Basic to Advanced Principles. 2017. Furukawa TA. Assessment of mood: guides for clinicians. J Psychosom Res. 2010;68(6):581e589. Baer L, Blais MA. Handbook of Clinical Rating Scales and Assessment in Psychiatry and Mental Health. New York: Humana; 2012.

102

Major Depressive Disorder

72. Kessler RC, Adler L, Ames M, et al. The World Health Organization Adult ADHD Self-Report Scale (ASRS): a short screening scale for use in the general population. Psychol Med. 2005;35(2):245e256. 73. Mortimer AM. Symptom rating scales and outcome in schizophrenia. Br J Psychiatr Suppl. 2007;50:s7e14. 74. Maisto SA, Carey MP, Carey KB, Gordon CM, Gleason JR. Use of the AUDIT and the DAST-10 to identify alcohol and drug use disorders among adults with a severe and persistent mental illness. Psychol Assess. 2000;12(2):186e192.

75. Zimmerman M, Mattia JI. The psychiatric diagnostic screening questionnaire: development, reliability and validity. Compr Psychiatr. 2001;42(3):175e189. 76. Germans S, Van Heck GL, Hodiamont PP. Results of the search for personality disorder screening tools: clinical implications. J Clin Psychiatry. 2012;73(2):165e173. 77. Guo T, Xiang YT, Xiao L, et al. Measurement-based care versus standard care for major depression: a randomized controlled trial with blind raters. Am J Psychiatry. 2015; 172(10):1004e1013.