To this point, from Chapters 1, 2, 3, you have learned about the frequent physical symptom presentation of mental health problems in medical settings. And you have heard about the overarching treatment model, the Mental Health Care Model (MHCM), that guides treatment of all mental disorders. We now begin to provide the details, especially of medications, for the first of the three mental health problems medical clinicians will need to address in the future—depression.
The theme of this book is that all physicians require competence with common mental health problems, such as depression, not to the level of becoming psychiatrists but equivalent to their competence with, for example hypertension, asthma, or diabetes.1 Given the shortage of psychiatrists,2 many believe that medical physicians can provide effective treatment for “treatment-responsive” depression, which we will define for you later in this chapter.3
This chapter provides you with tools to recognize and manage depression in its many forms.
Depression is the leading cause of disease burden, work disability, and death by suicide worldwide and, yet, most patients go untreated.4,5 An estimated 350 million people are affected. In the United States, approximately 7% of the population has depression, a rate that is even higher in females and young people.6 One in every 5 women and 1 in every 10 men are affected, and the prevalence increases with each successive birth cohort and progressively with older age, affecting 9% of the elderly living in the community, and 25% of those living in institutions. Among older adults, the presence of depression also is associated with increased chronic disease burden 10 years later.7 The economic impact in the United States is estimated at $210 billion per year.8 There are additional personal costs to families,9 and research demonstrates that effective treatment can save over $5 for every $1 spent on treatment.10
Indeed, treatment has been demonstrated to be very effective in multiple clinical trials, including a recent meta-analysis.11 Not only do antidepressants help for psychological symptoms, but they also have been demonstrated to improve medical outcomes, for example improved survival following an acute coronary syndrome.12 Risk factors for depression include economic poverty, being single, a history of abuse (emotional, physical, or sexual), and a family history of depression. Recent data indicate that severe affective disturbances during adolescence are associated with increased premature mortality—indicating the need for early intervention.13
Depressive disorders have been recognized since antiquity. In Hippocratic writings, melancholia (black bile) was attributed to disrupted humoral balance. In the 1960s, the amine hypothesis emerged following the discovery of antidepressant medications. Depressed patients had lower levels of urinary metabolites of the indoleamine serotonin and the catecholamine norepinephrine. In the 1980s, it was observed that depressed patients displayed aberrant hypothalamic-pituitary-adrenal (HPA) function: they had higher serum levels of cortisol and a failure to suppress cortisol following administration of dexamethasone. The dexamethasone suppression test emerged as a possible biomarker for depression. In the 1990s, the inflammatory model emerged. Patients with depression were found to have elevated levels of inflammatory markers such as C-reactive protein, interleukin-6, and tumor necrosis factor. It was later discovered that these factors impede the synthesis of neurotransmitters, enhance glutamate neurotoxicity, and impede hippocampal neurogenesis. With effective treatment, levels of inflammatory markers decline, and neuroplasticity is restored.
The pathogenesis of depressive disorders is multifactorial and reflects the interplay of many biopsychosocial factors important to treatment. From Table 4-1, for example, you may find that a patient who is depressed has adverse biological predisposing factors (such as a family history of depression and refractory diabetes), psychological factors (learned helplessness), and social contributors (childhood trauma). On the other extreme, such adverse influences could perhaps be offset by aerobic exercise (biological), mindfulness meditation (psychological), and networking (social). This is an example of the biopsychosocial model you learned about in Chapter 3.14
|Social||Childhood trauma or neglect|
Loss of employment
DIAGNOSIS AND TREATMENT ISSUES COMMON TO ALL DEPRESSIVE DISORDERS
There are over a dozen recognized variants of depression in the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) (Table 4-2).6 We will focus primarily on the most common problem—major depressive disorder. Then we consider briefly the less common disorders. Last, we’ll consider bipolar disorder in considerable detail. While it has similarities to other depressive disorders, its differences are greater than among the other depressive disorders.6,15
Depression is a heterogenous group of disorders that share hallmark symptoms of low mood, lack of interest, and diminished pleasure. As you know from Chapters 1 and 2, many depressed patients also will present with physical symptoms of an underlying physical disease or as a manifestation of medically unexplained symptoms, with chronic pain being among the most common.
In addition to having common symptom presentations, the depressive disorders have common treatment approaches.
You’ve already learned the MHCM in Chapter 3; see Figure 4-1. It applies to all health care disorders but is especially useful in patients with mental disorders. Here is a very brief summary: the centerpiece of the MHCM is the patient-centered interaction (PCI),16 which maximizes communication and the clinician-patient relationship. The first of the four spokes of the model is education, which involves determining the patient’s understanding of their disorder, clarifying any misunderstandings and providing your general recommendation for treatment. Second, you obtain a commitment to treatment, emphasizing the patient’s responsibility as well as your own. Third, we develop the patient’s long-range goals for care, such as what he/she would like to do if they were not ill. The fourth dimension of treatment is negotiating a treatment plan. This includes the specific pharmacologic and non-pharmacologic treatments unique to the mental health disorder—which in this chapter is depression.
Fortunately, the medications and non-pharmacologic approaches for most depressive disorders are the same, and the medications are used in similar doses. As you’ll learn in Chapter 5, the medications for anxiety disorders also are much the same as those used for depression—but in lower starting doses. You thus can learn a few of these medications and apply that knowledge to both depression and anxiety disorders. You will need to understand these medications as well as you now understand medications for hypertension and diabetes. We will provide clear instructions to guide you in mastering them.
MAJOR DEPRESSIVE DISORDER
Major depressive disorder is the most prevalent and serious of the depressive disorders. The diagnosis is characterized by at least 5 of the 9 following depressive symptoms during a 2-week period, which must include 1 of the first 2 criteria listed: (1) a sad or depressed mood; (2) lack of interest or pleasure (anhedonia); (3) insomnia or hypersomnia; (4) lack of energy and tiredness; (5) loss of appetite or excessive appetite; (6) guilt or self-loathing; (7) difficulty concentrating; (8) psychomotor agitation or retardation; and (9) feelings of hopelessness or thoughts of dying or self-harm.
To make the diagnosis of major depressive disorder, the symptoms must create significant dysfunction and not be otherwise explainable by medications or a medical disorder. Table 4-3 summarizes the DSM-5 diagnostic criteria.6
What exactly might the clinician say to identify these symptoms of depression if they don’t arise spontaneously in the patient-centered portion of the interaction. One uses the physician-centered skills of direct inquiry, relying on closed-ended questioning. For example, in a patient with chronic pain who has mentioned nothing about depression, you can explore with very direct and specific questions. Here are some examples.
“How’s your mood, you know, have you felt depressed?”
“Have you been feeling sad or having crying spells with all this pain?”
“What do you like to do for fun, the things you do for pleasure?” (This key question gets at the criterion for lack of pleasure in one’s life, so-called anhedonia.)
“How’s your sleep been? How long does it take to get to sleep? Do you waken and are unable to get back to sleep?”
“What’s your energy level, is it up to par, can you do as much as in the past when you felt well?”
“How’s your appetite and weight with all this trouble?”
“When you awaken at night or at other times, what kinds of thoughts go through your mind, do you feel guilty or are you critical of yourself?”
“How’s your ability to concentrate on something when you need to?”
“Do you get agitated or the opposite when you just can’t get the energy to do anything?”
“Do you ever feel like there’s just no hope?”
“How solid are your relationships with…spouse…children…friends?”
“Have you ever thought of harming or injuring yourself, or does taking your life ever cross your mind?”
Shown in Table 4-4, the Patient Health Questionnaire-9 (PHQ-9) is a reliable, valid, and well established measure that represents the 9 DSM-5 diagnostic criteria for Major Depressive Disorder. There is a minimum score of 0 and a maximum score of 27. Normal = 0 to 4; mild depression = 5 to 9; moderate depression = 10 to 14; severe depression = 15 to 19; very severe depression = 20 or more.17 Thus, easier to remember cut-points are 5, 10, 15, and 20. Many clinics use the PHQ-9 routinely to identify depressed patients, and it should be performed in all patients where there is suspicion of depression; it’s useful for following patients’ progress as well as for diagnosis. Some guidelines recommend annual screening for depression in all adults.18
|Over the last 2 weeks, how often have you been bothered by any of the following problems?|
Not at all
More than half the days
Nearly every day
|1. Little interest or pleasure in doing things||❑||❑||❑||❑|
|2. Feeling down, depressed, or hopeless||❑||❑||❑||❑|
|3. Trouble falling or staying asleep, or sleeping too much||❑||❑||❑||❑|
|4. Feeling tired or having little energy||❑||❑||❑||❑|
|5. Poor appetite or overeating||❑||❑||❑||❑|
|6. Feeling bad about yourself—or that you are a failure or have let yourself or your family down||❑||❑||❑||❑|
|7. Trouble concentrating on things, such as reading the newspaper or watching television||❑||❑||❑||❑|
|8. Moving or speaking so slowly that other people could have noticed? Or the opposite—being so fidgety or restless that you have been moving around a lot more than usual||❑||❑||❑||❑|
|9. Thoughts that you would be better off dead or of hurting yourself in some way||❑||❑||❑||❑|
|Add the score from each column|
|Add column scores =||Total Score = ________|
The Patient Health Questionnaire-2 (PHQ-2) comprises just the first 2 items of the PHQ-9, and can be self-administered via a patient portal or by the clinician during the visit. A score of 3 or more has a sensitivity of greater than 80% for the diagnosis of major depressive disorder. A patient who endorses a positive response with either item on the PHQ-2 scale should complete the PHQ-9.
In Table 4-5, we present commonly used antidepressants, the starting and therapeutic doses used, and the side effects. Effective in all age groups and all levels of depression severity,19 they are classified as selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), and a miscellaneous group of various mechanisms labeled “other.” You’ll see how we use medications from each of these pharmacological classes.
|Antidepressant Medications||Antidepressant Side Effects|
|Class||Initial Dosea (mg/d)||Therap. Dose (mg/d)||Half-Life||Sedation||Weight Gain||Sexual||Cardiac||Anticholinergic||Seizures||Drug Interactionb|
2D6 inhibitor +/−
At high doses only
2D6 inhibitor 4+
Incr. flecainide and β-blocker level
|20||20-60||Short||+/−||+||++||QTc increased||−||−||Incr. flecainide level|
|10||10-20||Short||−||+||++||QTc increased||−||−||Incr. flecainide level|
2D6 inhibitor 4+
Incr. flecainide and β-blocker level
Increased BP & heart
|−||−||Decr. Indinavir level|
|30||30-60||Short||−||+/−||+++||+/−||−||−||2D6 inhibitor 1+|
|+++||+++||2D6 inhibitor 1+|
|−||−||−||+ Increased BP||+++||+++|
|150||300-450||−||−||−||+ Increased BP||+++||+++|
Despite the different mechanisms of action, all antidepressants are equally effective in alleviating the core symptoms of depression. This means that selecting which one to use depends on the other factors we now review.
Side effects: It is important to avoid adverse side effects (see Table 4-5), especially if they may aggravate a preexisting medical condition. For instance, you might avoid mirtazapine because it can increase appetite and weight and impair glycemic control in an obese patient with diabetes. Conversely, the side effects of increased appetite and sedation associated with mirtazapine may benefit patients receiving cancer chemotherapy who have lost appetite, become cachectic, and experience trouble sleeping. Another example is the orgasmic delay commonly associated with the SSRIs paroxetine and fluoxetine. It may be unacceptable for some patients, but it can be beneficial in men affected by premature ejaculation.
Nocebo effect: Some patients experience adverse effects from low doses of many medications and require special attention. The expectation of an adverse effect is called the nocebo effect, the opposite of a placebo effect.20-22 It is important to distinguish it from a true adverse effect because it does not require a medication change. The nocebo effect is more commonly observed in patients who have experienced adverse effects with previous drugs of many types (“…I just can’t handle medications, I’m allergic to everything…”) and in patients with chronic depression or anxiety. The nocebo effect has caused great problems with adherence to antidepressant medications and we work hard to offset it; this is where the MHCM comes in. Initially anticipating and addressing the problem is key when starting an antidepressant. It works best to start with a low dose and increase the dose more gradually than usual into the therapeutic range. Initially, we explain to the patient that they likely will have some jitteriness, dry mouth, and constipation (expected side effects) but that the symptoms usually clear in a week or so. We then strongly advise them not to stop the medication if they have any problems. Instead, we ask them to call and we typically will reduce the dose.
Possible drug interactions: Some antidepressants interfere with the metabolism of drugs concurrently prescribed for a physical or psychiatric illness. For instance, as in Table 4-5, the SSRIs fluoxetine and paroxetine taken by a patient on the β-blocker metoprolol for hypertension can lead to a twofold increase in serum levels of metoprolol, resulting in postural hypotension; this, in turn, may then be inadvertently attributed to the SSRI.23-25 The full effect of a drug inhibitory interaction also may not be fully realized until it achieves a steady state. Since fluoxetine has a prolonged half-life, the peak effect on blood pressure may only be apparent 1 to 2 weeks following its initiation.
Patient preference: Even a patient who has never previously received a prescription for an antidepressant medication may have strong opinions about the efficacy and side effects of one drug over another.3 As you recall from the MHCM, we need first to understand the patient and their concerns for a treatment to be successful. For example, direct-to-consumer advertising and personal stories about benefits and adverse effects may convey an understanding counter to scientific evidence. Also, some patients voice a strong preference for a nonsedating or weight sparing compound. Others express a preference for a medication that does not produce sexual dysfunction.
Past history or family history of antidepressant response: Make a detailed inventory of previous medications: duration, dosage, adverse effects, and response. It is reasonable to reinstitute an antidepressant that has worked in the past. However, if the patient has tried numerous drugs and failed to respond to any, or has experienced adverse effects, it is wise to choose a different agent from a different therapeutic class. For instance, a patient who has failed to respond to previous trials of the SSRIs fluoxetine, paroxetine, and citalopram, may benefit from an SNRI such as duloxetine or venlafaxine, rather than an alternative SSRI such as sertraline. Antidepressant responses are heritable and a history of response to a specific antidepressant in a first-degree relative may suggest an initial choice.
Presence of concurrent psychiatric or medical disorders (eg, panic disorder, neuropathic pain, hypertension): While we’ve said antidepressants are equally effective in the management of depression, they may vary somewhat in the spectrum of therapeutic activity. Food and Drug Administration (FDA) approval reflects this variation and it may be reasonable to begin with a medication they approve. For instance, while all SSRIs are commonly prescribed for panic disorder, only sertraline, paroxetine, and fluoxetine are approved for this indication. In addition to the depression spectrum, several of these medications have therapeutic impacts on various medical disorders. The SSRI paroxetine is approved for managing vasomotor symptoms in perimenopausal women. Bupropion is approved for smoking cessation and winter depression. In addition, it has demonstrated efficacy in the management of ADHD. SNRIs may be more effective in managing musculoskeletal and neuropathic pain syndromes. Duloxetine specifically has been reported effective in the treatment of stress urinary incontinence. Conversely, at high doses, the SNRI venlafaxine is associated with an elevation of blood pressure and should not be an initial choice in the patient with poorly controlled hypertension. Table 4-6 summarizes the current FDA approval status of several commonly used antidepressants.26
Safety in overdose: The old tricyclic antidepressants (TCA) fell into disfavor following the introduction of less toxic SSRIs, SNRIs, and the other new antidepressants. The medical consequences of a TCA drug overdose are more serious than overdose with the newer antidepressant compounds. For this reason, although of equivalent antidepressant effect, TCAs are not considered first-line agents any longer and are reserved for patients who fail to respond to several trials of newer and safer compounds. Similarly, the old monoamine oxidase inhibitors have severe side effect profiles, and we recommend that you never use them.
Cost: Considering that all antidepressants are equally effective it is reasonable to initiate treatment with an inexpensive generic formulation. All the SSRIs, the majority of SNRIs, mirtazapine, and bupropion are available in inexpensive generic formulations. There is no evidence that the newer, expensive antidepressant compounds are superior to generic agents.
Gender: Women are more susceptible to depression than men and experience more recurrences and treatment resistance. A variety of psychosocial and biological (neuroendocrine) factors have been implicated in this gender discrepancy. Treating depression during pregnancy and lactation requires knowledge of teratogenicity and fetal toxicity and the excretion of compounds in breast milk. Prenatal exposure to the SNRI venlafaxine is associated with an increased risk of hypertensive disorders of pregnancy. Paroxetine is associated with a higher risk of cardiovascular malformations as compared to other SSRIs. The pharmacokinetic profiles of breast milk excretion have been defined, and SSRIs sertraline and paroxetine are first line choices, but other medications also can be used because the effect on the infant is small. Mothers need not discontinue either breastfeeding or taking an antidepressant.27
|FDA Indications Other Than MDDa|
|Sertraline (Zoloft)||OCD, PD, PTSD, PMDD, SAD|
|Fluoxetine (Prozac)||OCD, BN, PD|
|Paroxetine (Paxil)||OCD, PD, SAD, PTSD, GAD, PMDD,|
|Venlafaxine (Effexor)||GAD, SAD, PD|
|Duloxetine (Cymbalta)||DNP, FM, GAD, CMP|
|Other New Antidepressants|
|Bupropion (Wellbutrin, Zyban)||WD, SC|
There are 3 essential considerations at the outset of treatment:
Avoiding early discontinuation
Reaching a therapeutic dose
In Table 4-7, we outline an initial medication treatment cycle using two different examples in patients with the common pattern of depression associated with insomnia. It highlights ensuring adherence, achieving a therapeutic dose, and managing insomnia. Finally, it indicates an endpoint of the treatment cycle at 8-12 weeks, as discussed later.
|Visita||PHQ-9||Key Issuesb||Dosing Example 1||Dosing Example 2|
Explain adverse effectsc
Sertraline 50 mg (subtherapeutic dose)
Trazodone 50 mg
|Mirtazapine 15 mg (low therapeutic dose)|
|Week 1||≥ 10|
Sertraline 75 mg (still subtherapeutic dose)
Trazodoned: increase if not sleeping through night; reduce dose if too sleepy
|Mirtazapine 15 mg: if too sleepy, change to SSRI or SNRI and use trazodone for sleep|
|Week 2||≥ 10|
Sertraline 100 mg (low therapeutic dose)
Adjust trazodone for sleep
Mirtazapine 30 mg (average therapeutic dose)
(if sleepy, stay at 15 mg)
|Week 3 or 4|
Sertraline 100 mg (increase to 150 mg if no response)
Adjust trazodone for sleep
|Mirtazapine 30 mg (if sleepy, stay at 15 mg)|
|Week 5 or 6|
|No change unless need to adjust trazodone||No change unless need to adjust mirtazapine for sleep|
Week 8-12e decision
1. < 10
2. ≥ 10
3. No change
1. Full remission
2. Partial remission
1. Continue present regimen
2. Increase sertraline to 200 or add “Other” medication
3. Completely change medication regimen
1. Continue present regimen
2. Increase mirtazapine to 45 mg or add SNRI or SSRI
3. Completely change medication regimen
A critical first treatment goal is achieving adherence to medications. Following a diagnosis of depression, rates of early discontinuation exceed 30% for specialists as well as medical clinicians.28 Adverse effects and the nocebo effect commonly lead patients to discontinue the medication, as does a poor clinician-patient relationship.29
A second major task of initial treatment is to ensure that you achieve a therapeutic dose of the antidepressant you selected. Research indicates that most clinicians fail to prescribe full therapeutic doses.5,30 Table 4-5 depicts starting and therapeutic doses of the antidepressants, and Table 4-7 provides specific examples for ensuring full therapeutic doses of two different medications. We generally start with a subtherapeutic dose to reduce side effects and, consistent with its toleration, gradually increase to a full therapeutic dose.
A third important focus of initial management is insomnia, defined as needing more than 30 minutes to fall asleep (initial insomnia) or to get back to sleep after awakening (maintenance insomnia) or being unable to return to sleep after awakening (terminal insomnia). Insomnia is present in most depressed patients and is terribly debilitating. We need to get them sleeping through the night. This achievement alone makes patients feel much better, well before the antidepressant takes effect, and greatly enhances their trust in you and their cooperation with other aspects of treatment. As in the two examples in Table 4-7, we recommend 2 ways for addressing insomnia in addition to the sleep hygiene measures outlined as part of the MHCM in Chapter 3.
Mirtazapine has prominent sleep-promoting side effect and is a good choice for patients with prominent insomnia. You also may achieve lesser sedation with SSRIs sertraline, citalopram, and paroxetine.
Alternatively, you may want to avoid the weight gain that can occur with mirtazapine. In this case, we recommend trazodone. It is an atypical antidepressant with a sleep-promoting side effect so strong that trazodone cannot be used in antidepressant doses. It is useful, however, as a “sleeping pill” when used in conjunction with an SSRI or SNRI. We typically begin at 50 mg at bedtime and increase the dose once or twice weekly by 25 to 50 mg increments until the patient is sleeping through the night, seldom needing more than 100 to 150 mg. Trazodone sometimes can cause sleepiness in the mornings, and we address this by moving the dose from bedtime to several hours before bedtime, say, at supper time. Trazodone is given concurrently with the antidepressant you have selected to treat the depression.
We recommend weekly (or biweekly if the situation demands) contact until a full therapeutic dose is achieved, the patient is sleeping through the night, and there are no problems with adverse drug effects. Over the next 6 to 12 weeks, we advise contact every 2 weeks and then every 3 weeks for follow-up to monitor progress. Once stability is established, you can use the telephone for alternating contacts. Further, well-trained office personnel or professional care managers can sometimes handle visits and/or phone contacts in stable patients. Because depression is often comorbid with medical diseases, these must also be addressed, watching carefully for adverse impacts of the disorders and/or their medications on the depression.3 At each contact, you must always check for suicidality and act immediately in its presence; see the end of this chapter on how to identify and manage the suicidal patient.
Recalling from Chapter 2 that depression is often comorbid with other psychiatric disorders,3 we briefly mention the following, addressed in greater detail in Chapters 5 and 6, respectively.
Managing concurrent anxiety in the depressed patient begins with determining whether the patient meets diagnostic criteria for an anxiety disorder, such as Generalized anxiety or panic disorder. Although SSRIs and SNRIs are also treatment for anxiety, they take 3 to 4 weeks to have an anti-anxiety (and anti-depressant) effect. To address the anxiety occurring in depression, you can combine the antidepressant with a brief course (2-4 weeks) of an adjunctive antianxiety agent. Benzodiazepines such as clonazepam (0.5 mg 2 times a day) produce a rapid anxiolytic effect, but have the limitations of sedation, tolerance, withdrawal, dependence, and misuse—if used chronically. Alternatives to benzodiazepines are preferred in patients with comorbid substance use disorders. Hydroxyzine, diphenhydramine, gabapentin, and pregabalin also may be effective and are not associated with tolerance, withdrawal, or misuse although gabapentin may potentiate opioid highs and has some street value. β-Blockers are also useful, particularly in patients with performance anxiety. Buspirone, which has an antidepressant effect as well, is approved also for managing generalized anxiety disorder (but not for panic disorder). Adjunctive anti-anxiety agents can be prescribed around the clock to prevent panic attacks, or as needed upon the earliest signs of anxiety. Prescribing them initially on a regular schedule is more effective, since the anticipation of panic often contributes to anxiety.
Chronic pain, is observed in many patients with depression.31 The comorbidity of depression and chronic pain decreases the likelihood of response to treatment of either condition and decreases patient satisfaction with care. Adverse effects of opioid analgesics such as somnolence and cognitive dysfunction may confound symptoms commonly observed in depression—and opioids themselves cause depression with chronic use. Chapter 6 describes in detail how you first establish a scheduled (non-prn) dosing regimen of the opioid and then taper slowly by, say, one tablet per day every 1 to 2 weeks, for example from 4 tablets per day to 3 tablets per day of oxycodone. Often presenting primarily as a patient with a pain complaint, the associated depression is treated as outlined here—as one also attends to other aspects of the MHCM, especially the clinician-patient relationship and physical exercise. Resistance exercise training, for example, has been demonstrated to significantly reduce depressive symptoms.32
While we worked to prevent and educate the patient about adverse medication effects, we must also address them when they arise.