78-1 MAJOR DEPRESSION A Life Worth Living . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level I Brian L. Crabtree, PharmD, BCPP CASE SUMMARY A 41-year-old woman presents to an outpatient mental health clinic on referral by her family physician. She has complaints, signs, and symptoms indicative of a major depressive episode with melancholic features. She has undergone treatment for alcohol use disorder within the last year. She is experiencing severe family stressors, namely, her children have moved out of the home. She is already receiving antidepressant therapy, mirtazapine, prescribed by her family physician, without improvement, and complains of weight gain as a side effect. Nondrug therapies such as psychotherapy and a support group should be initiated concurrently with alternate pharmacotherapy. Feasible drug treatment options for this patient include selective serotonin reuptake inhibitors (SSRIs), agents with mixed-reuptake-inhibition pharmacology, and tricyclic antidepressants (TCAs). Efficacy is determined by evaluating target signs and symptoms; standardized rating scales may also be used. It is important to question the patient about adverse effects at each visit and to encourage adherence to the prescribed therapy. QUESTIONS Problem Identification 1.a. Create a list of this patient’s drug therapy problems. • Major depression, poorly responsive to current therapy • Current use of St. John’s wort, with possible implications for other medication therapy, including adverse drug–drug interactions • Stable problems not requiring treatment at this time include headaches treated with acetaminophen. Headaches may be improved by successful antidepressant therapy. 1.b. What signs, symptoms, and laboratory values indicate the presence and severity of depression in this patient?1 • Sleep disturbance • Fatigue (feeling tired much of the time) • Increased eating (loss of appetite with weight loss is more common, but increased eating can occur. This patient may have increased eating as an adverse effect of mirtazapine.) • Concentration impairment • Feeling down and sad • Anxiety (commonly comorbid with depression), “pounding heart” • Crying spells • Anhedonia • Social withdrawal • Passive suicidal ideas (no active plan, but wants to “go to sleep and not wake up”) • Normal physical and laboratory exams help to rule out nonpsychiatric causes of depression • Previous alcohol abuse and dependence • The melancholia specifier is met by the inclusion of severe loss of pleasure in usual activities, depressed mood with despondency, motor slowing, and guilt 1.c. What factors in the family history support a diagnosis of depression? • A sister has depression and anxiety and takes antidepressant medication. • Another sister committed suicide. 1.d.Is there anything in the patient’s medication history that could cause or worsen depression? • Oral contraceptives can worsen depression, but this is unlikely in this case because of her long history of recurrent episodes and the fact that she has not taken them for 2 months before this presentation. Desired Outcome 2.What are the goals of pharmacotherapy in this case?2 • Eliminate or significantly reduce symptoms. Remission (symptom-free or nearly symptom-free) should be the goal of treatment of depression although a majority of patients continue with residual symptoms. • Restore functioning to premorbid levels, especially with regard to employability. • Prevent depressive relapse. • Minimize medication side effects. • Ensure adherence with the prescribed regimen. Therapeutic Alternatives 3.a. What nonpharmacologic treatments are important in this case? Should nonpharmacologic treatments be tried before beginning medication? • Psychotherapy, supportive counseling, and support groups are important nondrug therapies. Because of the severe psychosocial aspects of this patient’s depression, including multiple unstable marriage relationships, current conflict with her children, the history of alcoholism treatment, and financial stress, it is important for her to work through issues in her life with a therapist and support group for at least a few months in addition to taking medication. Different types of psychotherapy vary in cost, but support groups are usually free of charge. Research indicates that psychotherapy combined with drug therapy in the treatment of major depression is often associated with better response than with pharmacotherapy alone.3 • Pharmacotherapy should be initiated concurrently with nonpharmacologic therapy. 3.b.What pharmacotherapeutic options are available for the treatment of depression? • Existing therapy with mirtazapine should be discontinued concurrent with beginning alternate therapy because of poor response and an adverse effect. The mirtazapine dosage could possibly be increased, but she is already experiencing weight gain at a dosage that is effective for many patients. Copyright © 2017 by McGraw-Hill Education. All rights reserved. Major Depression Lydia E. Weisser, DO, MBA • Mental status examination findings help to determine drug therapy target symptoms CHAPTER 78 78 • Frequent headaches 78-2 SECTION 7 • Antidepressant medications are generally considered equally effective. Comparative efficacy trials vary in outcomes, and some meta-analyses suggest modest differences of questionable clinical significance.4 Choice of medication is usually based on factors such as side-effect profile, ease and frequency of dosing, and cost. • SSRIs include the following agents: ✓Citalopram (Celexa, generics) ✓Escitalopram (Lexapro, generics) Psychiatric Disorders ✓Fluoxetine (Prozac, generics) ✓Fluvoxamine (Luvox, Luvox CR, generics) ✓Paroxetine (Paxil, Paxil CR, Pexeva, Brisdelle [vasomotor symptoms of menopause], generics) ✓Sertraline (Zoloft, generics) • SSRIs are often considered antidepressants of first choice, among the most commonly prescribed drugs in primary care, and the most commonly prescribed antidepressants. Advantages include an extensive research basis, ease of use in a once-daily regimen, efficacy at starting dosages, generally good tolerability, and a wide therapeutic index. SSRIs are often more easily tolerated than the TCAs. TCAs are no longer generally considered first-line therapy. • Disadvantages of SSRIs include their typical side-effect profile and a propensity for drug–drug interactions. The most common side effects of SSRIs are GI (nausea and diarrhea), insomnia, somnolence, headache, sexual dysfunction, nervousness, and restlessness. The most significant SSRI class drug–drug interactions involve inhibition of drug-metabolizing enzymes or serotonin syndrome. ✓Serotonin syndrome includes neurobehavioral (confusion, agitation, and seizures), motor (myoclonus, rigidity, and tremor), and autonomic (hypertension and hyperthermia) features. ✓Drugs that also increase serotonin have the potential to cause serotonin syndrome when combined with SSRI agents. Important examples are meperidine, tramadol, dextromethorphan, and other antidepressants, particularly monoamine oxidase inhibitors (MAOIs). ✓Fluoxetine is a potent inhibitor of the CYP2D6 and 2C19 isoenzymes. Its active metabolite, norfluoxetine, is an inhibitor of the CYP3A pathway. Important and/or common interactions include phenytoin, carbamazepine, propranolol, metoprolol, morphine, and oxycodone. Although sometimes coprescribed, fluoxetine significantly slows clearance of haloperidol, risperidone, and some antianxiety drugs (eg, diazepam, alprazolam). ✓Paroxetine is a potent inhibitor of the CYP2D6 isoenzyme. Important and/or common interactions include those with phenytoin, benztropine, trihexyphenidyl, propranolol, metoprolol, opioids listed above, dextromethorphan, and atomoxetine. Paroxetine 7.5 mg (Brisdelle) is FDA approved only for managing vasomotor symptoms of menopause. ✓Fluvoxamine is a potent inhibitor of the CYP1A2 and 3A pathways. Important and/or common interactions include those with warfarin, carbamazepine, olanzapine, propranolol, metoprolol, and alprazolam. ✓Citalopram, escitalopram, and sertraline are associated with fewer drug–drug interactions than other SSRIs because they have minimal effect as inhibitors of metabolic enzymes.5 Copyright © 2017 by McGraw-Hill Education. All rights reserved. • Mixed serotonin effects and mixed reuptake inhibitors include the following: ✓Venlafaxine (Effexor, Effexor XR, generics): affects serotonin and norepinephrine reuptake. ✓Desvenlafaxine (Pristiq, Khedezla): affects serotonin and norepinephrine reuptake. This is the major active metabolite of venlafaxine. ✓Duloxetine (Cymbalta): affects serotonin and norepinephrine reuptake. ✓Milnacipran (Savella, Savella Titration Pack): affects serotonin and norepinephrine reuptake. ✓Levomilnacipran (Fetzima): affects serotonin and norepinephrine reuptake with preference for norepinephrine. ✓Mirtazapine (Remeron, generics): affects norepinephrine and serotonin release via α-2 antagonism. Mirtazapine does not inhibit serotonin or norepinephrine reuptake. ✓Bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL, Aplenzin, generics): affects dopamine and norepinephrine reuptake. ✓Trazodone (Oleptro, generics): affects serotonin reuptake, blocks serotonin (5-HT2) receptors. ✓Nefazodone (generics): affects serotonin reuptake, blocks 5-HT2 receptors. ✓Vilazodone (Viibryd): affects serotonin reuptake and partially agonizes the serotonin type 1A (5-HT1A) receptor. ✓Vortioxetine (Brintellix): affects serotonin reuptake, blocks 5-HT3 receptors, and agonizes 5-HT1A receptors • Mixed reuptake inhibitors may also be used as first-choice agents, but there is no evidence for superior efficacy compared with SSRIs. These drugs also have their own advantages and disadvantages. Advantages of the mixed reuptake inhibitors are largely related to adverse effect profiles (eg, fewer serotoninrelated side effects). They may also be useful in patients who fail to respond to SSRIs, although research is inconclusive on this point. Bupropion is associated with less sexual dysfunction than SSRIs, but it is contraindicated in patients with a history of seizures or eating disorder. Vilazodone did not separate from placebo regarding sexual adverse effects and weight changes in clinical trials. Venlafaxine, bupropion, trazodone, and levomilnacipran are available in extended-release formulations for once-daily administration. Duloxetine, mirtazapine, vortioxetine, desvenlafaxine (a metabolite of venlafaxine), and vilazodone can also be administered once daily. Vilazodone is recommended to be taken with food. Duloxetine has been researched particularly in depressed patients who have prominent physical symptoms such as pain. Duloxetine is also FDA-approved for peripheral neuropathy due to diabetes and for fibromyalgia. Trazodone is primarily used in low dosages as a sedative. Nefazodone is used less commonly because of a boxed warning regarding hepatotoxicity. • TCAs are the oldest antidepressant agents. Some of these drugs (many of which are available generically) include the following: ✓Amitriptyline (Elavil, Endep, generics) ✓Desipramine (Norpramin, Pertofrane, generics) ✓Doxepin (Silenor, generics) ✓Imipramine (Tofranil, Tofranil-PM, generics) ✓Nortriptyline (Pamelor, generics) 78-3 ✓Phenelzine (Nardil, generics) ✓Tranylcypromine (Parnate, generics) ✓Selegiline (Emsam) • MAOIs are not usually used as first-line agents because of necessary dietary restrictions and the associated risk of a hypertensive reaction. Foods high in tyramine such as aged cheeses, aged or cured meats, and soy products should generally be avoided. Drugs with sympathomimetic effects, including nonprescription decongestants such as pseudoephedrine should be avoided. MAOIs should not be combined with SSRI antidepressants. Selegiline is available in a patch formulation and does not require dietary modification at 6 mg/day, the lowest strength. Higher strengths do require dietary restrictions. • Antipsychotic drugs (aripiprazole, quetiapine, and olanzapine): Aripiprazole (Abilify) and quetiapine (Seroquel XR) are FDAapproved for adjunctive treatment in combination with antidepressant drugs for patients who have inadequate response to antidepressant monotherapy. Olanzapine is approved in combination with fluoxetine for patients who fail usual therapy. • Central nervous system (CNS) stimulants (methylphenidate and dextroamphetamine) are not used as first-line agents because of their stimulant side-effect profile and controlled-substance regulatory status. They are sometimes used as adjunctive agents in medically ill or elderly patients. Optimal Plan 4.a. What drug regimen (drug, dosage, schedule, and duration) is best for this patient? • If the patient could tell us the name of the sister’s medication and how she responds to it, this information could possibly serve as the basis for an initial choice of treatment for this patient, although the basis for this judgment is mainly intuitive and has not been established in well-designed controlled trials. In the absence of such information, the choice is not clear. • Use of a medication that can be given once daily and is likely to be effective with the initial dosage is desirable. The SSRI antidepressants fit this description well. A mixed reuptake inhibitor would also be appropriate for initial treatment. A TCA would be an acceptable first-line treatment because of the melancholic features but should be used with caution because of toxicity in overdose. ✓Example of initial SSRI regimens is fluoxetine, 20 mg PO once daily, or sertraline, 50 mg PO once daily, in the morning. The dosage of fluoxetine can range up to 80 mg/day. The dosage of sertraline can range up to 200 mg/day. Fluoxetine and sertraline are usually given in the morning to minimize the risk of insomnia. Among the other SSRIs, paroxetine is often associated with drowsiness, and it is not unusual for it ✓Patients who respond well to fluoxetine may benefit from a dosage formulation for weekly administration called Prozac Weekly. It is indicated for patients who have responded to at least 3 months of daily therapy with fluoxetine. Prozac Weekly is a 90-mg capsule containing enteric-coated pellets that dissolve in the lower GI tract. It should be started 7 days after stopping daily administration of fluoxetine. Prozac Weekly is not indicated for initial treatment. • Other SSRIs, or mixed reuptake inhibitors would also be appropriate as first-line therapy for this patient. Refer to the textbook chapter on depressive disorders for a listing of the usual starting dosages. ✓Sustained-release dosage forms that allow for single daily dosing are available for bupropion (Wellbutrin XL), venlafaxine (Effexor XR), and levomilnacipran (Fetzima). Another sustained-release dosage form of bupropion (Wellbutrin SR) is also available but may require divided daily dosing. ✓Duloxetine (Cymbalta), desvenlafaxine (Pristiq), vilazodone (Viibryd), vortioxetine (Brintellix), and mirtazapine (Remeron) can be given once daily. ✓Trazodone, nefazodone, and immediate-release formulations of venlafaxine and bupropion usually require more than one dose per day. ✓Nefazodone is no longer considered first-line therapy because of a risk of potentially fatal hepatotoxicity. The product label includes a boxed warning about this risk. TCAs often cause side effects that increase the likelihood of nonadherence, but prescription costs are lower for TCAs than for branded antidepressants. Some TCAs, including imipramine, desipramine, and nortriptyline, can be monitored with serum concentrations as an additional parameter in assessing and adjusting therapy. ✓If the patient responds satisfactorily, antidepressant therapy should be continued for at least 6–12 months before an attempt is made at tapering reduction. For a patient such as this with a strong family history of depression, including suicide, it is appropriate to continue medication at the same dosage longer. Patients with a history of recurrent episodes are often treated on an indefinite maintenance basis. 4.b. How should the patient be advised about the herbal therapy, St. John’s wort? • She should be advised to stop taking the St. John’s wort because it could interact adversely with both the mirtazapine she is currently talking and any antidepressant medication that will be recommended as well as her Ortho-Novum. Although she has not taken the contraceptive recently, it is likely she will take it in the future. St. John’s wort is a strong inducer of cytochrome enzymes, particularly the 3A3/4 pathway, which enhances metabolic clearance of many coadministered drugs leading to subtherapeutic drug levels. 4.c.What alternatives are appropriate if the patient fails to respond to initial therapy? • In the absence of significant side effects, initial therapy should be optimized with dosage increases and a trial of at least 4 weeks. The most common reasons for poor response to initial therapy are underdosing and inadequate length of therapy. If a Copyright © 2017 by McGraw-Hill Education. All rights reserved. Major Depression • MAOIs include the following: to be given at bedtime. The frequency of dosage adjustments depends on clinical response and tolerability, keeping in mind that several weeks are required for optimum effect. CHAPTER 78 • Tricyclics may be particularly useful in patients with melancholic features of depression,6 but they require especially careful adjustment to find the correct dosage and commonly cause bothersome side effects, particularly sedation, anticholinergic effects, and orthostatic hypotension. They also are problematic in patients with comorbid nonpsychiatric disease such as cardiovascular disease or benign prostatic hyperplasia and especially in elderly individuals. Research has shown the TCAs to be less well tolerated than many other antidepressants, including an overdose situation with patients who may have suicidal ideas. 78-4 SECTION 7 switch to a different agent is advisable, a drug from a different chemical class may be considered. The SSRIs are not a chemical class, however, and many patients respond to one SSRI after failing another. Psychiatric Disorders • If an SSRI was used initially, options include a different SSRI or non-SSRI antidepressant. Nefazodone would most likely not be tried next because of the hepatotoxicity risk. Because of dietary restrictions and adverse drug–drug interactions, MAOIs are reserved for particularly difficult or otherwise refractory patients or for patients with atypical depression. • If the patient fails multiple trials of antidepressants, augmenting strategies may be implemented to enhance response. The antipsychotic drugs aripiprazole and quetiapine are FDAapproved for adjunctive treatment of depression in patients who show an inadequate response to antidepressant monotherapy. Among mood stabilizing drugs, lithium has been used for antidepressant augmentation. Less well-established alternatives include thyroid hormone supplementation, pindolol, and antidepressant combinations. Electroconvulsive therapy is often effective treatment for refractory patients. • Pharmacogenetic testing to assist with personalized treatment selection for patients who fail to respond to multiple drug trials or who experience intolerability on multiple trials is an emerging trend. It is a highly active area of research but is not yet considered standard of care in routine practice.7 Outcome Evaluation 5.What clinical and laboratory parameters are necessary to evaluate the therapy for efficacy and adverse effects? • The principal drug therapy outcomes are the target signs and symptoms identified in the history, review of systems (ROS), and physical examination, particularly the mental status examination findings. Some clinicians also use standardized rating scales such as the Hamilton Depression Rating Scale. Patient self-rated scales include the Beck Depression Inventory. Various Internet-based versions of standardized rating scales are available for both clinicians and patients. • Monitoring of potential adverse effects should be specific to the antidepressant agent being used. With SSRIs, common side effects include GI disturbance such as nausea and diarrhea; CNS effects such as irritability, jitteriness, and headache; sleep disturbance such as insomnia; and sexual disturbances including erectile dysfunction, anorgasmia, and loss of libido. Side effects are assessed primarily on the basis of the clinical interview. Some differences may exist within the SSRIs, but these adverse effects are common to all agents in the group. Paroxetine is especially associated with a discontinuation syndrome. Patients should be counseled to not stop therapy abruptly. • Assess for the occurrence of side effects at each clinical interaction because side effects are the most common reason for nonadherence to antidepressant therapy. Interview patients briefly during clinic visits or visits to the pharmacy for prescription refills. A general question such as “Are you having any problems with your medication?” can be asked within the context of reassurance that some side effects are common but may be temporary. If side effects are particularly bothersome or interfere with daily function or quality of life, encourage the patient to report these so that appropriate adjustments in therapy can be made. • Laboratory data monitoring is not always indicated with antidepressant therapy. The SSRIs can cause hyponatremia in some patients, and electrolyte monitoring at 6 months and Copyright © 2017 by McGraw-Hill Education. All rights reserved. annually may be prudent. The TCAs are well known for their cardiac effects; electrocardiographic (ECG) monitoring at baseline and annually is advisable, especially in patients older than 40 years of age. Patient Education 6.What information should be provided to the patient to enhance adherence, to ensure successful therapy, and to minimize adverse effects? • Patient education should be individualized to patient needs and the agent being used. Important points with this case include these items. • Fluoxetine (example): ✓ The name of this medication is fluoxetine (Prozac). It is used for your depression. ✓Take this medication every day in the morning. ✓Medication for depression often takes up to 6 weeks, or even longer, to be optimally effective. Do not be discouraged if you do not feel better in the first few days. ✓Some symptoms may improve before others. Sleep, energy, and appetite sometimes get better before the depressed feeling goes away. ✓If you miss a dose, take it as soon as you remember. If you forget until the next day, skip the missed dose and continue with the regular schedule. ✓Common side effects to watch for with this medication include upset stomach, a jittery feeling, headaches, and sleep disturbance. These do not occur with every patient, and some of these side effects are similar to the symptoms of depression. If they are caused by depression, they should improve as the medication works. If they are caused by medication, the symptoms may linger or get worse. It is possible that side effects will occur before your depression improves, so it is important to continue treatment as prescribed, if the side effects are not too bothersome, until the medication has had time to work properly. If you feel your depression is worsening or you have thoughts of harming yourself, contact your physician immediately. ✓If you have questions or problems with your medication, contact your physician or pharmacist for more information and assistance. ■■ CLINICAL COURSE: ALTERNATIVE THERAPY Mrs Flowers understands that she must stop the St. John’s wort she has been taking because of an interaction with her prescribed mirtazapine and Ortho-Novum, but she wonders if it would have been helpful if she had started it when she first began feeling depressed. See Section 19 (Complementary and Alternative Therapies) in this Instructor’s Guide for questions and answers about the use of St. John’s wort for treatment of depression. REFERENCES 1. American Psychiatric Association. Depressive disorders. In: Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC, American Psychiatric Association, 2013. p. 155–188. 2. Teter CJ, Kando JC, Wells BG. Major depressive disorder. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach, 9th ed. New York, NY, McGraw Hill, 2014. p. 1047–1066. 78-5 6. Perry PJ. Pharmacotherapy for major depression with melancholic features: relative efficacy of tricyclic versus selective serotonin reuptake inhibitor antidepressants. J Affect Disord 1996;39:1–6. 7. Bishop JR, Stevenson JM, Burghardt KJ. Pharmacogenetics in mental health. In: Johnson JA, Ellingrod VL, Kroetz DL, Kuo GM, eds. Pharmacogenomics: Application to Patient Care, 3rd ed. Lenexa, KS, American College of Clinical Pharmacy, 2015. p. 115–134. CHAPTER 78 3. Cuijpers P, Dekker J, Hollon SD, Anderson G. Adding psychotherapy to pharmacotherapy in the treatment of depressive disorders in adults: a meta-analysis. J Clin Psychiatry 2009;70:1219–1229. 4.Linde K, Kriston L, Rucker G, et al. Efficacy and acceptability of pharmacological treatments for depressive disorders in primary care: systematic review and network meta-analysis. Ann Fam Med 2015;13:69–79. 5. Spina E, Santoro V, D’Arrigo C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther 2008;30:1206–1227. Major Depression Copyright © 2017 by McGraw-Hill Education. All rights reserved.