Major Depression: Treatment in Primary Care

ABSTRACT: Several nonpharmacologic options and a host of medications are available for the treatment of depression. Because the various second-generation antidepressants have similar efficacy, the American College of Physicians guidelines recommend selecting an agent based on patient preference, adverse effects, and cost. Selective serotonin receptor inhibitors (SSRIs) are a common choice for initial drug therapy; the response rates range from 25% to 65%. Be aware that the adverse effects of antidepressants may limit their effectiveness. Assess patients for response and side effects regularly beginning 1 to 2 weeks after initiation of therapy, and modify the treatment regimen if there is no response after 6 to 8 weeks. If patients do not respond to an initial SSRI, changing to another SSRI or a different class of second-generation antidepressants or adding a second antidepressant can improve response and increase the likelihood of remission.

In this two-part series, I discuss the diagnosis and management of major depression in primary care. In the first part (CONSULTANT, December 2011, page 897), I reviewed the current United States Preventive Services Task Force (USPSTF) guideline and the criteria for screening and diagnosing depression in primary care. This second part will focus on initial treatment options for patients with depression. I will also discuss some of the common side effects of medications, monitoring of response, complications of abruptly stopping medications, and signs of serotonin toxicity. I will use patient scenarios to answer a series of questions.

The first patient is a 26-year-old medical resident who is depressed during his internship year.

Question 1: What are the
non-drug options for treatment?

A. Watchful waiting

B. Psychotherapy

C. Exercise

D. Electroconvulsive therapy

E. All of the above

Answer: E. All of the above

Stressful situations, such as starting an internship, moving to a new city, or the death of a friend or family member, can elicit several of the symptoms of depression. Patients may have minor depression, adjustment disorder, or bereavement. It is imperative to determine the precise diagnosis. A conservative approach of watchful waiting with repeated face-to-face contact to assess symptoms can be an appropriate initial management for patients with minor depression, adjustment disorder, or bereavement. If non-drug initial treatment is preferred, the Agency for Healthcare Research and Quality 2010 National Guideline Clearinghouse review of the published literature gives the highest ratings for psychotherapy, including cognitive behavioral therapy, behavioral activation, and interpersonal therapy.¹ There is some evidence to support management with structured exercise or psychodynamic psychotherapy. Clearly, if a patient has complex medical and psychiatric comorbid conditions, a psychiatric referral may be indicated. Patients with severe depression who are referred to a psychiatrist may respond rapidly to electroconvulsive therapy.

Question 2: What antidepressants do you prescribe?

A. Tricyclic antidepressant (TCA)

B. Monoamine oxidase inhibitor (MAOI)

C. Selective serotonin receptor inhibitor (SSRI)

D. Serotonin norepinephrine receptor inhibitor (SNRI)

E. Norepinephrine dopamine receptor inhibitor (NDRI)

F. Serotonin agonist (SA)

ANTIDEPRESSANTS

More than 75% of prescriptions for antidepressants are written by primary care physicians.² The commonly used antidepressants can be divided into two categories, first generation and second generation, and further classified based on their mechanism of action (Table 1).³

Selecting an antidepressant. TCAs are effective but not well tolerated, particularly in the elderly, because of anticholinergic symptoms of dry mouth, constipation, dizziness, sweating, orthostatic hypotension, and blurred vision. They should also be used with caution in patients with heart disease because of the risk of cardiac complications. MAOIs are effective in patients with atypical depression, but these agents require dietary restrictions and should not be used in combination with SSRIs or any other drug that can increase serotonin activity because of the risk of serotonin
syndrome.

A comparative review found similar efficacy and effectiveness between various second-generation antidepressants.⁴ The American College of Physicians clinical practice guidelines recommend selecting a second-generation antidepressant based on patient choice, side effects, and cost.⁵

Question 3: What are common side effects of second-generation antidepressants?

A. Nausea

B. Weight gain

C. Decreased sexual arousal

D. Sleep disturbance

E. All of the above

Answer: E. All of the above

Side effects. The adverse effects of antidepressants often limit their effectiveness. In research trials, nausea and vomiting are the most common reasons patients stop taking their medications. Other common side effects include headache, dizziness, constipation, diarrhea, weight gain, sexual dysfunction, and sleep disturbance. Some of these symptoms, such as nausea and headache, occur within hours and can be self-limited. Advise patients that these symptoms may occur and may resolve with time. Other symptoms, such as weight gain, sexual dysfunction, and insomnia, may occur more gradually.

It can be beneficial to prescribe medications based on their side-effect profile. For example, certain classes of antidepressants are more likely than others to cause weight gain, and these may be appropriate choices for patients with depression who would benefit from this effect. Weight gain is more common with tertiary amine TCAs than with secondary amine TCAs. It also occurs more frequently with certain SSRIs such as paroxetine than with others such as escitalopram. Patients who take SSRIs can gain as much as 7% of their body weight within 4 months. Those who take an SA such as mirtazapine can also gain weight. Weight gain may be least common with an NDRI such as bupropion.

Sexual dysfunction is more common with certain antidepressants than with others. SSRIs and SNRIs are associated with decreased libido, genital arousal, and orgasm. This may be related to impairment in nitric oxide synthase and dopamine levels. Patients who experience SSRI-related sexual dysfunction may respond to taking a phosphodiesterase-5 (PDE-5) inhibitor before intercourse or adding buspirone (60 mg/d), which dampens effects on dopamine. Sexual dysfunction is less common with an NDRI such as bupropion.

Sleep disturbance and sedation are common with medications that block histamine. TCAs have a high affinity for blocking histamine and are best taken at night. This is also true for an SA such as mirtazapine in low doses. SSRIs in general are energizing and are best taken in the morning, except for paroxetine, which can be sedating and is best taken at night. For those patients who experience day time sedation with an SSRI, one strategy is to take the medication in the evening or change to a different class of antidepressant.

The following are other adverse effects to be aware of:

•Paroxetine should be avoided in pregnancy because it can cause congenital malformations.

•Nefazodone can result in hepatoxicity.

•Bupropion can lower the seizure threshold.

All antidepressants carry a “black box” warning of increased risk of suicidality in children and adolescents. This is particularly true during the first few months of treatment. One specific SSRI, paroxetine, has been linked to suicidal behavior risk in adults aged 18 to 30 years.⁶ The risk of suicidality due to antidepressants is lower for adults aged 65 years and older than for children and adolescents.

The next patient is an 80-year-old man who does not respond to initial SSRI treatment.

Question 4: How can you objectively monitor response to antidepressant therapy?

A. Ask your patient

B. Use a standardized form

C. Ask a family member of your patient

D. Ask the psychiatrist

Answer: B. Use a standardized form

MONITORING THE RESPONSE TO THERAPY

In caring for our patients with chronic illness, it is helpful to have objective measures to follow their response to treatment. We monitor blood pressure in our patients with hypertension and follow blood glucose and hemoglobin A_1c levels in our patients with diabetes to guide us in adjusting their medication. Similarly, our patients with depression have a chronic illness that can initially respond to treatment, but later relapse or recur following periods of remission. Once patients have a first episode of major depression, the probability of a second episode is greater than 50%; following a second episode, there is an 80% to 90% probability they will experience a third episode some time during their life.⁷ The course of depression can be characterized by response, remission, recovery, relapse, and recurrence (Figure 1).

The American College of Physicians clinical practice guidelines recommend that primary care providers assess patients for response and side effects regularly beginning 1 to 2 weeks after initiation of therapy and modify the treatment regimen if there is no response after 6 to 8 weeks.⁵ Unfortunately, only 20% of patients have three or more visits; 40% of patients stop taking their medications in 30 days and 70% within 90 days. This may result from multiple factors including adverse reactions, cost, and underlying illnesses.

The patient’s response can be measured using various standardized forms. One such form that can be self-administered and is validated for depression severity—and is even available as a free Apple application—is the Patient Health Questionnaire–Nine (PHQ-9) (Figure 2).⁸ The PHQ-9 has nine questions and a point system based on frequency of symptoms. The severity of depression is based on a scale: a score of 5 to 9 points indicates mild depression; 10 to 14 points, moderate depression; 15 to 19 points, moderate to severe depression; and 20 or more points, severe depression. Patients can be monitored with this form every 2 weeks for 8 weeks.

Patients with a decrease of 5 points or more from baseline have had a response to treatment, and no change in therapy may be necessary. Patients with a decrease of 2 to 4 points from baseline have a possibly inadequate response, and an increase or change in medication may be warranted. Patients with a decrease of 1 point from baseline, no change, or an increase from baseline have an inadequate response and may require psychiatric consultation.

The goal of the acute phase of treatment is remission of symptoms with a PHQ-9 score of less than 5 points. Patients who maintain a score of less than 5 points for 2 months are in remission. After 8 weeks of treatment, response rates are 50% to 55% and remission rates 35% to 40% in most studies.⁹

The American College of Physicians clinical practice guidelines recommend the continuation of treatment for 4 to 9 months following a satisfactory response after the first episode and treatment of even longer duration after a second episode to prevent relapse.⁵ Patients may benefit from maintenance treatment; however, the optimal length of therapy is controversial. In one study of patients older than 70 years with a first episode of depression, antidepressant therapy for 2 years reduced the rate of recurrence compared to no therapy.¹⁰ Some patients may need to continue antidepressant therapy for 1 to 2 years, and others indefinitely.

Question 5: What are possible antidepressant options if a patient does not respond to an initial SSRI?

A. Change to another SSRI

B. Change to another class of drug

C. Add a second antidepressant

D. All of the above

Answer: D. All of the above

SSRIs are a common choice for initial drug therapy. The response rates range from 25% to 65%. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial studied patients who did not respond to citalopram as their initial antidepressant.⁹ The investigators found that changing to another SSRI (sertraline), an SNRI (venlafaxine-XR), or an NDRI (bupropion-SR) resulted in additional 25% response and 25% remission rates in each of these classes of drugs for up to 14 weeks.

In a second study, the addition of bupropion or buspirone to citalopram resulted in 30% response and 30% remission rates for up to 14 weeks.¹¹ The addition of bupropion, however, produced a greater reduction in symptoms and fewer side effects compared to buspirone. If patients do not respond to an initial SSRI, changing to another SSRI or a different class of second-generation antidepressants or adding a second antidepressant can increase response and remission.

Question 6: What symptoms may patients experience if they abruptly stop taking an SSRI?

A. Flu-like symptoms

B. Nausea

C. Electric shock–like sensations

D. Anxiety

E. All of the above

Answer: E. All of the above

SSRI DISCONTINUATION SYNDROME

If a patient has been taking an SSRI for more than 5 weeks and the dosage is reduced or the medication is stopped abruptly, he or she may experience withdrawal symptoms, or the more preferred term discontinuation syndrome. This can occur in 30% of patients usually a few days to weeks after the medication is reduced or stopped. The exact mechanism is unknown but may be related to decreased serotonin levels and down-regulation of receptors. This syndrome is characterized by constitutional symptoms such as fatigue, flu-like symptoms, insomnia, and vivid dreams; gastrointestinal symptoms such as nausea, vomiting, and diarrhea; neurologic symptoms such as gait instability, paresthesias, and electric shock–like sensations; and psychiatric symptoms such as agitation, irritability, impaired concentration. A mnemonic to remember these symptoms is “ABCDEF” (Table 2).

The SSRI discontinuation syndrome is more common with short-acting medications, such as paroxetine, than with medications that have a longer half-life, such as fluoxetine. To prevent withdrawal symptoms, you may want to consider a gradual taper of the dosage. Sample tapering SSRI regimens are listed in Table 3.¹²

Question 7: What physical examination findings may alert you to elevated serotonin levels or SSRI overdose?

A. Temperature of 40°C (104°F)

B. Pinpoint pupils

C. Dilated pupils

D. A and C

E. A and B

Answer: D. A and C

SEROTONIN SYNDROME

A potentially life-threatening condition known as the serotonin syndrome may result from excess serotonin agonism. This may be caused by an adverse drug reaction, intentional overdose, or drug-drug interaction. One of the most recognized cases was the death of Libby Zion from the coadministration of phenelzine with meperidine. Examples of drug interactions associated with severe serotonin syndrome are listed in Table 4.

The clinical manifestations of serotonin syndrome can range from mild diarrhea and tremor to hemodynamic instability. The syndrome is often described as the clinical triad of mental status changes, autonomic dysfunction, and neuromuscular abnormalities. Patients may present with delirium, agitation, diaphoresis, fever (temperature as high as 40°C [104°F]), tachycardia, hypertension, mydriasis, muscular rigidity, hypertonicity, hyperreflexia, and clonus. The treatment of this syndrome includes removal of the offending agents, supportive care, and control of agitation with benzodiazepines.