Introduction

Major depressive disorder (MDD) is a common problem in the primary health care setting. The recognition of depression requires a high index of suspicion, as depression can masquerade as many different problems. Depression also commonly coexists with other medical conditions and can be a side effect of medications.

Recently, evidence-based Canadian guidelines for treating depression have been published. The Canadian Network for Mood and Anxiety Treatments (CANMAT) developed Guidelines for the Diagnosis and Pharmacological Treatment of Depression for primary care physicians[1] and, in partnership with the Canadian Psychiatric Association, Clinical Guidelines for the Treatment of Depressive Disorders for psychiatrists[2-8] (guidelines available at www.canmat.org [10]).

We now summarize these guidelines to provide an overview of treatment strategies for MDD in primary care. This article, “Treatment of depression in primary care—Part 2: Principles of maintenance treatment,” and its companion article, “Treatment of depression in primary care—Part 1: Principles of acute treatment” [11] are organized in a simple, practical, and easy-to-use format. In Part 1 [11], we dealt with the principles of acute treatment, including psychoeducation, selection of treatment, and monitoring of response. In Part 2, we continue with principles of maintenance treatment of depression, management of side effects, and strategies for inadequate treatment response.

Maintenance-phase treatment

Major depression is often a chronic and recurrent illness. It is estimated that at least 30% of patients presenting with a depressive episode will have recurrent episodes.[9] Hence, once patients are in full remission from MDD, maintenance issues (e.g., how long should a patient continue on their medication?) become important.

Table 1 shows the phases of treatment for depression. Remission is an important target for both acute and maintenance phases, because residual symptoms increase the relapse/recurrence rate and the degree of chronicity and suicide rate, and are associated with poor quality of life and greater use of health services. Table 2 shows recommendations for maintenance-phase treatment. Psychoeducation in the maintenance phase focuses on recognizing early signs of relapse or recurrence, and on adherence to medications.

Managing adverse effects of antidepressants

Adherence to medications is a significant issue when treating depression. Studies in primary care settings show that 28% of patients stop their antidepressant within the first month, and 44% discontinue the medication within 3 months.[10] Side effects are cited as one of the most common reasons for discontinuation in the maintenance phase. Patients will often tolerate side effects in the acute phase of treatment because they are feeling so much better. However, once they are well, the same degree of side effects may not be tolerated.

Following are management tips for the common side effects of newer antidepressants (Table 3). Unfortunately, while some side effects can be ameliorated, persistent and troublesome side effects may require switching antidepressants.

Gastrointestinal side effects (anorexia, nausea, diarrhea, dyspepsia): These symptoms commonly occur with onset of treatment or when the dose is increased, but patients often develop tolerance after 1 to 2 weeks. The side effects can be minimized by starting at a low dose and increasing the dose gradually. Symptomatic treatment with antiemetics (e.g., diphenhydramine) or H₂-blockers (e.g., ranitidine) can also be helpful.

Central nervous system side effects (headache, nervousness, insomnia, drowsiness, anxiety/agitation): Many antidepressants can disturb sleep, especially in the short term before onset of antidepressant effect. Short-term treatment with hypnotics (e.g., zopiclone or zaleplon), benzodiazepines (e.g., temazepam), or small doses of trazodone (25 mg to 50 mg) may be indicated. Analgesics and anxiolytics (e.g., lorazepam) may also be used for headaches and agitation. Patients should be warned about potential daytime somnolence with concomitant use of sleep and anxiolytic medications, and additional caution is warranted for patients who may have potential to abuse sedative/hypnotic drugs.

Sexual side effects (decreased libido, anorgasmia, delayed ejaculation, erectile dysfunction): Sexual side effects can occur in up to 50% of patients treated with SSRIs, but may not be recognized because patients are reluctant to spontaneously report these side effects, and physicians are not comfortable asking about them. Unlike other side effects, patients do not usually develop tolerance to sexual side effects. Sildenafil is an effective treatment for men with erectile dysfunction secondary to antidepressants. Other reported antidotes for antidepressant-induced side effects include yohimbine, bromocriptine, amantidine, bupropion, or cyproheptadine, but these agents are variably effective. Alternatively, physicians can consider the use of antidepressants that are less likely to cause sexual side effects, including bupropion-SR, mirtazapine, moclobemide, and nefazodone.

Use of antidepressants during pregnancy and lactation

The management of depression during pregnancy and postpartum involves weighing the potential harmful effects of medications on the fetus/baby against the known harmful effects of untreated depression. Consultation from a psychiatrist or reproductive psychiatry specialist is recommended.

Increasing evidence indicates that use of SSRIs or tricyclic antidepressants (TCAs) during pregnancy do not result in increased risk of harm to the baby.[11] As for breastfeeding, antidepressants are variably excreted in breast milk. However, studies of SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), particularly at low therapeutic doses, report very low to undetectable serum levels of the drug in the infant. Most studies have shown no evidence of behavioral effects in breastfed infants. The Motherisk Program is an important resource for up-to-date information about medication use in pregnancy and postpartum ([416] 813-6780, www.motherisk.org [12]).

There is still limited evidence to support the efficacy of psychotherapy for treatment of MDD during pregnancy and postpartum. However, psychotherapy alone can be considered for patients with mild symptoms.

The SSRIs (with or without psychotherapy) are now first-line treatments for depressions of moderate or greater severity and are second-line treatments for mild depression.

Discontinuing antidepressants

Tapering doses over several weeks is recommended when the decision to discontinue medications is made. Some patients will experience discontinuation symptoms if antidepressants are abruptly discontinued[12] (Table 4). Paroxetine, venlafaxine, TCAs, and monoamine oxidase inhibitors (MAOIs) tend to have higher rates of discontinuation symptoms, while bupropion-SR, citalopram, fluoxetine, mirtazapine, and sertraline have lower rates.

Strategies for poor response to an antidepressant

After an adequate trial of the first antidepressant, about one-half of patients will have full remission (symptom-rating scale scores within the normal range), one-quarter will have partial response (>20% reduction in scores on rating scales, but still symptomatic), and another one-quarter will have no response (<20% reduction in scores). Hence, many patients will have a sub-optimal response to medications and go on to have a treatment-resistant depression.

Table 5 summarizes the strategies for managing nonresponse or partial response to an antidepressant. Optimizing is always the first step. Switching strategies are generally used when there is minimal response to an antidepressant, while augmentation and combination strategies are used later in the treatment course, or if there has been a partial response to the first antidepressant. Psychotherapy and electroconvulsive therapy can be considered at any step for nonresponse.

Optimization

At least minimal (>20% reduction in depression scores) or partial response should occur after 3 to 4 weeks of treatment at a therapeutic dose. If there is no response, the antidepressant dose should be increased every 2 to 4 weeks until response occurs, maximum dose is reached, or limiting side effects are experienced. If there is still inadequate response after dose increase, physicians should re-evaluate diagnostic issues (e.g., bipolarity, depressive subtypes, co-morbidity, substance abuse, personality traits/disorders), re-evaluate treatment issues (e.g., compliance, side effects), and, if using TCAs, check serum levels.

Switching

Antidepressants can be switched either within the same medication class (e.g., from one SSRI to another) or to a different class (e.g., from an SSRI to a serotonin and noradrenaline reuptake inhibitor). Switching within the class is an effective strategy for SSRIs but less effective for TCAs. Drug-drug interactions should be considered before switching. Many antidepressants can be tapered while a second is being started, with only a small risk of additive side effects of two drugs. A washout period, however, is recommended for some switches (Table 6). TCAs can be particularly useful for treatment-resistant depression, in part because therapeutic serum levels can be monitored.

Augmentation

Augmentation refers to adding a medication that by itself is not an antidepressant, but in combination produces a synergistic antidepressant effect. Examples of augmenting agents for antidepressants are lithium (600 mg/day to 1200 mg/day; check serum levels), triiodothyronine (T3, 25 mg/day to 50 mg/day), d-amphetamine (15 mg/day to 60 mg/day), tryptophan (1.5 g/day to 3 g/day), buspirone (30 mg/day to 45 mg/day), and atypical antipsychotics such as olanzapine (5 mg/day to 15 mg/day). Lithium has the most evidence supporting its efficacy in treatment-resistant depression, but triiodothyronine is also an effective augmentation agent and has fewer side effects.

Combination

Combination involves adding one antidepressant to another to produce a synergistic effect. While the use of combination antidepressants is common in clinical practice, there is still little evidence to support this strategy for treatment-resistant depression. Combination strategies usually incorporate medications with different neurochemical actions, for example, SSRIs with bupropion-SR, or venlafaxine-XR with mirtazapine.

Psychotherapy

There is increasing evidence that psychotherapy is an effective adjunctive treatment for medication-resistant depression. Patients with severe depressive symptoms, co-morbidity, and chronicity benefit the most from combining psychotherapy with pharmacotherapy.

Electroconvulsive therapy

Electroconvulsive therapy (ECT) remains the most effective somatic treatment for depression. While electroconvulsive therapy is generally used for treatment-resistant depression, it can be considered at any stage of treatment when rapid response is required (acute suicide risk, physical deterioration) or when patients are unable to tolerate medication side effects. The greatest barrier to electroconvulsive therapy is stigma; patients need to know that modern electroconvulsive therapy is a safe, effective, and well-tolerated treatment. Provincial guidelines for the use of electroconvulsive therapy are now available.[13]

Referral

The timing for a referral to a psychiatrist will depend on a number of factors, including experience and comfort-level of the primary care physician, patient preference, and availability of psychiatrists. Typical situations that might trigger a referral include severe depressive symptoms (active suicidality, psychosis), diagnostic uncertainty, significant psychiatric/medical co-morbidity, and unsatisfactory response to adequate trials of two or more antidepressants. “Shared care” is an effective collaborative model that may be more available in future.[14]

Conclusion

Maintenance treatment of depression has its own objectives and strategies, including psychoeducation and management of side effects. Medication issues relating to pregnancy/lactation and discontinuing drugs should be addressed. While effective strategies are available to treat patients with treatment-resistant depression, there is still little information on the optimal sequencing of strategies. A collaborative, shared-care model between psychiatrists and family physicians may enhance outcomes for these patients.

Competing interests

Dr Lam is on the advisory/speaker boards of Cyberonics Inc., Eli Lilly Canada, GlaxoSmithKline US, Litebook Inc., Lundbeck Canada, Organon Canada, Pfizer Canada, and Wyeth-Ayerst Canada. He is undertaking research grants/clinical trials with the support of Astra Zeneca Canada, Eli Lilly Canada, Merck-Frosst Canada, Roche Canada, and Servier Canada.

Table 1. The phases of depression treatment.

Table 2. Recommendations for maintenance treatment of depression.

Table 3. Newer antidepressants and adverse effects profile.

CYP450 = Cytochrome P450 system, GI = gastrointestinal, CNS = central nervous system

Table 4. The antidepressant discontinuation syndrome.

Table 5. Strategies for limited or no response to the first antidepressant

Table 6. Washout recommendations for switching antidepressants. Adapted from Kennedy SH, Lam RW, Cohen NL, et al.[5]

Agnes To, MD, Heidi Oetter, MD, and Raymond W. Lam, MD, FRCPC

Dr To is a senior resident in the Department of Psychiatry at the University of British Columbia, Vancouver. Dr Oetter is with the Department of Family Practice at UBC and the Department of Psychiatry at Royal Columbian Hospital in New Westminster. Dr Lam is a professor and head of the Division of Clinical Neuroscience at UBC and the director of the Mood Disorders Centre at UBC Hospital in Vancouver.