Treatment of depression in primary care—Part 1: Principles of acute treatment

Treatment of major depression involves establishing a correct diagnosis and applying clear, evidence-based, and goal-directed principles. Treatment principles include recognizing and treating any coexisting medical conditions, building a therapeutic alliance with patients, choosing an appropriate treatment, and monitoring response. The goals of treatment are to achieve remission of symptoms, improve quality of life, and prevent relapse/recurrence. Antidepressants and time-limited psychotherapies are effective treatments, but each has their own advantages and limitations.

The authors summarize the new Canadian depression treatment guidelines and focus on the principles of acute treatment.


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 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 specialists[2-8] (guidelines available at

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 1: Principles of acute treatment” and its companion article, “Treatment of depression in primary care—Part 2: Principles of maintenance treatment,” are organized in a simple, practical, and easy-to-use format. In Part 1, we deal 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 and strategies for inadequate treatment response.

Once the diagnosis of depression is established, the principles of acute MDD treatment include:

• Set clear goals for treatment.
• Assess and treat co-morbid medical conditions.
• Assess suicide risk.
• Establish a therapeutic alliance.
• Consider psychotherapy.
• Choose an appropriate antidepressant.
• Enhance adherence.
• Monitor response.

Set goals of treatment

The treatment of depression consists of two phases: acute and maintenance. Table 1 summarizes the duration, objectives, and activities of each phase. There is increasing recognition of the importance of achieving full remission of symptoms and returning to baseline psychosocial function.

Treat co-morbid medical conditions

Many medical conditions and medications are associated with symptoms of depression. It is important to recognize, investigate, and treat co-morbid conditions. Table 2 shows the general medical conditions that are frequently associated with depression. However, depression can also coexist with these conditions and require independent treatment.

Assess suicide risk

Suicide risk should be regularly assessed throughout the course of treatment. Where appropriate, family or friends should also be consulted. Paradoxically, suicide risk may increase when patients begin to show response, partly because energy level may improve before the mood does.

One of the strongest clinical predictors of suicide is hopelessness, so the assessment of suicide risk should include inquiries into the patient’s plans or hopes. Questions to help assess suicide risk are included in another article in this series.[9] Other risk factors for suicide include demographic factors (male gender, adolescent or geriatric age, unemployment, socially isolated status, single/separated status, and poor support network), history and severity of prior attempts, presence of substance abuse and impulsiveness, recent discharge from the hospital, family history of depression and suicide, presence of psychosis, agitation, borderline and antisocial personality traits, and concurrent chronic medical or psychiatric illnesses.

Management of suicidal thoughts can include distraction techniques (taking a walk, calling a friend), keeping a list of reasons for living, and having access to telephone crisis lines. Patients who are at high suicide risk require urgent referral or hospitalization, which may include certification under the Mental Health Act.

Establish a therapeutic alliance

As with any treatment plan, informed consent should be obtained from the patient and/or the family. This is also an opportunity for psychoeducation, which includes brief discussion of the causes of depression, its symptoms, options for treatments, risks and benefits of such treatments, possible side effects, and expectation of response (Table 3). Family physicians are in a good position to establish a strong alliance as they already have a therapeutic relationship with the patient from continuity of care. Through better understanding of the illness and its expected course, patients may have more trust in the proposed treatment plans. Patients may also feel more in control as they are actively involved in the decision-making process.

Consider psychotherapy

Psychotherapy is an effective treatment for depression for motivated patients. The evidence for efficacy is greatest for structured, time-limited psychotherapies, including cognitive behavioral therapy (CBT), interpersonal psychotherapy (IPT) and problem-solving therapy (PST, developed specifically for primary care practitioners)[10] (Table 4). For mildly to moderately severe major depression, these psychotherapies are as efficacious as antidepressants and can be used as monotherapy. Unfortunately, access to evidence-based psychological treatments remains limited. Table 5 shows some available resources for psychological treatment in British Columbia.

Combining pharmacotherapy and psychotherapy in mildly to moderately severe major depression is no more effective than either treatment alone. However, combining antidepressant and psychotherapy treatment is recommended for patients with severe or chronic depression, with co-morbid medical or psychiatric conditions, or for nonresponders to either treatment alone.

Whether or not formal psychotherapy is offered, physicians can also provide supportive interventions that can improve patient outcomes (Table 6).

Choice of antidepressant

Antidepressants are often the treatment of choice for depression in primary care settings. A number of antidepressants are now available with different neurochemical actions and side effect profiles. Most systematic reviews have not shown any clinically significant differences in efficacy among antidepressants, but there are some clinical factors that are important to consider when choosing a medication.

Previous response to treatment

Previous response to an antidepressant highly predicts future response. Previous nonresponse should be assessed for adequacy of antidepressant trial, including doses, duration, and compliance. Previously experienced side effects (or lack thereof) also highly predict compliance and thus are important to assess.

Family history

Contrary to popular belief, there is no evidence that response of a family member to an antidepressant predicts a patient’s response to that medication. However, information about treatment in the family can help strengthen the therapeutic alliance. For example, a patient may be more likely to adhere to a medication that produced a positive experience for a family member (and vice versa).

Depressive subtypes

There are different subtypes of depression, each of which presents unique symptoms and tends to respond to different classes of antidepressants. Here are some common examples:

• Anxiety symptoms. If significant anxiety symptoms (e.g., excessive worry, panic attacks, hypervigilance) occur with depression, selective serotonin reuptake inhibitors (SSRIs, such as paroxetine, sertraline), mirtazapine, moclobemide, and venlafaxine-XR are first-line agents.

• Atypical depression. For atypical depression (reactive mood, hypersomnia, increase in appetite, weight gain, rejection sensitivity, extreme fatigue), SSRIs (e.g., fluoxetine, sertraline) are first-line medications. Previous evidence found that monoamine oxidase inhibitors (MAOIs) were more effective than tricyclic antidepressants, but moclobemide, a reversible inhibitor of MAO-A, can also be helpful.

• Seasonal pattern. If the depressive episodes have a seasonal pattern (recurrent autumn/winter onset with spring/summer remission), light therapy is the first-line treatment. Antidepressants, including SSRIs (e.g., fluoxetine, sertraline) and moclobemide, are also effective.

• Psychotic symptoms. If there are psychotic symptoms associated with depression (e.g., delusions of guilt, hallucinations), recommended treatment is an antidepressant combined with an atypical antipsychotic (e.g., olanzapine, quetiapine, risperidone), or electroconvulsive therapy.

• Severe depression. There is some evidence that severe depression is less likely to respond to SSRIs than it is to mirtazapine, venlafaxine-XR, and tricyclic antidepressants (TCAs).

Concomitant medications

Many antidepressants can interfere with the metabolism of a wide variety of medications through their effects on cytochrome P450 liver enzymes (CYP450). For example, by inhibiting CYP450 2D6, fluoxetine and paroxetine can cause clinically significant increases in blood levels of tricyclic antidepressants, haloperidol, risperidone, codeine, dextromorphan, and beta blockers. By inhibiting CYP450 3A4, fluvoxamine and nefazodone can cause increases in blood levels of benzodiazepines, carbamazepine, erythromycin, calcium channel blockers, and corticosteroids.

When antidepressants are prescribed to patients on other medications, physicians should be cautious about possible drug-drug interactions and, where appropriate, start the antidepressant at a lower dose, increase the dose slowly, and monitor drug serum levels if available. Alternatively, physicians can select an antidepressant that minimally affects the CYP450 system (e.g., citalopram, mirtazapine, moclobemide, sertraline, venlafaxine-XR).

Detailed information about interaction between antidepressants and other medications is available in the Canadian clinical guidelines.[1,5] Web sites such as also provide up-to-date information on drug-drug interactions.

Side effects

Side effects are among the most common reasons that patients prematurely stop taking medications. Most side effects are mild and transient, but patients should be informed about any serious side effects so they know what to watch for and what to do should they occur. An inquiry about side effects should be part of every follow-up visit.

The 10 most common side effects of antidepressants are nausea, headache, somnolence, dry mouth, insomnia, dizziness, diarrhea, agitation, fatigue, and constipation. Sexual dysfunction is also common, though patients may be reluctant to mention it to their physicians. Management of common side effects is discussed in Part 2.


For many patients, particularly those without medication benefit plans, the cost of antidepressants is important and should be considered in treatment choice (Table 7). Older medications like tricyclic antidepressants are generally much cheaper, but have a greater side effect burden.

Enhance treatment adherence

Adherence or compliance to treatment is crucial in successfully treating depression. Some simple messages to patients from their family physicians have been shown to greatly enhance adherence to medication (Table 8).

Monitor treatment response

Patients should initially be followed at least weekly or biweekly until they show clear improvement. Follow-up frequency can then be reduced to monthly or less often, depending on individual circumstances.

Many patients begin to respond to treatment within 2 to 4 weeks, show a good clinical response within 6 to 8 weeks, and achieve full remission of symptoms by 8 to 12 weeks. Recovery of baseline function may take longer. If there is no response at all after 4 weeks of treatment, a change in the treatment plan is indicated (e.g., increasing the dose).

Response can be most easily tracked by using validated symptom-rating scales. For example, good response can be defined as 50% or greater reduction in scores from baseline, while full remission is defined as a score within the normal (not depressed) range. Decisions about strategies for nonresponse or inadequate response (see Part 2) are often based on degree of response as measured by severity scores. Simple, validated measures to monitor response are discussed in a previous article in this series.[9]


The acute treatment of depression is an organized, strategic process. By applying basic principles for treatment, primary care physicians can optimize their treatment of patients with depression. Psychoeducation and a strong therapeutic alliance play major roles in enhancing adherence to treatment. Full remission of symptoms and a return to pre-morbid psychosocial function should be the goals of acute treatment for depression.

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.


The authors would like to thank Mr Andrew Chan, BSc (Pharm), for his contribution on information about the BC Pharmacare Program and the cost of medications.

Table 1. The phases of depression treatment.






6– 12 weeks, or longer

• Remission of symptoms
• Return to previous full function

• Establish therapeutic alliance
• Psychoeducation
• Choose treatment
• Monitor response


6 months following remission, or longer

• Prevention of relapse and recurrence

• Psychoeducation
• Manage side effects
• Rehabilitation
• Monitor for recurrence

Table 2. General medical conditions frequently associated with depression.[11]

Neurological disorders
Extrapyramidal diseases
Parkinson’s disease
Huntington’s disease
Progressive supranuclear palsy
Alzheimer’s disease
Cerebrovascular disease
Cerebral neoplasms
Cerebral trauma
CNS infections
Multiple sclerosis
Sleep apnea
Wilson’s disease

Systemic disorders
Endocrine disorders
• Cushing’s
• Addison’s
Parathyroid disorders 
Thyroid disorders
Vitamin deficiencies
• Folate
• Vitamin B12
• Niacin
• Vitamin C
• Thiamine

Inflammatory disorders
Systemic lupus erythematosus
Rheumatoid arthritis
Temporal arteritis
Sjögren’s syndrome
Other disorders
Cardiopulmonary disease
Myocardial infarction
Renal disease and uremia
Systemic neoplasms
Klinefelter’s syndrome
Postpartum mood disorders
Postoperative mood disorders

Table 3. Suggested topics to be discussed before initiating treatment.

  • Depression is a medical disorder with serious consequences.
  • The cause of depression is multifactorial, including biological/genetic factors (chemical imbalance in the brain), psychological experiences, and social and economic stressors.
  • Effective treatment is available with medications and/or psychotherapies.
  • Adherence to treatment is important, because the treatments take time.

Table 4. Evidence-based psychotherapies for treating depression.


General principles

Length of therapy

Cognitive behavioral therapy (CBT)

• Identify automatic, maladaptive thoughts and distorted beliefs that lead to depressive moods.
• Learn strategies to modify these beliefs and practise adaptive thinking patterns.
• Use a systematic approach to reinforce positive coping behaviors.

12 to 16 sessions

Interpersonal therapy (IPT)

• Identify significant interpersonal/relationship issues that led to, or arose from, depression (unresolved grief, role disputes, role transitions, social isolation).
• Focus on one or two of these issues, using problem-solving, dispute resolution, and social skills training.

12 to 16 sessions

Problem-solving therapy (PST)

• Use a structured approach to identify and actively solve problems that contribute to depression.

6 to 8 sessions

Table 5. Resources for psychological treatment in BC.

• Private psychiatrists by referral.
• The College of Psychologists of British Columbia ([604] 736-6164).
• Ambulatory psychiatric clinics at hospitals or community mental health centres.
• Changeways, a best-practices, group-based psychoeducational program for depression, offered in a number of hospitals and community health centres throughout the province (
• Consumer and self-help organizations, including the Canadian Mental Health Association ([604] 688-3234) and the Mood Disorders Association ([604] 873-0103).

 Table 6. Simple, supportive interventions to manage depression.

• Arrange regular follow-up visits.
• Use the power of the prescription pad to “prescribe” one brief walk per day and one pleasurable activity per day.
• Have patients keep a daily mood chart.
• Recommend self-help workbooks for depression, such as the Self Care Depression Program Patient Guide, available for free by downloading at; the Feeling Good Handbook by David D. Burns, Plume Books, 1999, about $30; Mind Over Mood by Dennis Greenberger and Christine A. Padesky, Zipper Books, about $40.

 Table 7. Therapeutic doses and costs of commonly prescribed antidepressants.


Usual daily dose (mg) Cost per day ($)




150 – 300

0.87 – 3.74


30 – 60

1.33 – 2.66


200 – 400

1.00 – 2.00


200 – 400

0.80 – 1.60




450 – 600

1.29 – 1.64




75 – 225

1.67 – 3.43




20 – 40

1.33 – 2.66


20 – 40

1.03 – 2.06


100 – 200

0.91 – 1.82


20 – 40

1.79 – 3.58


50 – 150

1.16 – 2.43




100 – 250

0.04 – 0.10


100 – 250

0.84 – 2.10


100 – 250

0.84 – 2.04


100 – 250

0.04 – 0.10


75 – 150

0.78 – 1.56




30 – 75

0.36 – 0.90


20 – 60

0.37 – 0.74

RIMA = Reversible inhibitor of monoamine oxidase A
SSRI = Selective serotonin reuptake inhibitor
SNRI = Serotonin and noradrenaline reuptake inhibitor
TCA = Tricyclic antidepressant
MAOI = Monoamine oxidase inhibitor
Data adapted from the BC Drug Formulary and the Manufacturers’ list (2001)

 Table 8. Five simple messages to promote adherence to antidepressant medication.

• Antidepressants are not addictive.
• Take your medication daily.
• It may take 2 to 4 weeks to start noticing improvement.
• Do not stop medication without talking to your doctor, even if you are feeling better.
• Mild side effects are common, but are usually temporary. If you have more side effects than reasonable, call your doctor.


1. Canadian Network for Mood and Anxiety Treatments (CANMAT). Guidelines for the Diagnosis and Pharmacological Treatment of Depression. 1st ed. revised. Toronto, ON: CANMAT, 1999. 76 pp. 
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5. Kennedy SH, Lam RW, Cohen NL, et al. Clinical guidelines for the treatment of depressive disorders. IV. Medications and other biological treatments. Can J Psychiatry 2001;46(suppl 1):38S-58S.PubMed Abstract Full Text   
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7. Thorpe L, Whitney DK, Kutcher SP, et al. Clinical guidelines for the treatment of depressive disorders. VI. Special populations. Can J Psychiatry 2001;46(suppl 1):63S-76S.PubMed Abstract Full Text 
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9. Anderson E, Michalak EE, Lam RW. Depression in primary care: Tools for screening, diagnosis, and measuring response to treatment. BC Med J 2002;44:415-419. 
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11. Cummings JL. Clinical Neuropsychiatry. Orlando, FL: Grune & Stratton, 1985:187 

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 in 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.

Agnes To, MD, Heidi M. Oetter, MD, Raymond W. Lam, MD, FRCPC. Treatment of depression in primary care—Part 1: Principles of acute treatment. BCMJ, Vol. 44, No. 9, November, 2002, Page(s) 473-478 - Clinical Articles.

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