Major Depressive Disorder in Primary Care

1. Definition
2. Evaluation of the Depressed Patient
3. Psychiatric Differential Diagnosis
4. Treatment Strategies
5. Change in Drug Treatment: When and How Should a Primary Care Physician Do It?
6. Continuation and Maintenance Therapies
7. When Should a Primary Care Physician Refer a Patient to a Psychiatrist?

I. Definition

Unipolar depressive disorders are characterized by a constellation of symptoms which include depressed mood, loss of pleasure (anhedonia), excessive guilt, poor energy, poor concentration, disturbances in appetite, psychomotor agitation or retardation and suicidal ideation. The most severe form of unipolar depression is major depressive disorder (MDD), which consists of a history of one or more major depressive episodes. A major depressive episode is defined as the presence of depressed mood and/or lack of pleasure/interest and at least 4 more symptoms for at least two weeks.

In addition, these symptoms must cause significant distress and impairment in psychosocial functioning and occur in the absence of a history of significant mood elevation (mania or hypomania). Dysthymic disorder is a milder but chronic form of depression and minor depressive disorder is characterized by fewer than five symptoms of MDD, with the duration of the illness being at least two weeks.


II. Evaluation of the Depressed Patient

A. General Recommendations

1. The evaluation of the depressed patient should include a determination of the following:

  • Physical, behavioral, and psychological symptoms. 
  • Onset, duration, and course of these symptoms. 
  • Current and past psychiatric history, in particular the presence of possible anxiety disorders and substance use disorders.

2. Clinicians must be aware that many patients who abuse drugs or alcohol may experience depression as result of their psychotropic substance use. Before making the diagnosis of depressive disorder, it is imperative to make sure that the symptoms of depression are not the result of recent bereavement (i.e., the patient has not experienced the loss of a loved one in the past month).

3. The use of self-rating scales (e.g., the Beck Depression Inventory or the HANDS) may help the clinician in making the diagnosis of unipolar depressive disorders.

4. When evaluating a patient with unipolar depressive disorders, the clinician must address the following questions:  

  • What are the depressive symptoms reported by the patient?
  • How severe and frequent are these symptoms?
  • For how long have they been present? 
  • Are these symptoms new or have they occurred before?  
  • What is the impact of these symptoms on daily life activities?

5. The communication with the depressed patient should include the following: 

  • Discuss that depression is a medical illness and refer to a neurochemical dysregulation in the brain. 
  • Emphasize that having depression is not indicative of a personal weakness or fault.

6. When proposing the treatment to the patient, it is important to explain that: 

  • It takes three to five weeks for antidepressants to work 
  • Adhering to treatment is very important and treatment itself should have a minimum duration (i.e., 6 months)

B. Medical History
The evaluation of the depressive disorder patient should also include a determination of the following:

  • Medical history and medications currently being used. Several medical conditions may be associated with the emergence of depressive symptoms, and the use of certain medications may trigger symptoms of depression. 
  • Assess the patient’s use of psychotropic drugs, alcohol, and other dietary habits.

C. Examination of the Patient
In addition to obtaining psychiatric and medical history, the examination of the patient should include a mental status examination, possibly a physical examination, and laboratory tests, when indicated.

III. Psychiatric Differential Diagnosis
A. Patients with dementia complain of symptoms (e.g., apathy, diminished concentration, and reduced memory) that may be hard to distinguish from the cognitive symptoms of unipolar depressive disorders. It is rare to see depressed outpatients with Mini Mental State Examination (MMSE) scores of less than 23.

B. Bipolar depression may present with depressive symptoms mimicking unipolar depressive disorders. However, patients with bipolar disorder typically have a history of periods of mood elevation or irritability (mania or hypomania) that will help clinicians in recognizing these patients as being bipolar. This is important, as the use of antidepressants alone may trigger episodes of mania/hypomania in these patients.

IV. Treatment Strategies

A. Antidepressants

1. Selective Serotonin Reuptake Inhibitors (SSRIs) have been widely used over the past few years as a treatment for depressive disorders. The rationale for their use as a first-line treatment is based on their excellent safety record and their safety during overdose. The most common side effects of the SSRIs are nausea, lack of appetite, weight loss, excessive sweating, nervousness, insomnia, sexual dysfunction, sedation, fatigue, headache, and dizziness.

SSRIs do not have cardiac toxicity or blood pressure effects. Uncommon side-effects reported with SSRIs are dry mouth, constipation, bleeding difficulties, nocturnal bruxism, hair loss, and reduced short-term memory. Most side effects tend to subside after a few weeks, particularly if dosage escalation has been slow and gradual. The starting dose for fluoxetine (Prozac), paroxetine (Paxil), citalopram (Celexa) is 20mg daily, with a maximum of 80 mg daily, while the staring dose for Sertraline (Zoloft) is 50mg daily with a maximum of 200mg, and the starting dose for escitalopram (Lexapro) is 10mg daily, with a maximum of 40mg daily.

2. Serotonin Norepinephrine Reuptake Inhibitors (SNRIs i.e. venlafaxine and duloxetine) have an excellent efficacy track record, are safe during overdose, and appear to be particularly efficacious in the treatment of physical/somatic symptoms of depression. The most common side effects of the SNRIs are nausea, lack of appetite, weight loss, excessive sweating, nervousness, insomnia, sexual dysfunction, sedation, fatigue, headache, and dizziness. SNRIs do not have cardiac toxicity. At higher doses, venlafaxine treatment has been associated with blood pressure elevations in some patients. The starting dose for venlafaxine (Effexor) XR is 75mg daily with a maximum of 300mg daily. The starting dose for duloxetine is 60mg daily with a maximum dose of 120-180mg daily.

3. Tricyclic Antidepressants (TCAs) are agents structurally related to each other that have been used for decades in the treatment of depressed patients. Because of their side-effect profile they are no longer used as first-line treatment. By blocking cholinergic muscarinic receptors, TCAs can cause dry mouth, constipation, urinary retention, sinus tachycardia, blurred vision, and memory dysfunction. Through a blockade of histamine H1-receptors, TCAs can also produce sedation, increased appetite, weight gain, and potentiation of central depressant drugs. 

Finally, by blocking alpha1-adrenergic receptors, TCAs can cause postural hypotension, dizziness, reflex tachycardia, and potentiation of the antihypertensive effect of drugs such as prazosin, terazosin, doxazosin, and labetalol. Sexual dysfunction can occur during treatment with TCAs, which can also have significant effects on cardiac conduction, through a quinidine-like effect. TCAs are contraindicated in the treatment of patients with narrow-angle glaucoma and prostatic hypertrophy. Most side effects tend to subside after a few weeks, particularly if dosage escalation has been slow and gradual. Persistence of bothersome anticholinergic side effects is usually handled by decreasing the dose or by adding cholinergic smooth-muscle stimulants (e.g., bethanecol). An important caution in the use of TCAs is their lethality in overdose.

It is useful to obtain an EKG before and after four weeks of TCA treatment, with plasma levels of TCAs being a rough guide to dosing adequacy. The side-effect profile of TCAs may be advantageous in the treatment of depressed patients who complain of insomnia and weight loss, as these symptoms can be helped quite rapidly by these drugs. On the other hand, side effects such as weight gain and sedation may create difficulties with atypical depressed patients complaining of hypersomnia and hyperphagia. For these reasons, and because of the required dose titration, adherence to TCA treatment can be poor at times, in spite of the relatively low cost of these drugs.

4. A number of atypical antidepressants (bupropion, nefazodone, mirtazapine, and trazodone) have been used in the treatment of depression. These agents have chemical structures different from those of TCAs and SSRIs, and their side-effect profile is variable depending on the agent. They are all relatively safe in overdose, as they lack significant cardiac effects. Common side effects of bupropion include agitation, insomnia, weight loss, dry mouth, headache, constipation, and tremor.

It has been noted to cause seizures, at a rate of 4/1,000 in its immediate release form. Its sustained release (SR) form is associated with a seizure risk comparable to that of the SSRIs. However, the risk of seizure markedly increases at doses > 450 mg/day in divided doses and may be more likely to induce seizures in patients with bulimia nervosa. It is generally safe in overdose. It is less likely to induce sexual dysfunction than the SSRIs, and can even be beneficial as an adjunct in SSRI-induced sexual dysfunction. A sustained release formulation is now available, allowing a safe q.d. and b.i.d. dosing. Mirtazapine lacks significant anticholinergic and anti-alpha1-adrenergic effects. Mirtazapine does have significant antihistamine H1-receptor blocking activity, which accounts for the sedation, drowsiness, increased appetite, and weight gain observed with this drug.

Other side effects of mirtazapine are dry mouth, constipation, and dizziness. The relative lack of significant drug-drug interactions with other antidepressants makes mirtazapine a good candidate for combination strategies (i.e., combining two antidepressants together at full doses). Trazodone (Desyrel) is less lethal in overdose than the TCAs, though slightly more lethal than the SSRIs. The most common side effects are sedation, orthostatic hypotension, and headache. Priapism is a rare but serious side effect that requires immediate medical attention. Trazodone may induce arrhythmias in those with pre-existing heart disease and may increase levels of digoxin and phenytoin (Dilantin). Trazodone is most commonly used as an adjunctive medication for insomnia due to its sedating properties. Nefazodone (Serzone). Nefazodone is chemically related to trazodone, with serotonin blockade but with less alpha-1 blockade. It is less likely to cause sexual dysfunction than SSRIs, and is less anticholinergic and histaminergic than the TCAs. Common side effects include somnolence, dizziness, dry mouth, nausea, constipation, headache, amblyopia, and blurred vision. Nefazodone has been implicated in cases of catastrophic hepatic failure. It should not be used in patients with liver dysfunction, and monitoring of serum transaminases in patients taking nefazodone is prudent.

Any elevation of serum transaminases should lead to discontinuation of nefazodone treatment. Nefazodone is a potent inhibitor of cytochrome P450 3A4 isoenzymes, and by interacting with cisapride (Propulsid), terfenadine (Seldane) or astemizole (Hismanal) may lead to QT prolongation and torsades de pointes.

5. Monoamine Oxidase Inhibitors (MAOIs) have been used primarily in the treatment of certain depressive subtypes (i.e., atypical) or as a third or fourth line of treatment of depression, mostly in treatment-resistant patients. MAOIs inhibit the MAO enzymes (type A and B) located in monoamine-containing nerve terminals, and in the liver and other tissues that metabolize such monoamines as norepinephrine, serotonin, and dopamine. Since MAO enzymes are crucial in inactivating exogenous monoamines arising from foods or the action of bacteria in the gut, including the sympathomimetic pressor amine tyramine, the use of MAOIs is associated with a risk of lethal hypertensive crisis related to interactions with foods containing tyramine, and with sympathomimetic drugs.

They can also be associated with severe drug-drug interactions with meperidine. Serotonergic syndromes, characterized by heat stroke, vascular collapse, fever, tachycardia, or even death, have been reported when MAOIs have been combined with potent serotonergic agents (e.g., the SSRIs). The most common side effects of MAOIs are insomnia, sedation, orthostatic hypotension, weight gain, and sexual dysfunction, with less common side effects being tremor, blurred vision, dry mouth, constipation, and urinary retention. It is usually best to administer the last MAOI dose in the early afternoon, as insomnia is a potential side effect. To avoid the risk of severe (and possibly lethal) drug-drug interactions, one must wait 2 weeks after discontinuing antidepressants and 5 weeks after discontinuing fluoxetine or protriptyline before starting treatment with MAOIs. It is also recommended to wait 2 weeks before starting another antidepressant following discontinuation of an MAOI.

B. Psychotherapy

1. Cognitive therapy and interpersonal psychotherapy are probably the most efficacious forms of psychotherapy in the treatment of patients with depressive disorders.

2. Behavioral therapy and short-term dynamic psychotherapy have also been studied in the treatment of major depression, but their efficacy is less well established.

3. Many other forms of therapy are currently used in the treatment of depressed patients, but more studies are needed to establish their usefulness.

C. Other Treatments
Electroconvulsive treatment (ECT) should primarily be used only after several adequate antidepressant trials have failed or with patients with depression marked by delusions or other psychotic symptoms. The most common side effect of ECT is retrograde and anterograde amnesia; patients very frequently experience difficulty retaining new information during the course of ECT and up to several months after the last treatment, followed by gradual normalization of memory functions. Heart arrhythmias or hypertension can also occur during the course of ECT, and death, mostly caused by cardiovascular complications, is an extremely rare complication of ECT. Although there are no absolute contraindications to ECT, relative contraindications are the presence of coronary artery disease, digitalis toxicity, increased intracranial pressure, and intracranial lesions (e.g., arteriovenous malformation, arterial aneurysm, hemorrhagic stroke). Specific modifications in anesthetic technique are necessary to safely treat patients with recent myocardial infarction, congestive heart failure, conduction abnormalities, coronary artery disease, hypertension, and impaired pulmonary function.

Light therapy involves the exposure of the eyes to light containing very little ultraviolet light. Its primary indication for use is seasonal affective disorder (SAD), characterized by recurrent fall and winter depressions alternating with nondepressed periods in spring and summer. There is no clear evidence yet for the efficacy of light therapy in nonseasonal depressives. Most frequent side effects observed during the course of phototherapy are insomnia, headaches, eyestrain, and irritability.

Many drug treatments have shown some efficacy in the treatment of depressive disorders either in small studies or case reports. Their efficacy, however, has not been established yet. These agents include s-adenosyl-l-methionine (SAMe), St. John’s wort (hypericum), psychostimulants (i.e., dextroamphetamine and methylphenidate), certain anticonvulsants (i.e., gabapentin, lamotrigine, carbamazepine, and valproic acid), dehydroepiandrosterone (DHEA), methylfolate, inositol, and dopaminergic agonists. Many of these agents are used as adjuncts to standard antidepressants in the event of nonresponse.

V. Change in Drug Treatment: When and How Should a Primary Care Physician Do It?
A. Circumstances in which prescribers should change pharmacologic strategy: 

  • Patients who do not experience significant improvement with continuing current medication at full dose for 4 weeks. 
  • Patients who experience a relapse within a few months of treatment initiation. The change in treatment may either include raising the dose, switching to a different antidepressant or augmentation with a second anti-depressant or agent.

B. Augmentation strategies are typically carried out by adding: 

  • Lithium (i.e., 600 to 900 mg/day, often at bedtime) 
  • Thyroid (i.e., 50 to 75 µg/day of T3) 
  • Psychostimulants (i.e., 20 to 40 mg/day of methylphenidate or dextroamphetamine 10 to 20 mg/day) 
  • Dopaminergic Agents (i.e., 0.125-0.25 mg t.i.d. of pramipexole or ropinirole) 
  • Atypical Antipsychotic Agents (i.e., 5-15 mg qhs of olanzapine, 40-160 mg/day of ziprasidone, or 1-4 mg/day of risperidone) 
  • Anticonvulsant Agents (i.e., 600-1800 mg/day of gabapentin, or 100-200 mg of lamotrigine) 
  • Antianxiety drugs (i.e., 10-30 mg b.i.d. of buspirone, or benzodiazepines)

C. Combination strategies are usually obtained by combining the following drugs: 

  • an SSRI at full dose and a low-dose TCA (i.e., 25 to 50 mg/day) 
  • an SSRI at full dose and mirtazapine at full dose (i.e., 15 to 30 mg/day) 
  • an SSRI at full dose and bupropion at full dose (i.e., 100 to 200 mg b.i.d. of its sustained release formulation)

D. Switching antidepressants is usually carried out by the following means:

  • Switching to an agent of the same class (i.e., from an SSRI to another SSRI) 
  • Switching to an agent of a different class (i.e., from an SSRI to an SNRI or a TCA) 
  • Switching to an atypical agent (i.e., bupropion, mirtazapine)
  • Switching to an MAOI

VI. Continuation and Maintenance Therapies

A. Continuation Therapy
There are three phases in the treatment of depressive disorders with antidepressant drugs: acute therapy (the first 8 to 12 weeks), continuation therapy, and maintenance therapy. Whereas continuation therapy is the continued administration of the drug for 4 to 6 months following the disappearance of acute symptoms in order to treat fully the episode, maintenance therapy refers to pharmacologic treatment extending beyond the continuation phase and being administered for long periods of time (months or years) to prevent recurrences. The risk of relapse is significantly higher when recently improved patients discontinue their antidepressant, as compared to patients receiving continuation treatment with antidepressants. Therefore, it is best to continue the antidepressant treatment for at least 4 to 6 months after obtaining clinical response.

B. Maintenance TherapySince most of the patients who have had at least one prior episode of major depression are likely to suffer a recurrence, maintenance antidepressant treatment is important, particularly for patients with a high probability of having recurrences. The main risk factors for recurrent depression are a history of frequent or multiple episodes of depression, a history of double-depression (i.e., major depression superimposed upon chronic, mild depression), and a long duration of the index episode (i.e., more than 2 years).

VII. When Should a Primary Care Physician Refer a Patient to a Psychiatrist? 

A. Primary care physicians should consider referring a patient to a psychiatrist under the following circumstances

  • The patient presents a significant suicidal risk.
  • The patient is pregnant or plans to become pregnant. 
  • There is very little or no social support. 
  • The patient is disabled by the depression, or presents with psychotic features, or is actively suicidal. In the latter two cases, this should be considered a psychiatric emergency and immediate psychiatric evaluation/consultation should be sought. 
  • The patient has certain comorbid conditions (i.e., substance use disorder, panic disorder, obsessive-compulsive disorder).
  • The patient fails to respond to one or two adequate trials of antidepressants.


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