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Pharmacological Treatment of Mental Disorders in Primary Health Care. Geneva: World Health Organization; 2009.

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Pharmacological Treatment of Mental Disorders in Primary Health Care.

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Chapter 4Medicines used in depressive disorders

1. Definition of depressive disorders

1.1.

Depression is a condition characterized by episodes of depressed mood. Each episode is characterized by lowering of mood, reduction of energy, and decrease in activity. Capacity for enjoyment, interest, and concentration is reduced, and marked tiredness after even minimum effort is common. Sleep is usually disturbed and appetite diminished. Self-esteem and self-confidence are almost always reduced and, even in the mild form, some ideas of guilt or worthlessness are often present. The lowered mood varies little from day to day, is unresponsive to circumstances and may be accompanied by so-called “somatic” symptoms, such as loss of interest and pleasurable feelings, waking in the morning several hours before the usual time, depression worst in the morning, marked psychomotor retardation, agitation, loss of appetite, weight loss, and loss of libido. Though depressive feelings are common, especially after experiencing setbacks in life, depressive disorder is diagnosed only when the symptoms reach a threshold and last at least two weeks. Depression needs to be distinguished from states of subjective distress and emotional disturbance, possibly interfering with social functioning and performance, arising in the period of adaptation to a significant life change or a stressful life event (e.g. death of a loved one).

1.2.

In some circumstances, symptoms of anxiety and depression are both present, but neither is clearly predominant, and neither type of symptom is present to the extent that justifies a diagnosis if considered separately. In these situation the term mixed anxiety and depressive disorder is generally used.

1.3.

Depression is usually grouped into mild, moderate and severe. Mild to moderate depression is characterized by depressive symptoms and some functional impairment; severe depression is characterized by depressive symptoms, functional impairment, agitation or psychomotor retardation, and marked somatic complaints.

1.4.

Depression is more common in women than in men. The average point prevalence of unipolar depressive episodes has been estimated to be 1.9% for men and 3.2% for women, and that 5.8% of men and 9.5% of women will experience a depressive episode in a 12-month period. These prevalence figures vary across populations. Depression can affect individuals at any stage of the life span, although the incidence is highest in middle age.

1.5.

Depressive symptoms often markedly impair everyday functioning. Global burden of disease 2004 update analysis shows that unipolar depressive disorders place an enormous burden on society and are ranked as the third leading cause of burden among all diseases, accounting for 4.3% of the total disability-adjusted life years (DALYs). While these estimates clearly demonstrate the current very high level of burden resulting from depression, the outlook for the future is even starker. By the year 2030, if current trends for communicable disease control and demographic and epidemiological transition continue, the burden of depression will increase to 6.2% of the total burden of disease, becoming the leading cause of DALYs lost.

1.6.

The term unipolar depression is sometimes used to make a distinction between depressive episodes in the course of major (or unipolar) depression and depressive episodes in the course of bipolar disorder (bipolar depression).

1.7.

Depression is essentially an episodic recurring disorder, each episode lasting usually from a few months to a few years, with a normal period in between. In about 20% of cases, however, depression follows a chronic course with no remission, especially when adequate treatment is not available. The recurrence rate for those who recover from the first episode is around 35% within 2 years and about 60% at 12 years. The recurrence rate is higher in those who are more than 45 years of age. One of the particularly tragic outcomes of a depressive disorder is suicide.

1.8.

Considering that it is unclear whether health care providers should routinely screen all patients seen in primary care for depression, it is generally recommended to screen only patients at risk (family or personal history of depression, multiple medical problems, unexplained physical symptoms, chronic pain, or use of medical services that is more frequent than expected) using very simple questions. A two-question case-finding instrument has been shown to be reliable in primary care. Only individuals with affirmative answers to both questions should be further investigated for depressive symptoms.

1.9.

Depressive symptoms can be confused with those of other medical illnesses (i.e. weight loss and fatigue may be associated with diabetes, cancer, and thyroid disease). In addition, the use of some medicines is associated with depressive symptoms (benzodiazepines, beta-blockers, narcotics and steroids).

1.10.

Depressive symptoms can also be confused with normal, subjective distress arising after exposure to extreme stressors (e.g. domestic violence, death of a loved one, disaster). Yet, such events are at the same time also risk factors for depressive disorders. If the subjective distress of the patient is in terms of intensity and persistence out of proportion of the patient's life situation, then depressive disorder is likely present.

The following two questions may be used in patients who might be at risk for depression:

  1. “During the past 4 weeks have you often been bothered by feeling down, depressed or hopeless?”
  2. “During the past 4 weeks have you often been bothered by having little interest or pleasure in doing things?”

2. Preliminary assessment and initial management strategies

2.1.

Health care providers should initially exclude the possibility that an organic illness or a substance abuse disorder is the underlying cause of depressive symptoms. A detailed medical and psychiatric history, physical and neurologic examination, and mental status assessment should be carried out.

2.2.

Depressed patients may contemplate self-injury and suicide. Health care providers may use the patient's history and current behaviour to assess the risk. In addition, the following questions may help:

  1. “Do you ever think of hurting yourself or taking your own life?”
  2. (if YES) “Do you currently have a plan?”
  3. (if YES) “What is your plan?”
2.3.

Health care providers should not avoid these questions for fear of suggesting the idea of suicide. Even in the absence of immediate risk, physicians should emphasize to patients the importance of reporting suicidal thoughts, especially if they are becoming more intense or frequent.

Patients with major depression contemplating self injury should be intensively monitored; monitoring may include admission to an inpatient facility, close supervision by family members or by other individuals who know the patient well

3. Short-term treatment with antidepressants

3.1.

Antidepressants are effective in around 60% of patients, although more than 30% of patients are placebo responders. Antidepressants may take up to 6-8 weeks to have a full therapeutic effect.

3.2.

Antidepressants are classified into several classes according to the mechanism of action: tricyclic or related antidepressants (amitriptyline, clomipramine, desipramine, dothiepin, dosulepine, doxepin, imipramine, lofepramine, nortriptyline, trimipramine, mianserine, trazodone); monoamine oxidase inhibitors (moclobemide, isocarboxazid, phenelzine, tranylcypromine); selective serotonin reuptake inhibitors (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline); other antidepressants (duloxetine, mirtazapine, reboxetine, venlafaxine).

3.3.

All antidepressants are similarly effective in the acute treatment of depressive symptoms. However, antidepressants differ in terms of adverse effects. The efficacy of antidepressants has been demonstrated in clinical trials conducted in patients with moderate to severe depression only. In contrast, the efficacy of antidepressants in mild depression is unproven.

3.4.

Health care providers should offer information, empathetic listening, reassurance and psychological support (e.g. problem solving counselling) and referral to relevant social services and resources in the community. This may also help develop a good relationship and a therapeutic alliance that may positively influence the patient's subjective well-being. If feasible, plan a new visit after 2-4 weeks. In mild depression, health care providers may consider treatment with antidepressants if symptoms get worse or persist after 4 weeks of watchful waiting.

3.5.

According to the WHO EML, essential medicines for depressive disorders are amitriptyline and fluoxetine. Amitriptyline is indicated as an example of the class for which there is the best evidence for effectiveness and safety. Thus amitriptyline represents tricyclic antidepressants.

3.6.

In patients with moderate to severe symptoms, functional impairment, or a long duration of illness, health care providers should consider the prescription of an oral antidepressant. If more than one antidepressant is available, health care providers should choose the most suitable agent for each patient taking into consideration the following aspects: 1) Inclusion in the WHO EML: this list includes the most efficacious, safe and cost-effective medicines; 2) Past history of antidepressant responsiveness: if a patient has already responded well, without intolerable side-effects, to a specific agent, that agent might be chosen; if a patient failed to respond, or had intolerable side-effects, to a specific agent, that agent should generally not be prescribed any more; 3) Medical comorbidities: if a patient suffers from specific medical problems, some agents might be better avoided (e.g. amitriptyline should be avoided in elderly patients with cardiac problems if regular electrocardiogram checks are not feasible; venlafaxine should be cautiously prescribed in patients with high blood pressure); 4) Plausible impact of adverse reactions: the subjective impact of side-effects should be taken into consideration (e.g. the relevance of sexual dysfunctions varies between males and females and in different age groups); 5) Cost implications: these may change according to the health care system in which antidepressants are prescribed; 6) New/old agent: as a general rule, it is wise to prescribe well known medicines, since the side-effect profile of new medicines becomes clear only after years of practice.

Health care providers should consider treatment with antidepressants in individuals with moderate to severe major depression

3.7.

The use of monoamine oxidase inhibitors is generally not recommended in primary care due to risk of significant side-effects and no obvious therapeutic advantage as first-line medications.

3.8.

While tricyclic antidepressants are toxic when taken in overdose, fluoxetine and other selective serotonin-reuptake inhibitors are less dangerous and may be prescribed in patients at risk of self-harm.

3.9.

Assess treatment effectiveness after 6-8 weeks. If no improvement is seen after 8 weeks, discuss with the patient the possibility to increase the dose or to switch to another antidepressant (it is generally recommended to change medicine class if antidepressants of different classes are available). If treatment adherence is a major problem, discuss with the patient the possibility to switch to another antidepressant that may be better tolerated. If adverse reactions are a major problem, discuss with the patient the possibility to decrease the dose. If adverse reactions persist despite a dose reduction, a switch to another antidepressant with a different pattern of adverse reactions may be considered.

3.10.

Health care providers should take into consideration that the risk of self-harm may increase as depression lifts and energy returns with treatment. Health care providers may consider to offer psychological support by scheduling follow-up visits at regular time intervals.

3.11.

Substance abuse is relatively common among depressed patients and should not be considered a contraindication to therapy: treating depression can decrease the use of tobacco, alcohol and possibly other medicines of abuse.

3.12.

Depressive episodes in patients with bipolar disorder (bipolar depression) generally respond to the same treatment of unipolar depression. However, antidepressant medicines may induce a switch from depression to mania. In patients with bipolar depression health care providers should prescribe antidepressants in association with an anti manic medicine, as this combination treatment decreases the risk of switching.

4. Long-term treatment with antidepressants

4.1.

According to local circumstances, health care providers may plan regular visits during the first 12 weeks of antidepressant treatment (at least 3 visits are generally recommended), considering that antidepressants may take up to two months to be effective.

4.2.

After the acute episode has resolved, it is generally suggested to continue treatment for at least 6-8 months to prevent relapse. Patients at high risk of relapse (e.g. those with 2 or more previous episodes, or those with major depression lasting more than 2 years) should be offered to continue pharmacotherapy for at least 2 years.

Antidepressants should be continuously and regularly taken for 6-8 months after recovery

4.3.

Health care providers should prescribed the same dose as used for acute treatment.

4.4.

Follow-up visits should be scheduled every 3 to 6 months.

4.5.

If depressive symptoms return, health care providers may consider the possibility of adjusting the dosage and check with patient treatment adherence. If symptoms get worse, health care providers should consider a change of medication.

5. Administration of antidepressants

5.1.

As a general rule, health care providers should not prescribe two antidepressants simultaneously. Potential dangers include the development of a serotonin syndrome (restlessness, diaphoresis, tremor, shivering, myoclonus, confusion, convulsions).

5.2.

It is generally suggested to start with low doses, and to increase gradually, approaching the target dose over a period of 7 to 14 days.

5.3.

Switching from one antidepressant to another should be performed with caution. Health care providers should gradually reduce the dose of the first antidepressant and gradually increase the dose of the new antidepressant.

5.4.

Treatment discontinuation should be gradual, with tapering over a period of 2 to 3 months. Abrupt antidepressant withdrawal can cause rebound symptoms.

6. Adverse reactions of antidepressants

6.1.

Side-effects associated with tricyclics include sedation, anticholinergic effects (dry mouth, blurred vision, constipation, urinary retention, agitation, confusion), cardiovascular effects (orthostatic hypotension, tachycardia, arrhythmias), prostatism, narrow angle glaucoma and weight gain.

6.2.

Side-effects associated with selective serotonin-reuptake inhibitors include activation, agitation, tremor, dizziness, insomnia, nausea, diarrhoea, sexual problems, headache, hyponatraemia, weight loss and rash.

6.3.

In patients taking venlafaxine, blood pressure should be regularly checked. Common side-effects associated with venlafaxine include nausea, headache, insomnia, somnolence, dry mouth, dizziness, sexual dysfunction, elevation of blood pressure at high doses. Health care providers should additionally monitor for the signs and symptoms of cardiac dysfunction, particularly in those with known cardiovascular disease.

6.4.

Health care providers should take into consideration that antidepressants may induce/ worsen suicide ideas and attempts during early phases of treatment. During these early phases health care providers should plan follow-up visits at short intervals and should consider the possible supporting role of family members and/or hospital admission.

6.5.

Hyponatraemia is a rare but potentially serious adverse effect of antidepressants. Health care providers may suspect hyponatraemia if patients develop lethargy, confusion, nausea, muscle cramps and seizures. If hyponatraemia occurs, withdraw antidepressant immediately.

6.6.

Tricyclics are associated with higher rates of adverse effects than selective serotonin-reuptake inhibitors, but the difference is small and of uncertain clinical significance.

6.7.

Side-effects tend to diminish over time, with the exception of weight gain and sexual dysfunction that may persist longer than other side effects.

6.8.

Health care providers should stop treatment gradually, as antidepressants can cause rebound symptoms. Withdrawal symptoms include agitation, anxiety, insomnia, tremor, dizziness, paraesthesia, mood swing and rhinitis. These symptoms are more likely to occur with medicines with a short half life, such as paroxetine.

7. Overdosage of antidepressants

7.1.

If antidepressant overdosage is suspected, referral to acute medical facility is recommended.

7.2.

The clinical features of tricyclic overdose is characterized by sedation, hypotension, tachycardia, electrocardiogram abnormalities, dry mouth, blurred vision, dilated pupils, urinary retention, absent bowel sounds, convulsions, seizures. The overall incidence of serious cardiovascular arrhythmias is low, while hypotension is more common.

7.3.

In general, overdoses with selective serotonin-reuptake inhibitors alone very rarely result in fatality. The clinical features of serotonin-reuptake inhibitors overdose is characterized by vomiting, tremor, drowsiness, tachycardia, electrocardiogram changes, convulsions. At high doses decreased consciousness may occur.

7.4.

Antidepressant overdose in combination with alcohol or other medicines appear to be associated with increased toxicity.

7.5.

Ingestion of large amounts of venlafaxine may lead to fatalities. Venlafaxine overdose is characterized by sedation, tachycardia, electrocardiogram changes, convulsions.

8. Special patient populations

8.1.

In the elderly low mood may be masked, and anxiety, memory impairment with poor concentration and psychomotor retardation, may be the main symptoms. Since cognitive impairment may result from either depression or dementia, dementia should be considered in the differential diagnosis of depression in older adults. Health care providers may prescribe antidepressant therapy in patients with apparent dementia who meet diagnostic criteria for major depression.

8.2.

Since tricyclics are associated with postural hypotension, cardiac conduction abnormalities and arrhythmias, health care providers should ask the patient and/or family member about the existence of cardiovascular abnormalities, and whether drug therapies for cardiac problems have ever been prescribed and taken. If arrhythmia or ischemic heart disease or other serious cardiac problems are present, health care providers should obtain an electrocardiogram before therapy is initiated. If electrocardiogram is not feasible, health care providers may chose not to prescribe tricyclics. Health care providers should consider that the arrhythmogenic potential of tricyclics is dose-related.

8.3.

In elderly patients selective serotonin-reuptake inhibitors may increase the risk of gastrointestinal bleeding. Health care providers should cautiously prescribe these agents in elderly patients that concurrently use drugs that may cause bleeding abnormalities (non steroidal anti-inflammatory drugs for example).

8.4.

In the elderly, health care providers should prescribe reduced initial doses of tricyclics, with lower final doses. The effective doses of fluoxetine and other selective serotonin-reuptake inhibitors in the elderly may be similar to those for younger adults.

8.5.

Antidepressants are hepatically metabolised, so they should be prescribed at lower starting dose, with longer intervals between dosage increases, in patients with liver disease.

8.6.

Health care providers should avoid antidepressants in pregnant women. However, if maternal depression is a major concern, an antidepressant may be prescribed. Current evidence suggests that there is no increased risk of malformations in women exposed to fluoxetine and no evidence of teratogenicity. Similarly, there is no convincing evidence that tricyclics are teratogenic in the first trimester, but there is an almost complete absence of formal studies. Rebound symptoms have been observed in some newborns.

8.7.

Although less than 10% of the adult therapeutic dose of antidepressants is excreted in breast milk, these agents should be used with care in breast feeding women.

8.8.

In children and adolescents there is little evidence that tricyclics are efficacious and, considering the side-effects and risks of toxicity in overdose, they are generally not recommended. Similarly, the balance between benefit and harm is considered unfavourable for the selective serotonin-reuptake inhibitors citalopram, escitalopram, paroxetine, sertraline, and for mirtazapine and venlafaxine. By contrast, fluoxetine has been shown to be effective for treating depressive illness in children and adolescents. However, considering that antidepressants in children and adolescents may induce/ worsen suicide ideas and attempts, health care providers should decide use of these medicines on a case-by-case basis. Health care providers should consider that any possible increased risk needs to be balanced against the well established risk of suicide in untreated depression.

9. Potentially relevant interactions

Alcohol and tricyclics. Enhanced sedation may be expected.

Antipsychotics and fluoxetine. Levels of antipsychotics are generally raised.

Barbiturates and tricyclics. Serum levels of amitriptyline are generally reduced.

Carbamazepine and tricyclics. The metabolism of amitriptyline may be accelerated.

Phenytoin and fluoxetine. Levels of phenytoin are generally raised.

Vasoconstrictor sympathomimetics and tricyclics. Response is enhanced, e.g. hypertension and arrhythmias.

Warfarin and fluoxetine. INR (international normalised ratio) may be raised.

10. Essential medicines for depressive disorders

Amitriptyline

  • Starting dose: 50-75 mg/day orally in divided doses (or as a single dose at night).
  • Therapeutic dose: 150-200 mg/day orally.
  • Common adverse effects: dry mouth, constipation, urinary retention, blurre dvision and disturbances in accommodation, increased intraocular pressure, hyperthermia, drowsiness and increased appetite with weight gain, orthostatic hypotension, tachycardia, sexual dysfunction.
  • Serious adverse effects: electrocardiogram changes, confusion or delirium, hyponatraemia associated with inappropriate secretion of antidiuretic hormone, peripheral neuropathy, tremor, ataxia, dysarthria, convulsions.
  • WHO Model List: tablet 25 mg.

Fluoxetine

  • Starting dose: 10 mg/day orally. After a week the dose should be increased to 20 mg/day.
  • Therapeutic dose: 20-40 mg/day orally. Further increases to 60 mg daily may be considered if no improvement is seen after several weeks.
  • Common adverse effects: gastrointestinal disturbances such as nausea, vomiting, dyspepsia, constipation, diarrhoea, anorexia, weight loss, anxiety, restlessness, nervousness, insomnia; headache, tremor, dizziness, agitation, sexual dysfunction
  • Serious adverse effects: convulsions, hallucinations, extrapyramidal effects, depersonalisation, panic attacks, hyponatraemia associated with inappropriate secretion of antidiuretic hormone, bleeding disorders, electrocardiogram changes.
  • WHO Model List: capsule or tablet 20 mg.
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