Elderly

• Baseline ECG is recommended for patients over age 50

• May be more sensitive to anticholinergic, cardiovascular, hypotensive, and sedative effects

• Initial dose 50 mg/day; increase gradually up to 100 mg/day

• Reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 and older

Children and Adolescents

• Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and make sure to document this in the patient’s chart

• Monitor patients face-to-face regularly, particularly during the first several weeks of treatment

• Use with caution, observing for activation of known or unknown bipolar disorder and/or suicidal ideation, and inform parents or guardians of this risk so they can help observe child or adolescent patients

• Not recommended for use in children under age 12

• Several studies show lack of efficacy of TCAs for depression

• May be used to treat enuresis or hyperactive/impulsive behaviors

• Some cases of sudden death have occurred in children taking TCAs

• Adolescents: initial dose 50 mg/day; increase gradually up to 100 mg/day

Pregnancy

• Risk Category C [some animal studies show adverse effects; no controlled studies in humans]

• Crosses the placenta

• Adverse effects have been reported in infants whose mothers took a TCA (lethargy, withdrawal symptoms, fetal malformations)

• Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

• For many patients this may mean continuing treatment during pregnancy

Breast Feeding

• Some drug is found in mother’s breast milk

✽ Recommended either to discontinue drug or bottle feed

• Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

• Must weigh the risk of treatment (first trimester fetal development, third trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, maternal health, infant bonding) to the mother and child

• For many patients this may mean continuing treatment during breast feeding

TRIMIPRAMINE: THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages

• Patients with insomnia, anxiety

• Severe or treatment-resistant depression

Potential Disadvantages

• Pediatric and geriatric patients

• Patients concerned with weight gain and sedation

Primary Target Symptoms

• Depressed mood

• Symptoms of anxiety

• Somatic symptoms

Pearls

✽ May be more useful than some other TCAs for patients with anxiety, sleep disturbance, and depression with physical illness

✽ May be more sedating than some other TCAs

• Tricyclic antidepressants are often a first-line treatment option for chronic pain

• Tricyclic antidepressants are no longer generally considered a first-line option for depression because of their side effect profile

• Tricyclic antidepressants continue to be useful for severe or treatment-resistant depression

• TCAs may aggravate psychotic symptoms

• Alcohol should be avoided because of additive CNS effects

• Underweight patients may be more susceptible to adverse cardiovascular effects

• Children, patients with inadequate hydration, and patients with cardiac disease may be more susceptible to TCA-induced cardiotoxicity than healthy adults

• For the expert only: although generally prohibited, a heroic but potentially dangerous treatment for severely treatment-resistant patients is for an expert to give a tricyclic/tetracyclic antidepressant other than clomipramine simultaneously with an MAO inhibitor for patients who fail to respond to numerous other antidepressants

• If this option is elected, start the MAOI with the tricyclic/tetracyclic antidepressant simultaneously at low doses after appropriate drug washout, then alternately increase doses of these agents every few days to a week as tolerated

• Although very strict dietary and concomitant drug restrictions must be observed to prevent hypertensive crises and serotonin syndrome, the most common side effects of MAOI and tricyclic/tetracyclic antidepressant combinations may be weight gain and orthostatic hypotension

• Patients on tricyclics should be aware that they may experience symptoms such as photosensitivity or blue-green urine

• SSRIs may be more effective than TCAs in women, and TCAs may be more effective than SSRIs in men

• Since tricyclic/tetracyclic antidepressants are substrates for CYP450 2D6, and 7% of the population (especially Caucasians) may have a genetic variant leading to reduced activity of 2D6, such patients may not safely tolerate normal doses of tricyclic/tetracyclic antidepressants and may require dose reduction

• Phenotypic testing may be necessary to detect this genetic variant prior to dosing with a tricyclic/tetracyclic antidepressant, especially in vulnerable populations such as children, elderly, cardiac populations, and those on concomitant medications

• Patients who seem to have extraordinarily severe side effects at normal or low doses may have this phenotypic CYP450 2D6 variant and require low doses or switching to another antidepressant not metabolized by 2D6

Suggested Reading

Anderson IM. Meta-analytical studies on new antidepressants. Br Med Bull 2001;57:161–78.

Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Aff Disorders 2000;58:19–36.

Berger M, Gastpar M. Trimipramine: a challenge to current concepts on antidepressives. Eur Arch Psychiatry Clin Neurosci 1996;246:235–9.

Lapierre YD. A review of trimipramine. 30 years of clinical use. Drugs 1989;38(Suppl 1):S17–24; discussion S49–50.

VALPROATE

VALPROATE: THERAPEUTICS

Brands

• Depakene

• Depacon

• Depakote, Depakote ER

• Stavzor

see index for additional brand names

Generic?

Yes

Class

• Anticonvulsant, mood stabilizer, migraine prophylaxis, voltage-sensitive sodium channel modulator

Commonly Prescribed for

(bold for FDA approved)

• Acute mania (divalproex) and mixed episodes (divalproex, divalproex ER, valproic acid delayed-release)

• Complex partial seizures that occur either in isolation or in association with other types of seizures (monotherapy and adjunctive)

• Simple and complex absence seizures (monotherapy and adjunctive)

• Multiple seizure types, which include absence seizures (adjunctive)

• Migraine prophylaxis (divalproex, divalproex ER, valproic acid delayed-release)

• Maintenance treatment of bipolar disorder

• Bipolar depression

• Psychosis, schizophrenia (adjunctive)

How the Drug Works

✽ Blocks voltage-sensitive sodium channels by an unknown mechanism

• Increases brain concentrations of gamma-aminobutyric acid (GABA) by an unknown mechanism

How Long Until It Works

• For acute mania, effects should occur within a few days depending on the formulation of the drug

• May take several weeks to months to optimize an effect on mood stabilization

• Should also reduce seizures and improve migraine within a few weeks

If It Works

• The goal of treatment is complete remission of symptoms (e.g., mania, seizures, migraine)

• Continue treatment until all symptoms are gone or until improvement is stable and then continue treating indefinitely as long as improvement persists

• Continue treatment indefinitely to avoid recurrence of mania, depression, seizures, and headaches

If It Doesn’t Work (for bipolar disorder)

✽ Many patients have only a partial response where some symptoms are improved but others persist or continue to wax and wane without stabilization of mood

• Other patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory

• Consider checking plasma drug level, increasing dose, switching to another agent or adding an appropriate augmenting agent

• Consider adding psychotherapy

• Consider the presence of noncompliance and counsel patient

• Switch to another mood stabilizer with fewer side effects

• Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)