Pregnancy

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

• Avoid use during first trimester

• 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

• If child becomes irritable or sedated, breast feeding or drug may need to be discontinued

• 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 benefits of breast feeding with risks and benefits of antidepressant treatment versus nontreatment to both the infant and the mother

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

TRAZODONE: THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages

• For insomnia when it is preferred to avoid the use of dependence-forming agents

• As an adjunct to the treatment of residual anxiety and insomnia with other antidepressants

• Depressed patients with anxiety

• Patients concerned about sexual side effects or weight gain

Potential Disadvantages

• For patients with fatigue, hypersomnia

• For patients intolerant to sedating effects

Primary Target Symptoms

• Depression

• Anxiety

• Sleep disturbances

Pearls

• May be less likely than some antidepressants to precipitate hypomania or mania

• Preliminary data suggest that trazodone may be effective treatment for drug-induced dyskinesias, perhaps in part because it reduces accompanying anxiety

• Trazodone may have some efficacy in treating agitation and aggression associated with dementia

✽ May cause sexual dysfunction only infrequently

• Can cause carryover sedation, sometimes severe, if dosed too high

• Often not tolerated as a monotherapy for moderate to severe cases of depression, as many patients cannot tolerate high doses (>150 mg)

• Do not forget to try at high doses, up to 600 mg/day, if lower doses well tolerated but ineffective

✽ For the expert psychopharmacologist, trazodone can be used cautiously for insomnia associated with MAO inhibitors, despite the warning – must be attempted only if patients closely monitored and by experts experienced in the use of MAOIs

• Priapism may occur in 1 in 8,000 men

• Early indications of impending priapism may be slow penile detumescence when awakening from REM sleep

• When using to treat insomnia, remember that insomnia may be a symptom of some other primary disorder, and not a primary disorder itself, and thus warrant evaluation for comorbid psychiatric and/or medical conditions

• Rarely, patients may complain of visual “trails” or after-images on trazodone

Suggested Reading

DeVane CL. Differential pharmacology of newer antidepressants. J Clin Psychiatry 1998;59 (Suppl 20):S85–93.

Haria M, Fitton A, McTavish D. Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders. Drugs Aging 1994;4:331–55.

Rotzinger S, Bourin M, Akimoto Y, Coutts RT, Baker GB. Metabolism of some “second”- and “fourth”-generation antidepressants: iprindole, viloxazine, bupropion, mianserin, maprotiline, trazodone, nefazodone, and venlafaxine. Cell Mol Neurobiol 1999;19:427–42.

Stahl SM. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr 2009;14(10):536–46.

TRIAZOLAM

TRIAZOLAM: THERAPEUTICS

Brands

• Halcion

see index for additional brand names

Generic?

Yes

Class

• Benzodiazepine (hypnotic)

Commonly Prescribed for

(bold for FDA approved)

• Short-term treatment of insomnia

• Catatonia

How the Drug Works

• Binds to benzodiazepine receptors at the GABA-A ligand-gated chloride channel complex

• Enhances the inhibitory effects of GABA

• Boosts chloride conductance through GABA-regulated channels

• Inhibitory actions in sleep centers may provide sedative hypnotic effects

How Long Until It Works

• Generally takes effect in less than an hour

If It Works

• Improves quality of sleep

• Effects on total wake-time and number of nighttime awakenings may be decreased over time

If It Doesn’t Work

• If insomnia does not improve after 7–10 days, it may be a manifestation of a primary psychiatric or physical illness such as obstructive sleep apnea or restless leg syndrome, which requires independent evaluation

• Increase the dose

• Improve sleep hygiene

• Switch to another agent

Best Augmenting Combos for Partial Response or Treatment Resistance

• Generally, best to switch to another agent

• Trazodone

• Agents with antihistamine actions (e.g., diphenhydramine, tricyclic antidepressants)

Tests

• In patients with seizure disorders, concomitant medical illness, and/or those with multiple concomitant long-term medications, periodic liver tests and blood counts may be prudent

TRIAZOLAM: SIDE EFFECTS

How Drug Causes Side Effects

• Same mechanism for side effects as for therapeutic effects – namely due to excessive actions at benzodiazepine receptors

• Actions at benzodiazepine receptors that carry over to the next day can cause daytime sedation, amnesia, and ataxia

• Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal

Notable Side Effects

✽ Sedation, fatigue, depression

✽ Dizziness, ataxia, slurred speech, weakness

✽ Forgetfulness, confusion

✽ Hyperexcitability, nervousness

✽ Anterograde amnesia

• Rare hallucinations, mania

• Rare hypotension

• Hypersalivation, dry mouth

• Rebound insomnia when withdrawing from long-term treatment

Life-Threatening or Dangerous Side Effects

• Respiratory depression, especially when taken with CNS depressants in overdose

• Rare hepatic dysfunction, renal dysfunction, blood dyscrasias

Weight Gain

• Reported but not expected

Sedation

• Many experience and/or can be significant in amount

What to Do About Side Effects

• Wait

• To avoid problems with memory, take triazolam only if planning to have a full night’s sleep

• Lower the dose

• Switch to a shorter-acting sedative hypnotic

• Switch to a non-benzodiazepine hypnotic

• Administer flumazenil if side effects are severe or life-threatening

Best Augmenting Agents for Side Effects

• Many side effects cannot be improved with an augmenting agent

TRIAZOLAM: DOSING AND USE

Usual Dosage Range

• 0.125–0.25 mg/day at bedtime for 7–10 days

Dosage Forms

• Tablet 0.125 mg, 0.25 mg

How to Dose

• Initial 0.125 or 0.25 mg/day at bedtime; may increase cautiously to 0.5 mg/day if ineffective; maximum dose generally 0.5 mg/day

Dosing Tips

• Use lowest possible effective dose and assess need for continued treatment regularly

✽ Many patients cannot tolerate 0.5 mg dose (e.g., developing anterograde amnesia)

• Triazolam should generally not be prescribed in quantities greater than a 1-month supply

• Some side effects (sedation, dizziness, lightheadedness, amnesia) seem to increase with dose

• Patients with lower weights may require only a 0.125 mg dose

• Risk of dependence may increase with dose and duration of treatment

✽ Higher doses associated with more behavioral problems and anterograde amnesia

Overdose

• Can be fatal in monotherapy; poor coordination, confusion, seizure, slurred speech, sedation, coma, respiratory depression

Long-Term Use

• Not generally intended for long-term use

• Increased wakefulness during the latter part of night (wearing off) or an increase in daytime anxiety (rebound) may occur because of short half-life

Habit Forming

• Triazolam is a Schedule IV drug

• Some patients may develop dependence and/or tolerance; risk may be greater with higher doses

• History of drug addiction may increase risk of dependence

How to Stop

• If taken for more than a few weeks, taper to reduce chances of withdrawal effects

• Patients with seizure history may seize upon sudden withdrawal

• Rebound insomnia may occur the first 1–2 nights after stopping

• For patients with severe problems discontinuing a benzodiazepine, dosing may need to be tapered over many months (i.e., reduce dose by 1% every 3 days by crushing tablet and suspending or dissolving in 100 mL of fruit juice and then disposing of 1 mL while drinking the rest; 3–7 days later, dispose of 2 mL, and so on). This is both a form of very slow biological tapering and a form of behavioral desensitization