Children and Adolescents

• Not recommended for use in children under age 15

• 14 and older: recommended 3–5 mg/kg per day

Pregnancy

• There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

• Potential risks should be weighed against the potential benefits, and sulpiride should be used only if deemed necessary

• Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

• Atypical antipsychotics may be preferable to conventional antipsychotics or anticonvulsant mood stabilizers if treatment is required 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 relapse of psychosis

SULPIRIDE: THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages

• For negative symptoms in some patients

Potential Disadvantages

• Patients who cannot tolerate sedation at high doses

• Patients with severe renal impairment

Primary Target Symptoms

• Positive symptoms of psychosis

• Negative symptoms of psychosis

• Cognitive functioning

• Depressive symptoms

• Aggressive symptoms

Pearls

✽ There is some controversy over whether sulpiride is more effective than older conventionals at treating negative symptoms

• Sulpiride has been used to treat migraine associated with hormonal changes

✽ Some patients with inadequate response to clozapine may benefit from augmentation with sulpiride

• Sulpiride is poorly absorbed from the gastrointestinal tract and penetrates the blood-brain barrier poorly, which can lead to highly variable clinical responses, especially at lower doses

• Small studies and clinical anecdotes suggest efficacy in depression and anxiety disorders (“neuroses”) at low doses

• Patients have very similar antipsychotic responses to any conventional antipsychotic, which is different from atypical antipsychotics where antipsychotic responses of individual patients can occasionally vary greatly from one atypical antipsychotic to another

• Patients with inadequate responses to atypical antipsychotics may benefit from a trial of augmentation with a conventional antipsychotic such as sulpiride or from switching to a conventional antipsychotic such as sulpiride

• However, long-term polypharmacy with a combination of a conventional antipsychotic with an atypical antipsychotic may combine their side effects without clearly augmenting the efficacy of either

• For treatment-resistant patients, especially those with impulsivity, aggression, violence, and self-harm, long-term polypharmacy with 2 atypical antipsychotics or with 1 atypical antipsychotic and 1 conventional antipsychotic may be useful or even necessary while closely monitoring

• In such cases, it may be beneficial to combine 1 depot antipsychotic with 1 oral antipsychotic

• Although a frequent practice by some prescribers, adding 2 conventional antipsychotics together has little rationale and may reduce tolerability without clearly enhancing efficacy

Suggested Reading

Caley CF, Weber SS. Sulpiride: an antipsychotic with selective dopaminergic antagonist properties. Ann Pharmacother 1995;29(2): 152–60.

Mauri MC, Bravin S, Bitetto A, Rudelli R, Invernizzi G. A risk-benefit assessment of sulpiride in the treatment of schizophrenia. Drug Saf 1996;14(5):288–98.

O’Connor SE, Brown RA. The pharmacology of sulpiride – a dopamine receptor antagonist. Gen Pharmacol 1982; 13 (3): 185–93.

Omori IM, Wang J. Sulpiride versus placebo for schizophrenia. Cochrane Database Syst Rev 2009;15(2):CD007811.

Wang J, Omori IM, Fenton M, Soares B. Sulpiride augmentation for schizophrenia. Cochrane Database Syst Rev 2010;20(1):CD008125.

TEMAZEPAM

TEMAZEPAM: THERAPEUTICS

Brands

• Restoril

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, but can take longer in some patients

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

TEMAZEPAM: 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

• 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, only take temazepam 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

TEMAZEPAM: DOSING AND USE

Usual Dosage Range

• 15 mg/day at bedtime

Dosage Forms

• Capsule 7.5 mg, 15 mg, 30 mg

How to Dose

• 15 mg/day at bedtime; may increase to 30 mg/day at bedtime if ineffective

Dosing Tips

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

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

• Patients with lower body weights may require lower doses

✽ Because temazepam is slowly absorbed, administering the dose 1–2 hours before bedtime may improve onset of action and shorter sleep latency

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

Overdose

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

Long-Term Use

• Not generally intended for long-term use

Habit Forming

• Temazepam 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 history of seizure 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