Treatment Initiation and Dose Titration It is important to carry out a range of tests before embarking

on treatment to identify patients at increased risk of adverse effects (Table 3-4).

LITHIUM Pretreatment testing for lithium includes a complete blood count, electrolyte determinations, renal panel, and thyroid function tests. An electrocardiogram should also be obtained.

MOOD STABILIZERS 95 Pretreatment Tests

MEDICATION TESTING Any Medication

• Comprehensive medical history • Physical examination including vital signs and

weight • Pregnancy test, if applicable

Lithium • Complete blood count • Electrolytes • Renal panel (blood urea nitrogen, creatinine, and

routine urinalysis) • Thyroid panel plus thyroid-stimulating hormone • Electrocardiogram

Valproate • Complete blood count • Liver function tests

Carbamazepine • Complete blood count • Liver function tests • Renal panel • Urinalysis

Atypical • Blood glucose Antipsychotics

• Blood lipids

Lithium dosage may be based on a plasma concentration sampled 12 hours after the last dose, or the drug may be gradually titrated to a dose that is tolerated and within the range usually considered “therapeutic.” As with any drug, approximately five half-lives must elapse for steady state to

be achieved; for an average adult, this takes about five days for lithium (longer in the elderly or in patients with impaired renal function). To treat acute mania, plasma concentrations should typically be greater than 0.8 mEq/L but to avoid toxi- city the level should not exceed 1.5 mEq/L. It is important to know what other medications a patient may be taking because many drugs interact with lithium and can lead to increased or decreased lithium levels and possibly to adverse effects (see ‘Drug Interactions’ on page 119).

To reach therapeutic levels rapidly in healthy younger patients with normal renal and cardiac function, the psychiatrist may prescribe 300 mg of lithium carbonate four times daily from the outset, sampling the first plasma level after five days (or sooner should toxic signs become apparent). Thereafter,

96 HANDBOOK OF PSYCHIATRIC DRUGS

the dose should be adjusted to achieve a 12-hour plasma concentration between 0.8 and 1.3 mEq/L at steady state. By contrast, in a patient with mild hypomanic symptoms it may be wiser to begin with a lower lithium dose, such as 300 mg b.i.d., taking longer to achieve therapeutic levels but minimizing side effects that could trouble the patient and promote medication non-adherence. Once steady state has been achieved at therapeutic concentrations and the patient is clinically stable, lithium can be administered to most patients in a once-daily dose, usually at bedtime. Not only is this schedule easier to remember, but it tends to decrease such common side effects as tremor and polyuria.

ANTICONVULSANTS Before initiating treatment with valproate or divalproex, the psychiatrist should obtain a comprehensive medical history and ensure that a physical examination has been performed, with particular attention to suggestions of liver disease or bleeding abnormalities (see Table 3-4). Baseline liver and hematological functions are measured before treatment, every one to four weeks for the first six months, and then once every three to six months. Mild elevations in transaminase levels are not uncommon and should be monitored, but tend to be mild and self-limited, not requiring discontinuation of the medication. Evidence of abnormalities in hemostasis or coagulation, such as hemorrhage or increased bruising, should prompt a reduc- tion of dosage or withdrawal of therapy. The drug should be discontinued immediately in the presence of significant hepatic dysfunction.

In healthy adults, divalproex is started at 750 mg/day in divided doses and then adjusted to achieve a 12-hour serum

of dosing is determined by possible side effects (particularly sedation), and once-a-day dosing can be employed if tolerated. The use of slow-release formulations reduces side effects (particularly gastrointestinal) and facilitates the use of once daily dosing. As with lithium, the antimanic response to valproate typically occurs after one to two weeks. It may be possible to obtain a faster response with oral loading of divalproex at 20 mg/kg/day for the first five days. This produces

MOOD STABILIZERS 97 serum concentrations greater than 50 mg/L after two days of

treatment and is generally well tolerated with few side effects. Carbamazepine is typically started at 200 to 400 mg/day in three or four divided doses, and increased to 800 to 1000 mg/day by the end of the first week. As with divalproex, slow release formulations may improve tolerability and facili- tate use of once daily dosing. If clinical improvement is insuf- ficient by the end of the second week, and the patient has not had intolerable side effects to the drug, carbamazepine may

be increased to as high as 1600 mg/day. As there is little data relating carbamazepine blood levels and psychiatric efficacy, the anti-epileptic blood level range (4 to 15 ng/mL) is generally utilized. If carbamazepine is combined with lithium or antipsychotics, lower doses and blood levels of carbamazepine may suffice. If divalproex and carbamazepine are administered simultaneously, blood levels of each should be monitored carefully because of the complex pharmacokinetic interactions between the two agents.

ANTIPSYCHOTICS Although in the 1970s it was commonplace to use ultra- high doses of antipsychotics in attempts to suppress psychotic symptoms (sometimes in excess of 100 mg of haloperidol daily), this is seldom necessary and may be counterproduc- tive: it can increase the risk of acute cardiovascular complications, seizures, acute dystonia, and possibly neuroleptic malignant syndrome. However, in emergent situations, intra- muscular (IM) administration of an antipsychotic can help reduce agitation more rapidly than lithium or an anticon- vulsant. IM formulations exist for several first-generation antipsychotics and but only for one atypical antipsychotics, ziprasidone.

Dosing recommendations for atypical antipsychotics are listed in Table 3-5. Recently, significant concern has been raised about the risks of metabolic complications associated with the use of atypical antipsychotics. Weight gain, hyperlipidemia, and diabetes (including abrupt and often catastrophic new onset diabetes) have been observed to occur at relatively high rates. Although the FDA has mandated a black box warning for

98 HANDBOOK OF PSYCHIATRIC DRUGS

Atypicals in the Treatment of Acute Mania GENERIC

BRAND DOSE ON ACUTE DOSE MAINTENANCE NAME

NAME FIRST DAY ADJUSTMENT DOSE Aripiprazole Ability

15−30 mg q.i.d. − 15−30 mg q.i.d. Olanzapine

Zyprexa 10−15 q.i.d. increments of 5−20 mg q.i.d. 5 mg per day Quetiapine

Seroquel

50 mg b.i.d.

200 mg b.i.d. by 200−400 mg day 4 in

b.i.d. increments of 50 mg b.i.d. Risperidone Risperdal 2−3 mg q.i.d.

increments of 1−6 mg q.i.d. 1 mg per day Ziprasidone Geodon

60−80 mg b.i.d. 40−80 mg b.i.d. (po)

40 mg b.i.d.

on day 2 Geodon

10 mg q2hr

(im)

the entire class of atypical antipsychotics, the risk does appear to be greatest with clozapine and olanzapine. The Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes has made recommendations for screening prior to treatment with an atypical antipsychotic and for monitoring during treatment. Before starting the medication, weigh poten- tial benefits against metabolic and medical risks based upon the following assessments:

• Personal and family history of diabetes, obesity, hyperlipidemia, hypertension, and cardiovascular disease

• Baseline height and weight (which should be used to calcu- late the body mass index, BMI) and waist circumference (measured at the height of the umbilicus)

• Blood pressure • Fasting plasma glucose • Fasting lipid profile

The presence of metabolic abnormalities or significant personal or family history might prompt preferential use of atypical antipsychotics with lower risk (ziprasidone or aripiprazole) or intermediate risk (risperidone or quetiapine) relative to higher risk (olanzapine and clozapine).

MOOD STABILIZERS 99 Follow up monitoring of patients on atypical antipsychotics

should be conducted as follows: • Review personal and family history annually.

• Measure weight and BMI at 4, 8, and 12 weeks, then quarterly. • Measure waist circumference annually. • Measure blood pressure and fasting plasma glucose at 12

weeks, then annually. • Measure fasting lipids at 12 weeks, then every five years.

Treatment Initiation and Dose Titration It is important to carry out a range of tests before embarking