Original Author: Bruce Alexander, Pharm.D, BCPP
Latest Reviser: Bruce Alexander, Pharm.D, BCPP
Creation Date: 1996
Peer Review Status: Internally Peer Reviewed
The calming effect of lithium in mania was first reported in 1949 (Price and Heninger 1994). That same year lithium was recommended as a salt substitute and liberal use lead to several deaths, which slowed its acceptance in the US. The FDA did not approve lithium until 1970.
Recently, the American Psychiatric Association's Working Group recommended lithium as the first-line treatment for acute and maintenance treatment of bipolar illness ("The Pink Sheet" 1994). A three-week therapeutic trial is recommended, as lithium's onset of action is often delayed one to two weeks (Price and Heninger 1994). Though patients may not be completely well by three weeks, substantial improvement is often noted. Once a patient starts to improve, generally resolution of symptoms occur quickly. If lithium is abruptly discontinued during the manic phase, relapse may occur within several days.
If a patient is not acutely agitated, then he might be treated with just lithium (see lithium in combination with antipsychotics below).
Typical Mania
Lithium Alone
Open/Single Blind Reports. Ten reports involving a total of 413 patients reported that lithium produced an average improvement rate of 81% (range 68-100) (Goodwin and Zis 1979).
Placebo-Controlled Trials. In four studies, 76% (88/116) of the patients were rated as improved. Three of the four studies reported response rates of 75%, 75%, and 84%. Most of these studies included relatively young patients (Solomon and Bauer 1993). A recent review of patients aged 55 to 77 years treated with lithium for mania reported a similar percentage response range as with younger patients (Mirchandani and Young 1993). However, some of these patients did not tolerate typical antimanic lithium levels.
Lithium versus antipsychotics
Nine double-blind, controlled trials have compared lithium to typical antipsychotics (Goodwin and Zis 1979, Chou 1991). Seven of the nine studies involved chlorpromazine, while the other two used haloperidol and pimozide. The study results are summarized as follows: (1) lithium in doses of >1800 mg/d or plasma levels >0.8 mEq/L is associated with marked improvement or remission in >70% of patients; (2) the percentage of patients showing remission or marked improvement after three weeks of treatment was greater with lithium than with an antipsychotic; (3) lithium is particularly effective in ameliorating the affective and ideational symptoms associated with mania, whereas the antipsychotic is initially superior to lithium in controlling psychomotor activity; (4) inpatients treated with lithium are more likely to be discharged at the end of a three-week treatment period compared to patients receiving an antipsychotic alone.
Two controlled, double-blind studies reported that lithium combined with an antipsychotic was more efficacious in the acute treatment of mania than lithium alone (Chou 1991). One study reported that lithium combined with haloperidol produced a slightly greater control of symptoms than haloperidol alone.
Often the lithium-antipsychotic combination is started immediately with the rationale that the antipsychotic will control hyperactivity and irritability while waiting for lithium's to exert its effect (Chou 1991). After manic symptoms come under control, then the antipsychotic is discontinued when the patient's behavior normalizes.
Lithium plus a benzodiazepine
Cases Reports/Open Trials. Clonazepam and lorazepam alone or in combination with antipsychotics have been reported to control agitation when added to lithium treatment in many case reports (Gerner 1993).
In two open trials all 11 manic patients responded when lorazepam 30 to 80 mg/d was added to lithium treatment (Modell et al 1985, Lenox et al 1986). The dosing regimen was lorazepam 2-4 mg po/IM q2h prn for agitation. Sedation and clinical control were reported to occur within the first two days of treatment (Modell et al 1985).
Double-Blind Studies. In one trial lithium plus lorazepam was as effective in overall response and time of onset as lithium in combination with haloperidol (Lenox et al 1992). Both treatments resulted in onset of effect within five to seven days. More patients dropped from the lorazepam group secondary to nonresponse; however, more patients dropped from the haloperidol group due to adverse effects.
After manic symptoms come under control, then an attempt should be made to discontinue the benzodiazepine by tapering the dose over a week. The patient should be monitored for relapse of manic symptoms.
Atypical Mania
Patients with organic, psychotic, dysphoric, mixed, and rapid-cycling (>4 episodes in 1 year) features of mania and/or concurrent substance abuse are reported to be less responsive to lithium than to carbamazepine or valproic acid (Gerner 1993, Solomon and Bauer 1993, Price and Heninger 1994). However, this conclusion was not derived from controlled studies of lithium versus carbamazepine or valproic acid. A review suggested that approximately 10 to 35% and 15% to 39% of patients with rapid cycling illness and dysphoric or mixed mania, respectively, will respond to lithium (Gerner 1993, Dilsaver et al 1993). Therefore, patients with these features should not be labeled lithium-refractory unless a therapeutic trial has been accomplished.
Continuation Treatment
Continuation treatment is the uninterrupted extension of pharmacologic management after resolution of the acute episode. The mean duration of a manic episode is 3 months (Clayton 1994). Conservatively, antimanic lithium levels should be maintained for 3 to 6 months after resolution of manic symptoms (Solomon and Bauer 1993).
It is recommended that after a response in first-episode mania that lithium be administered as continuation treatment and then discontinued (see Chapter 21, Drug Therapy in the Prevention of Recurrences in Affective Illness). However, it is possible that the patient in consultation with family members and/or a significant other may wish to initiate maintenance treatment after the first manic episode. Considerations include complications that resulted from the first episode (i.e., legal and economic difficulties, sexual indiscretions, suicide attempt) and the high risk of relapse.
When continuation treatment has been completed in first or second-episode illness then lithium will be discontinued. It has been suggested that abrupt discontinuation of lithium may lead to a rapid return of manic symptoms in one-third of patients, typically within 2 to 14 days (Greil and Schmidt 1988). Another study suggested that tapering lithium over a two- to four-week period reduced the recurrence rate (Faedda et al 1993). Conservatively, if time permits lithium should be tapered over a four-week period by reducing the daily dose by 25% every week. It was noted that if abrupt lithium discontinuation lead to a rapid return of manic symptoms that patients often responded within 2 to 14 days of lithium reinstitution (Faedda et al 1993).
A complete discussion of the prophylactic use of lithium is discussed in the prevention of affective illness handout.
Rational Prescribing
CARBAMAZEPINE
Carbamazepine (CBZ) has been extensively investigated in the treatment of affective disorders since 1971. It is not approved by the FDA for the acute and prophylactic treatment of bipolar disorder.
There are 13 reports of CBZ in comparison to placebo, chlorpromazine, or lithium in mania.
The onset of action of CBZ varies from one to two weeks (Post 1988). A therapeutic trial is three weeks.
Suggested clinical predictors of CBZ response have included lithium nonresponders, rapid cyclers (e.g., >4 episodes/year) or continuous cycling, and patients with more severe mania. In addition, dysphoria mania, schizoaffective or psychotic features, evidence of organic brain damage, and patients with primarily manic episodes, no family history, and an early onset of bipolar illness may preferentially respond to CBZ (Ballenger 1988). Abnormal electroencephalograms have not been found to consistently predict a response to CBZ.
It is important to separate study populations into lithium-refractory and lithium-naive (e.g., lithium-responsive or potentially lithium-responsive) patients so to determine if CBZ's response rate is greater than, equal to, or less than lithiums' in lithium-naive patients. It is also important to determine the percentage of patients that will respond to carbamazepine in lithium-refractory patients so it can be compared to other suggested treatments such as valproic acid and verapamil. Unfortunately, many studies (1) do not provide information on the patient's past lithium experience; (2) include lithium-naive and lithium-refractory patients in the same study; and/or (3) do not report results by prior lithium treatment outcome.
Lithium Response Unknown
Open Reports. Of 109 patients in four reports treated with CBZ, 48 (44%) had a moderate to marked response (Stromgren and Boller 1985).
Double-Blind Study. One study reported that CBZ 600 mg/d was as effective as the combination of CBZ 600 mg/d plus haloperidol 24 mg/d (Chou 1991).
Lithium-Naive Patients
Studies were included if it was clear that patients either were not lithium-refractory or only a few patients in the study population were lithium-refractory.
Carbamazepine versus lithium. The overall response rate in five double-blind studies for CBZ (n = 164) and lithium (n = 120) was 62% and 67%, respectively (Lenzi et al 1986, Placidi et al 1986, Lerer et al 1987, Lusznat et al 1988, Okuma et al 1990).
Carbamazepine versus chlorpromazine. Two studies involving 43 patients receiving CBZ 200 to 1200 mg/d and 38 patients receiving chlorpromazine 200 to 800 mg/d reported response rates of 70% and 61%, respectively (Chou 1991).
Carbamazepine versus haloperidol. One study reported that 6/8 (75%) patients and 3/9 (33%) patients responded to CBZ and haloperidol, respectively (Chou 1991).
Lithium-Refractory Patients
Open Reports
Two reports of a total of 35 patients reported that 49% responded to CBZ (Fawcett and Kravitz 1985, Stromgren and Boller 1985).
Double-Blind Studies
CBZ versus placebo. All 6 double-blind studies were reported from the National Institutes of Mental Health and typically involved patients with rapid-cycling illness (i.e., >4 episodes/year) (Stromgren and Boller 1985, Ballenger 1988). Of a total of 84 patients, 52% responded to a trial of CBZ.
CBZ versus lithium. A recent eight-week, double-blind study involving 48 patients reported a 33% response rate for both CBZ and lithium (Small et al 1991). The average serum CBZ and lithium level at the end of the study was 9.1 ug/ml and 0.73 mEq/L, respectively. It is unknown if more patients may have responded to both drugs if higher levels had been achieved.
CBZ plus haloperidol versus haloperidol alone. Klein et al (1984) reported that CBZ plus haloperidol was about equal in efficacy to CBZ alone as approximately 46% and 43% of patients responded, respectively. About 50% of patients in this study were refractory to lithium. However, the authors did not report separate response rates based on prior lithium treatment outcome.
CBZ plus Lithium. Numerous uncontrolled reports have suggested that CBZ added to lithium resulted in a significant response in patients with mania who were partially or completely unresponsive to lithium alone (Ballenger 1988). This combination might be considered after the patient has failed an individual trial of each drug.
Rational Prescribing
VALPROIC ACID
Valproic acid is indicated alone or in combination with other anticonvulsants in the prophylactic management of simple and complex (petit mal) seizures. Valproic acid is not approved by the FDA for the treatment of affective disorders.
Sixteen open and six controlled trials have investigated the efficacy of valproic acid in the treatment of mania (McElroy and Keck 1993, Bowden et al 1994). The controlled trials compare valproic acid to lithium and/or placebo.
The onset of action of valproic acid varies from seven to fourteen days (Bowden et al 1994). A therapeutic trial is three weeks.
Suggested clinical predictors of response to valproic acid have included patients with rapid cycling illness(e.g., >4 episodes per year), dysphoric or mixed mania, neurological abnormalities (e.g., positive electroencephalogram, history head trauma, mental retardation, and/or a history of panic attacks (Freeman et al 1992, Schaff et al 1993, McElroy and Keck 1993). Conversely, a history of substance abuse predicts a poor outcome. It is important to note that these conclusions are preliminary and need to be replicated with controlled trials.
It is important to separate study populations into lithium-refractory and lithium-naive (e.g., lithium-responsive or potentially lithium-responsive) patients to determine if valproic acid's response rate is greater than, equal to, or less than lithiums' in lithium-naive patients. It is also important to determine the percentage of lithium-refractory patients that will respond to valproic acid so that it can be compared to other suggested treatments (e.g., carbamazepine, verapamil). Unfortunately, many studies (1) do not provide information on past lithium experience; (2) will include lithium-naive and lithium-refractory patients in the same study; and/or (3) may not report results by prior lithium treatment outcome.
Lithium-Naive Patients
There are no open or controlled trials in the acute treatment of mania.
Lithium-Refractory Patients
Open Reports
In most of these reports, valproic acid is added to existing regimens (McElroy and Keck 1993). Therefore, it is difficult to determine the role of valproic acid alone. Overall, 198 of 297 patients (67%) experienced a moderate to marked response to valproic acid.
Double-Blind Studies
Valproic Acid versus Placebo. Five double-blind studies reported an overall response rate to valproic acid and placebo to be 49% and 16%, respectively (McElroy and Keck 1993, Bowden et al 1994).
Valproic Acid versus Lithium. One double-blind study reported that 92% (12/13) and 64% (9/14) of patients responded to lithium and valproic acid, respectively (Freeman et al 1992). A larger sample size may have demonstrated a significant difference between the response rates.
A recent study reported that approximately 50% of valproic acid- and lithium-treated patients experienced >50% reduction in manic symptoms (Bowden et al 1994). However, 47% of the patients in the lithium group had failed a previous trial of lithium. It is important to note that lithium-responders in this study improved more with lithium than with valproic acid. Unfortunately, the authors did not provide enough information to conclusively compare the patient's outcome by previous lithium response status.
Valproic Acid versus Carbamazepine. One double-blind case study reported that a patient responded to carbamazepine but not valproic acid (Post et al 1984).
Dosage
The patient may be started at 500 to 1,000 mg/d in two to four divided doses with valproic acid (McElroy and Keck 1993). The dose can be adjusted upward by 250 or 500 mg/d every two to four days until a response occurs or adverse effects result (Gerner 1993). Most patients can be treated with valproic acid 1000 to 1500 mg/d (Brown 1989). However, the required dose may range from 750 to 6000 mg/d. Once a patient's dose is stabilized, the drug may be administered on a twice a day or once daily at bedtime dosing regimen (McElroy and Keck 1993, Gerner 1993).
One study administered a loading dose of divalproex sodium 30 mg/kg/d divided into three doses (Keck et al 1993). The calculated dose was administered for six consecutive days and was well tolerated by 19 patients as only four patients noted sedation and one complained of nausea. The drug was not discontinued in any patient because of adverse effects. This dose yielded average plasma valproic acid concentrations of 89 ug/ml + 19 ug/ml on day 2 of administration.
Rational Prescribing
VERAPAMIL
Verapamil, a calcium-channel blocking agent, is indicated for the treatment of supraventricular tachyarrhythmias, angina, and hypertension. It has been found useful in the treatment of acute mania. Though many calcium channel blockers are available on the market, verapamil is the most widely studied.
It is important to separate study populations into lithium-refractory and lithium-naive (e.g., lithium-responsive or potentially lithium-responsive) patients to determine if verapamil's response rate is greater than, equal to, or less than lithiums' in lithium-naive patients. It is also important to determine the percentage of lithium-refractory patients that will respond to verapamil so its efficacy can be ranked against other suggested treatments (e.g., carbamazepine, valproic acid).
Verapamil has not been systematically studied in carbamazepine responders or valproate responders or nonresponders.
The onset of action of verapamil varies from seven to fourteen days (Giannini et al 1985, Hoschl and Kozeny 1989, Garza-Trevino et al 1992). A therapeutic trial is three weeks.
Lithium-Naive Patients
Open Reports
One patient responded within 4 days of verapamil initiation (Patterson 1987).
Controlled Trials
Verapamil versus placebo. Three double-blind studies involving a total of 16 patients reported a 81% response rate to verapamil (Dubovsky et al 1982, Dose et al 1986, Dobovsky et al 1986). One study reported verapamil was more effective than placebo, but did not report the patient response rate (Giannini et al 1984).
Verapamil versus lithium. Three double-blind studies involving 36 patients reported that verapamil was as effective as lithium or lithium in combination with an antipsychotic. However, one study treated patients with an average lithium level of 0.75 mEq/L (Hoschl and Kozeny 1989). The other studies used a lithium level range of 0.75-1.5 mEq/L and 0.84-1.26 mEq/L, but did not report average or final individual lithium levels (Giannini et al 1984, Garza-Trevino et al 1992).
Verapamil combined with antipsychotics/benzodiazepines
Verapamil has been successfully combined with haloperidol and/or lorazepam for control of psychomotor agitation (Garza-Trevino et al 1992).
Lithium-Refractory Patients
Open Reports
Only 5 of 13 (38%) patients included in two reports responded to a verapamil trial (Brotman et al 1986, Barton and Gitlin 1987).
Controlled Trials
Verapamil versus clonidine. This double-blind study reported verapamil was significantly more effective than clonidine (Giannini et al 1985).
Carbamazepine-refractory patients
Only 4 of 14 patients demonstrated improvement with verapamil that had failed a carbamazepine trial (Barton and Gitlin 1987).
Dosage
Verapamil antimanic dosages range from 160 to 480 mg/d. The median dose is 320 mg/d. Verapamil can be started at 80 mg bid or tid and the dose increased daily or every other day to a dose of 320 mg/d. Nonresponse after two weeks should lead to dose increase to 480 mg/d, administered in a tid schedule. Doses >480 mg/d have not been investigated.
Rational Prescribing
BENZODIAZEPINES
The use of benzodiazepines alone compared to lithium and antipsychotics are presented. Benzodiazepines are not approved by the FDA for the acute or prophylactic treatment of unipolar or bipolar disorders.
Efficacy
Lorazepam
Open Reports. Thirteen patients in three reports experienced reduced agitation and hyperactivity when used alone or in combination with lithium and/or antipsychotics (Gerner 1993).
Double-Blind Studies. A study reported that the addition of lorazepam reduced the need for chlorpromazine dosage equivalence from 590 mg/d to 310 mg/d, as well as reducing the seclusion and restraint time (Gerner 1993).
Clonazepam
Open Reports. Over 70 cases of successful use of clonazepam alone or in combination with primary antimanic agents (i.e., lithium, carbamazepine) and/or antipsychotics have been reported (Aronson et al 1989).
Double-Blind Studies. Clonazepam was compared to placebo in a 5-day study (Edwards et al 1991). The mean daily chlorpromazine dose of 2597 mg in the clonazepam group was significantly lower than 3456 mg in the placebo group.
Twelve manic patients were treated in a ten-day study with clonazepam or lithium (Chouinard et al 1983). Clonazepam was significantly superior to lithium on ratings of motor overactivity and logorrhea, but there was no significant difference in elevated mood, pressure of speech, or insight. Nonsignificantly less haloperidol was used during the clonazepam period than with lithium therapy. As lithium may require >10 days to exert an antimanic effect, this study may have been to short in duration to detect a difference between the two treatments.
Lorazepam versus Clonazepam
One study reported that lorazepam was more efficacious than clonazepam in the management of mania (Bradwejn et al 1990). In two weeks the patient's response and remission rates for lorazepam was 61% and 39%, respectively. This compared to clonazepam's rates of 18% and 0%, respectively. Lithium was added from day 14-28 of the study. At the end of the study, 5 lorazepam plus lithium patients were discharged from the ward versus none of the clonazepam plus lithium patients.
Dosage
Lorazepam doses have ranged from 2 to 80 mg/d administered orally or parenterally (Gerner 1993). Typical doses are 2 to 4 mg PO/IM every two hours. Typical daily doses are <36 mg. Clonazepam doses ranged from 2 to 22 mg/d in controlled trials (Gerner 1993).
Rational Prescribing
MISCELLANEOUS TREATMENTS
The following sections include brief information on selected agents studied in the treatment of refractory bipolar illness. Cited references should be reviewed for a complete understanding of these agents. Reviews of treatment options in mania have recently been published (Chou 1991, Gerner 1993).
CLONIDINE
Efficacy
Open Reports
Overall, four open reports involving 36 patients suggested that 23 (66%) had a moderate to marked improvement with clonidine (Jouvent et al 1980, Zubenko et al 1984b, Hardy et al 1986, Kontaxakis et al 1989).
Controlled Trials
A total of 45 patients have received clonidine in controlled trials. Clonidine reduced manic symptoms in one study, but was equal in efficacy to placebo in another (Giannini et al 1983, Janicak et al 1989). In two comparison studies, lithium and verapamil were more effective than clonidine (Giannini et al 1985, Giannini et al 1986).
Dosage
Daily doses ranged from 0.2 to 1.2 mg/d divided into three doses.
Rational Prescribing
FENFLURAMINE
Efficacy
Open Reports
One uncontrolled report had all seven patients respond to fenfluramine (Cookson and Silverstone 1976).
Controlled Trials
Two double-blind studies reported improvement in 5 of 8 patients (Pearce 1973, Murphy et al 1978).
Dosage
The daily dose range was from 60 to 180 mg/d in the clinical reports.
THYROID SUPPLEMENTATION
Two reports of administering levothyroxine or triiodothyroinine in doses to produce thyroid levels above normal reported improvement in 10 of 15 rapid-cycling patients (Stancer and Persad 1982, Bauer and Whybrow 1990).
REFERENCES
Aronson TA, Shukla S, Hirschowitz J (1989). Clonazepam treatment of five lithium-refractory patients with bipolar disorder. Am J Psychiatry 146:77-80.
Ballenger JC (1988). The clinical use of carbamazepine in affective disorders. J Clin Psychiatry 49(Suppl 4):13-9.
Barr RD, Copeland SA, Stockwell ML, et al (1982). Valproic acid and immune thrombocytopenia. Arch Dis Child 57:681-4.
Barton BM, Gitlin MJ (1987). Verapamil in treatment-resistant mania: an open trial. J Clin Psychopharmacol 7:101-3.
Bauer MS, Whybrow PC (1990). Rapid cycling bipolar affective disorder. II: Treatment of refractory rapid cycling with high-dose levothyroxine: A preliminary study. Arch Gen Psychiatry 47:435-40.
Bowden CL, Brugger AM, Swann AC, et al (1994). Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA 271:918-24.
Bradwejn J, Shriqui C, Koszycki D, et al (1990). Double-blind comparison of the effects of clonazepam and lorazepam in acute mania. J Clin Psychopharmacol 10:403-8.
Brotman AW, Farhadi AM, Gelenberg AJ (1986). Verapamil treatment of acute mania. J Clin Psychiatry 47:136-8.
Brown R (1989). U.S. experience with valproate in manic-depressive illness: a multicenter trial. J Clin Psychiatry 50(Suppl 3):13-6.
Chou J C-Y (1991). Recent advances in treatment of mania. J Clin Psychopharmacol 11:3-21.
Chouinard G, Young SN, Annable L (1983). Antimanic effect of clonazepam. Biol Psychiatry 18:451-66.
Clayton PJ (1994). Bipolar illness. In Winokur G, Clayton PJ (eds): The Medical Basis of Psychiatry, second edition. Philadelphia, W.B. Saunders, 47-68.
Cookson J, Silverstone T (1976). 5-Hydroxytryptamine and dopamine pathways in mania: a pilot study of fenfluramine and pimozide. Br J Clin Pharmacol 3:942-7.
Dilsaver SC, Swann AC, Shoaib A, et al (1993). The manic syndrome: factors which may predict a response to lithium, carbamazepine, and valproate. J Psychiatr Neurosci 18:61-6.
Dose M, Emrich HM, Cording-Tommel C, et al (1986). Use of calcium antagonists in mania. Psychoneuroendocrinology 11:241-3.
Dubovsky SL, Franks RD, Lifschitz M, et al (1982). Effectiveness of verapamil in the treatment of a manic patient. Am J Psychiatry 139:502-4.
Dubovsky SL, Franks RD, Allen S, et al (1986). Calcium antagonists in mania: a double-blind study of verapamil. Psychiatry Res 18:309-20.
Edwards R, Stephenson U, Flewett T (1991). Clonazepam in acute mania: a double blind trial. Aust New Zeal J Psychiatry 25:238-42.
Faedda GL, Tondo L, Baldessarini RJ, et al (1993). Occurrence after rapid versus gradual discontinuation of lithium in bipolar disorders. Arch Gen Psychiatry 50:448-55.
Fawcett J, Kravitz HM (1985). The long-term management of bipolar disorders with lithium, carbamazepine, and antidepressants. J Clin Psychiatry 46:58-60.
Freeman TW, Clothier JL, Pazzaglia P, et al (1992). A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry 149:108-11.
Garza-Trevino ES, Overall JE, Hollister LE (1992). Verapamil versus lithium in acute mania. Am J Psychiatry 149:121-2.
Gerner RH (1993). Treatment of acute mania. Psychiatric Clin North Am 16:443-60.
Giannini AJ, Extein I, Gold MS, et al (1983). Clonidine in mania. Drug Dev Res 3:101-3.
Giannini AJ, Houser WL, Loiselle RH, et al (1984). Antimanic effects of verapamil. Am J Psychiatry 141:1602-3.
Giannini AJ, Loiselle RH, Price WA, et al (1985). Comparison of antimanic efficacy of clonidine and verapamil. J Clin Pharmacol 25:307-8.
Giannini AJ, Pascarzi GA, Loiselle RH, et al (1986). Comparison of clonidine and lithium in the treatment of mania. Am J Psychiatry 143:1608-9.
Goodwin FK, Zis AP (1979). Lithium in the treatment of mania. Comparison with neuroleptics. Arch Gen Psychiatry 36:840-4.
Grell W, Schmidt ST (1988). Lithium withdrawal reactions. In Birch NJ (ed), Lithium: Inorganic Pharmacology and Psychiatric Use. Washington, DC, IRL Press.
Hardy MC, Lecrubier Y, Widlocher D (1986). Efficacy of clonidine in 24 patients with acute mania. Am J Psychiatry 143:1450-3.
Hoschl C, Kozeny J (1989). Verapamil in affective disorders: A controlled, double-blind study. Biol Psychiatry 25:128-40.
Jouvent R, Lecrubier Y, Fuech AJ, et al (1980). Antimanic effect of clonidine. Am J Psychiatry 137:1275-6.
Keck PE, McElroy SL, Tugrul KC, et al (1993). Valproate oral loading in the treatment of acute mania. J Clin Psychiatry 54:305-8.
Klein E, Bental E, Lerer B, et al (1984). Carbamazepine and haloperidol vs. placebo and haloperidol in excited psychoses. Arch Gen Psychiatry 41:165-172.
Kontaxakis V, Markianos M, Markidis M, et al (1989). Clonidine in mixed bipolar disorder. Act Psychiatr Scan 79:108-110.
Lenox RH, Modell JG, Weinder S (1986). Acute treatment of manic agitation with lorazepam. Psychosomatics 27:28-32.
Lenox RH, Newhouse PA, Creelman WL, et al (1992). Adjunctive treatment of manic agitation with lorazepam versus haloperidol: a double-blind study. J Clin Psychiatry 53:47-52.
Lenzi A, Lazzerini F, Grossi E, Massimitti G, Placidi GF (1986). Use of carbamazepine in acute psychosis: a controlled study. J Int Med Res 14: 78-84.
Lerer B, Moore N, Meyendorf E, et al (1987). Carbamazepine versus lithium in mania. J Clin Psychiatry 48:89-93.
Lusznat RM, Murphy DP, Numm MH (1988). Carbamazepine versus lithium in mania: a double-blind study. Br J Psychiatry 153:198-204.
McElroy SL, Keck PE (1993). Treatment guidelines for valproate in bipolar and schizoaffective disorders. Can J Psychiatry 1993 38(Suppl 2):S62-S66.
Murphy DL, Slater S, de la Vega CE, et al (1978). The serotonergic neurotransmitter system in the affective disorders - a preliminary evaluation of the antidepressant and antimanic effects of fenfluramine. In: Deniker P, ed. Neuropsychopharmacology. Oxford:Pergamon, 675-82.
Okuma T, Yamashita I, Takahashi R, et al (1990). Comparison of the antimanic efficacy of carbamazepine and lithium carbonate by double-blind controlled study. Pharmacopsychiatry 23:143-50.
Patterson JF (1987). Treatment of acute mania with verapamil. J Clin Psychopharmacol 7:206-7.
Pearce JB (1973). Fenfluramine in mania (letter). Lancet 1:427.
Placidi GF, Lenzi A, Lazzerini F, et al (1986). The comparative efficacy and safety of carbamazepine versus lithium: a randomized, double-blind 3-year trial in 83 patients. J Clin Psychiatry 47:490-4.
Post RM, Berrettini W, Uhde TW, et al (1984). Selective response to the anticonvulsant carbamazepine in manic-depressive illness: a case study. J Clin Psychopharmacol 4:178-85.
Post RM (1988). Time course of clinical effects of carbamazepine: implications for mechanisms of action. J Clin Psychiatry 49(Suppl 4):35-46.
Price LH, Heninger GR (1994). Lithium in the treatment of mood disorders. NEJM 331:591-8.
Schaff MR, Fawcett J, Zajecka JM (1993). Divalproex sodium in the treatment of refractory affective disorders. J Clin Psychiatry 54:380-4.
Small JC, Klapper MH, Milstein V, et al (1991). Carbamazepine compared with lithium in the treatment of mania. Arch Gen Psychiatry 48:915-21.
Sobotka JL, Alexander B, Cook BL (1990). A review of carbamazepine's hematologic reactions and monitoring recommendations. DICP Ann Pharmacother 24:1214-9.
Solomon DA, Bauer MS (1993). Continuation and maintenance pharmacotherapy for unipolar and bipolar mood disorders. Psychiatric Clin North Am 16:515-40.
Stancer HC, Persad E (1982). Treatment of intractable rapid cycling manic-depressive disorder with levothyroxine. Arch Gen Psychiatry 39:311-2.
Stromgren LS, Boller S (1985). Carbamazepine in treatment and prophylaxis of manic-depressive disorder. Psychiatric Developments 4:349-67.
"The Pink Sheet" (1994). APA bipolar disorder guideline lists lithium as first choice. F-D-C Reports, December 12, T&G-11.
Zubenko GS, Cohen BM, Lipinski JF, et al (1984b). Clonidine in the treatment of mania and mixed bipolar disorder. Am J Psychiatry 141:1617-8.