Lithium in the Treatment of Mania Comparisons
With
Neuroleptics
Frederick K. Goodwin, MD, Athanasios P. Zis, MD, FRCP(C)
the original discovery of the antimanic properties of lithium nearly 30 years ago,1 a large number of studies, as well as extensive clinical experience, have confirmed the efficacy of this drug for the treatment of the manic phase of manic-depressive illness. The recent focus of questions concerning the role of lithium in the treatment of mania has shifted from efficacy per se to comparisons with other drug treatments and the related issue of specificity. This review will, therefore, focus on controlled studies comparing lithium with neuroleptics, following a brief historical review of the earlier studies. The studies comparing lithium with neuroleptics are of special importance not only from a practical point of view but also theoretically, in that they bear on the question of the specificity of lithium against the manic syndrome\p=m-\a question with implication for the underlying pathophysiology of mania.
Since
OPEN SINGLE-BLIND STUDIES
Table 1 summarizes the major uncontrolled and singleblind studies of lithium's effectiveness in acute mania.1-10 In general, these open studies represent the early clinical trials of lithium, and they do not utilize a double-blind design or placebo group comparison. Non-blind studies in
uninterpsychopharmacology frequently pretable. However, clinical experience suggests that mania, a major psychotic illness, is not particularly respon¬ sive to the subtle environmental and interpersonal factors that contribute to high placebo response rates. A greater difficulty in the interpretation of these open trials derives from the fact that mania is a cyclic phenomenon which, in the absence of intervention, will generally remit sponta¬ neously. However, it is unusual for this to occur over a period of time of several days to several weeks, ie, the time period within which most of the antimanic responses to lithium occurred. Thus it is quite unlikely that the rapid disappearance of manic symptoms during the first week of lithium therapy in the large majority of patients would be due to chance or to a placebo effect. are
dismissed
as
CONTROLLED STUDIES Lithium vs Placebo The first controlled study of the lithium treatment of acute mania was done by Schou et al in 1954.' Table 2 summarizes the four placebo-controlled studies of lithium in the treatment of acute mania.'11" Although each of From the Clinical Psychobiology Branch, National Institute of Mental Health, Bethesda, Md.
these studies comparing lithium with placebo in the treat¬ ment of mania has its own methodological strengths and shortcomings, reviewed in detail elsewhere," it can be said that, despite the methodological differences, the results are remarkably concurrent; that is, lithium is clearly superior to placebo in the acute treatment of the great majority of cases of mania. Lithium vs Neuroleptics: Review and Clinical Implications
In recent years, studies of lithium in mania have focused comparisons with chlorpromazine and other neurolep¬ tics (see Table 3). These studies could be said to represent a clinically more realistic test of the efficacy of lithium in mania since it is being compared with other drugs that were and still are widely used in the treatment of mania. Johnson et al" studied 29 manic-depressive patients treated with lithium and chlorpromazine and compared their response with a second group of 17 excited schizoafon
Table 1.—Lithium in Mania: and Single-Blind Studies
Open
Improve¬
ment, %*
Source, yr Cade,' 1949
100
Comments Individual case reports
presented reported
30
83
2
21
71
30
90
No case reports; lithium citrate used 12 "definite" responders; 15 "possible" respond¬ ers: ratings used and diagnostic criteria
119
76
Includes "typical" and "mixed" manic syn¬
Klngstone,·
17
94
3
Wharton and Fieve.'t 1960
25
68
Schlagenhauf
68
90
Single-blind ratings; diag¬ nostic criteria specified Some patients subsequently received other
Blinder,9 1968
22
95
medication Patients described
73
"hypomanic" Diagnostic criteria speci¬
Noack and
Trautner,'
cases
1951
Glesinger,3
1954
Schou et al,* 1954
specified Schou,s 1959
dromes cases
1960
et
al,» 1966
Van der
Velde,'
75
as
fied
1970
"The overall response for
reported
improvement in the studies is 81%. are reported as number of episodes of mania.
tThe data from this study were 19 patients in the trial.
There
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Table 2—Lithium in Mania: Placebo-Controlled Studies Response Rate, %·
Comments
90 63
Definite, 40%; possible, 50% Definite, 25%; possible, 37%
Source, yr Schou et al,' 1954
Method Random crossover!
Maggs," 1963
Random
Goodwin et al,'2 1969
Nonrandom
crossover
12
75
superior to placebo Complete, 67%; partial,
Stokes et al," 1971
Nonrandom
crossover
38
75§
Improved
30-Typical 8-Atyplcal
4
28
crossover
Lithium
•The overall response rate in the studies is 76%.
tMethod not applied to all
tlnformation
8%
Modified
Bunney-Hamburg Scale
Quantification of NOSIEII
rate derived from number of episodes. Observation Scale for Inpatlent Evaluation.
§Response
||Nurses'
cases.
could not be ascertained from
Wlttenborn Scale
placebo, 40%
on
Assessment Method Clinical impression
original reference. Table 3.—Lithium
vs
Neuroleptics
In Mania*
Qualitative Differences Marked
Source, yr Johnson et al,'s 1968 Johnson et al,,e 1971
Improvement
Drug LI CPZ LI
or
18 11
Remission 78% 36%
13 89%
CPZ LI
13
Prien et al," 1972
CPZ LI CPZ
10 59 1 66 I
50% Most None
LI
Takahashl et al,201975
CPZ LI CPZ
69 1 61 I 37 34
LI
10
70%
CPZ HAL
10 10
10% 20%
et al," 1970
Platman," 1970
Shopsin
et
al,!' 1975
>
LI
CPZ
>
LI
LI > CPZ
BPRS, CGI, NOSIE, TRAM, SCI
LI
CPZ
LI
Target symptom assessment;
Hyperactivity
Comments Clinical impression
CPZ LI
Spring
CPZ
Normalization of Mood and Ideation LI > CPZ
Decreased
>
LI
CPZ
>
LI
> >
CPZ
CPZ CPZ >
LI
CPZ> LI
Ll> CPZ
CPZ
LI
MA
in¬
cludes the crossover trials Quantified behavioral ratings
Multihospital study; BPRS, IMPS, PIP; HA group had higher dropout rate with LI MA group had higher dropout rate with CPZ
32% 12%
HAL
>
>
LI
LI
>
LI
CPZ
>
>
CPZ
HAL
>
CPZ
Multihospital study; Special Rat¬ ing Scale; 5-wk study; in¬ creased incidence of depres¬ sion with CPZ BPRS, CGI, SCI, NOSIE
'Except as indicated, all studies were double-blind, random assignment, three-week studies. Abbreviations are as follows: LI, lithium carbonate; CPZ, chlorpromazine; HAL, haloperidol; BPRS, Brief Psychiatric Rating Scale, CGI, Clinical Global Impression; NOSIE, Nurses' Observation Scale for Inpatlent Evaluation; TRAM, Treatment Response Assessment Method; SCI, Structured Clinical Interview; IMPS, Inpatient Multidimensional Psychiatric Scale; PIP, Psychotic Inpatient Profile; HA, highly active; MA, mildly active. Ellipses in the table indicate that information could not be ascertained from original reference.
fective patients. Patients were randomly assigned to ei¬ ther drug following a washout period of five days (aver¬ age). The lithium blood level obtained was 1.0 mEq/L or greater. Chlorpromazine was given in doses ranging from 200 to 1,800 mg/day. The diagnosis of manic-depressive illness, manic phase, was based on the criteria detailed in the Mayer-Gross textbook of psychiatry."- Schizoaffective patients were characterized by "psychomotor excitation and heightened affect in association with clear-cut schizo¬ phrenic symptoms, such as formal thought disorders, inap¬ propriate behavior, incongruity of affect and ideation, systematized delusions and hallucinations of more than transient nature." Of the 18 manies treated with lithium, marked improve¬ ment or remission was observed in 14; while only four of the 11 manies treated with chlorpromazine showed marked improvement. None of the ten schizoaffective patients became worse on chlorpromazine, and three exhibited marked improvement. In addition to those global impres¬ sions suggesting the superiority of lithium over chlorpro¬ mazine in the treatment of the manic phase of manic-
depressive illness, the authors also noted qualitative differ¬ ences between the two drugs. Although both drugs decreased psychomotor activity, this occurred earlier with chlorpromazine. On the other hand, normalization of affect and ideation
was
obtained consistently earlier with lithium
to two weeks after initiation of therapy) and was maintained at a lithium dose level that did not produce
(one
major side effects. With chlorpromazine, normalization of
affect and ideation was less consistent and slower to evolve (two to three weeks after initiation of therapy), and was maintained only at dose levels inducing considerable inter¬ ference with alertness and psychomotor performance. In another report, Johnson et al" presented data on 21 manic patients treated with lithium or chlorpromazine and compared the results with treatment results of 13 schizoaf¬ fective patients in an excited phase. It is unclear how many of the patients in this study were included in the earlier
report by the criteria and
changes
behavior
investigators. Similar patient selection design were used in both studies. Clinical same
were was
assessed in several different ways. Ward
quantified by use of the Nurses' Observation
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Inpatient Evaluation (NOSIE). Independent psychological assessments were made prior to medication and at several points after medication by the Structured Clinical Interview (SCI). The Brief Psychiatric Rating Scale (BPRS), Treatment Response Assessment Method (TRAM), and Clinical Global Impression (CGI) were also Scale for
used. On the BPRS and CGI, significant improvement was noted in all groups with the exception of the schizoaffec¬ tive patients treated with lithium. On the TRAM scale, only the lithium-treated manic-depressives had signifi¬ cantly improved at termination, whereas on the NOSIE, the results indicated no significant improvement for any of the treatment groups from baseline to termination. The analysis of the SCI scores showed that both lithium and chlorpromazine decreased the mean level of psychopathology in the manic and schizoaffective patients; the manic patient scores were decreased to within the normal range with both treatments, whereas schizoaffective patients continued to show a significant amount of abnormality after either treatment. However, it is noted that schizoaf¬
fective patients had a higher initial level of psychopathology than manic patients. Spring et al'7 reported a double-blind study comparing the effectiveness of lithium carbonate vs chlorpromazine in 14 patients with acute mania, the condition diagnosed independently by three psychiatrists. The following symp¬ toms were required for a diagnosis of mania: euphoria, expansiveness, grandiosity, flight of ideas, distractibility, pressured speech, accelerated motor activity, and sleep disturbance. Although positive criteria for the diagnosis of mania are carefully detailed, the authors do not define their criteria for excluding schizoaffective patients. Clini¬ cal response was quantified by having two psychiatrists rate the patients twice a week on a 0 to 3 scale for each of the target symptoms used to diagnose mania. The 14 patients were assigned randomly to a lithium or chlorpro¬ mazine treatment group for a three-week period. The lithium carbonate dosage was 1,800 mg/day for the first week, which could then be increased to a maximum of 3,000 mg/day, depending on the response. The maximum dose of chlorpromazine was 1,600 mg/day, depending on the sever¬ ity of mania. Six of the seven patients who initially received lithium responded to the drug, compared to three out of five who initially received chlorpromazine. The two patients who failed to respond to chlorpromazine were crossed over to lithium carbonate and both had a remission, while the one patient who failed to respond to lithium was crossed over to chlorpromazine and again no response was noted. Thus, in terms of total drug trials, responses to lithium were noted eight out of nine times, whereas responses to chlorpromazine occurred three out of six times. The authors' treatment of the data is somewhat confusing in that they do not define how they determined whether a patient had responded or not. A comparison of "mean relative improvement" of target symptoms in each group shows that the target symptoms of flight of ideas, euphoria, expansiveness, pressured speech, and motor hyperactivity respond more to lithium than to chlorproma¬ zine. However, if the "mean relative improvement" for each target symptom is summed and the data analyzed by the Mann Whitney test, the difference does not achieve
statistical significance. The sample in this study is small and may be skewed by the fact that the two patients who dropped out were both receiving lithium initially. Platman" compared the effects of lithium carbonate with chlorpromazine in 30 patients admitted to a research unit in the "manic phase of manic-depressive illness"; however, specific diagnostic criteria were not described. Patients were randomly assigned to three weeks of lithium or chlorpromazine therapy, in each case preceded by a two-week placebo period. The mean dose of lithium carbon¬ ate was 1,800 mg/day, with plasma levels maintained at a mean of 0.8 mEq/L; the mean chlorpromazine dose was 870 mg/day. Clinical change was quantified by the Psychiatric Evaluation Form completed by the ward staff, who were blind to medication. The scales used were belligerencenegativism, somatic complaints, grandiosity, denial, sleep, and severity of illness. Thirteen patients were eventually treated with lithium, ten with chlorpromazine, and seven were withdrawn from the study. By the third week of treatment, lithium was superior on all scales, but these differences did not reach statistical significance. The majority of patients receiving lithium were discharged on a regimen of it, while none of the patients were able to be discharged on a regimen of chlorpromazine. The author concludes that lithium carbonate is superior to chlorproma¬ zine in the treatment of mania, but that the difference is not marked. He also points out the difficulties in doing a true double-blind study comparing the two drugs, consider¬ ing the somewhat contrasting clinical pictures they
produce.
Prien et al"1 reported the results of the Veterans Admin¬ istration-National Institute of Mental Health (NIMH) collaborative study involving 18 VA hospitals and designed to compare lithium carbonate with chlorpromazine in newly admitted manic and schizoaffective patients. A consensus on diagnosis had to be reached by two psychiatrists who independently interviewed the patients. The diagnoses of manic-depressive psychosis, manic type, and schizoaffective psychosis, manic type, were based on the clinical descriptions of Mayer-Gross and also the American Psychiatric Association's (APA) Diagnostic and Statistical Manual of Mental Disorders, ed 2 (DSM II).23 After a baseline period of three to five days, patients were randomly assigned to lithium carbonate or chlorpromazine for three weeks of treatment with individualized dosages. Clinical change was measured by the BPRS completed by a psychiatrist on the basis of an interview before and after treatment, the Inpatient Multidimensional Psychiatric Scale (IMPS) completed before and after treatment by two psychologists on the basis of an interview, and the Psychot¬ ic Inpatient Profile (PIP) completed before treatment and twice weekly during treatment by two nurses on the basis of ward behavior. The total number of manic patients included in the study was 255. A large number of patients (n 45) were withdrawn from the study before completion of the three-week treatment period because of uncoopera¬ tive behavior, toxicity, or poor clinical response. Among those patients defined as "highly active" on the basis of their pretreatment IMPS profile, both lithium and chlorpromazine produced significant improvement in a wide range of symptom areas, but 38% of patients receiv¬ ing lithium failed to complete the study, as compared with =
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only 8% of patients receiving chlorpromazine. Among those who completed the three-week trial, there were no major differences between the lithium and the chlorpromazine groups. For the "mildly" active patients, there was no appreciable difference in incidence of early termination: 10% of patients receiving lithium and 20% of patients receiving chlorpromazine were withdrawn before three weeks. Again, both drugs produced significant improve¬ ment over the three-week period. The relatively high withdrawal rate from the study raises some questions; for example, it is not clear why there were almost as many terminators among the "mildly active" patients (n 19) as there were among the "highly active" patients (n 26). Chlorpromazine acted more quickly in controlling the manic behavior of the highly active group—not simply motor activity, but excitement, grandiosity, hostility, and psychotic disorganization. It also produced a sharp decrease in the amount of ward supervision required by the patient within the first week, while lithium did not. The authors of the VA-NIMH collaborative study conclude that chlorpromazine is superior to lithium in the initial treat¬ ment of highly active patients; in addition, they found no difference in the efficacy of the two drugs in this group at the end of three weeks. Among the "mildly active" patients, lithium appeared to be slightly better because it did not make the patient feel as "sluggish and fatigued." Takahashi et al20 reported a double-blind multi-institu¬ tional study conducted in Japan that compared lithium to chlorpromazine in the treatment of acute mania. Criteria for the diagnosis of the manic cycle, on which patient selection was based, are not reported. Following a oneweek washout period, 80 patients (71 completed the study) were randomly assigned to either drug. Lithium carbonate dosage ranged from 600 to 1,800 mg/day with a mean serum lithium level of 0.57 mEq/L. The chlorpromazine dosage ranged from 150 to 450 mg/day, with an average of 256 mg/day. These doses (and the resulting serum levels) =
=
are well below those used in the studies conducted in the West (eg, in the VA-NIMH collaborative study, the median lithium concentration was 1.4 mEq/L for the highly active group and 1.2 mEq/L for the mildly active group, and the mean chlorpromazine dose was 1,000 mg/day). Patients were rated weekly on a 5-point scale by the attending physician. A rating scale for mania developed by the Clinical Psychopharmacology Research Group (CPRG) in Japan was used to quantify changes in behavior. Marked improvement at the end of the study (five weeks) was noted in 32% of the patients receiving lithium and in 12% of those receiving chlorpromazine. In addition, the onset of the therapeutic effect was evident earlier with lithium than it was with chlorpromazine. As for target symptoms, the CPRG-derived data indicated that "lithium was characteristically effective in ameliorating basic mood, speech and voice, expression, attitude, sleep and within-day changes," whereas "chlorpromazine proved as effective as lithium carbonate against increased psychomo¬
tor
activity."
The study of Shopsin et al2' is of particular interest since lithium carbonate is compared (in a double-blind design) not only with chlorpromazine but also with haloperidol. Anecdotal reports had suggested that haloperidol, a butyrophenone, was particularly effective in the treatment of
acute mania. A total of 30 manic patients (ten in each group) were randomly assigned to either lithium, chlor¬ promazine, or haloperidol following a seven-day washout period. Patients were rated by two psychiatrists using the
CGI and the BPRS. The SCI was administered by a research psychologist, and the nursing staff rated ward behavior using the NOSIE. Seven of the ten patients treated with lithium were well enough to be discharged at the end of three weeks of treatment, as compared with two of the ten patients receiving haloperidol and one of the ten patients receiving chlorpromazine. All three drugs induced significant improvement as measured by both the CGI and the BPRS. Both scales revealed that the greatest improvement was obtained with either lithium or haloperidol as compared with chlorpromazine. In addition, the BPRS scale showed haloperidol to be faster acting than either lithium or chlorpromazine, since significant changes from baseline were obtained within one week from the start of treat¬ ment. Although comparison of baseline and termination SCI profiles indicated that all three drugs induced signifi¬ cant improvement, improvement was greatest for lithium. On the NOSIE, significant improvement for the "irritabil¬ ity" and "manifest psychosis" items occurred only in the lithium and chlorpromazine groups. In their discussion, the authors point out that the rating scales do not reflect accurately the qualitative differences between lithium and either neuroleptic. Thus, while halo¬ peridol rapidly improved hyperactivity without marked sedation and lithium appeared to act more evenly on all symptoms of mania, chlorpromazine had an "insignificant effect on manic ideation or behavior." These qualitative differences were reflected in the differential discharge rates (favoring lithium) rather than in improvement scores on the various rating scales. COMMENT With the exception of the Japanese study (in which relatively low doses were used), lithium treatment was associated with marked improvement or remission or both in at least 70% of the patients. This is in good agreement with the percentage of marked improvement reported in
the controlled studies of lithium alone (Table 2) and the open or single-blind studies (Table 1). Furthermore, with the exception of the VA-NIMH study, lithium was found superior to chlorpromazine in the treatment of acute mania, as judged by the overall percentage of patients showing marked improvement or remission. In addition, the available evidence strongly suggests that lithium appears to be particularly effective in ameliorating those affective and ideational symptoms that in a sense consti¬ tute the core phenomenology most specific to the manic syndrome. Chlorpromazine, on the other hand, appears to be at least equal to and probably superior to lithium in the initial control of increased psychomotor activity; the contribution of nonspecific sedation to this antihyperactivity effect is not clear. According to the VA-NIMH study, chlorpromazine was superior in the treatment of "highly active" patients, whereas the differences between lithium and chlorproma¬ zine treatment were less pronounced among "mildly active" patients, the results tending to favor lithium. The
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conclusion that chlorpromazine is superior to lithium in "highly active" patients was based on both the higher dropout rate with lithium, as well as on the results obtained on the various rating scales. Neither discharge rates nor overall improvement rates are reported. In this regard, it is worthwhile emphasizing that in the other studies it is precisely the differences in discharge rate and clinical impression (not the various rating scales) that differen¬ tiate between the two treatments.15'17·20·21 Furthermore, some of the rating instruments (eg, NOSIE) failed to demonstrate significant improvement with either drug.16 In the interpretation of dropout rates, it must be kept in mind that a dropout can reflect limitations in clinical management, not just an inherent limitation of the drug in question. That such issues must be taken into account in interpreting the VA-NIMH study is suggested by the 31% rate of severe side effects with lithium. Diagnosis, again, is a critical issue; Prien and his associates19 refer to the Mayer-Gross textbook and to the APA Diagnostic Manual as their diagnostic guidelines, but do not specify how the differential diagnosis was made between manic phase, manic-depressive illness and manic phase, schizoaffective psychosis. The "highly active" patients were noted to be more disturbed and disorganized than the "mildly active" group and conceivably might be diagnosed as schizoaffec¬ tive or "atypical" by other investigators. The available evidence suggests that these patients do not respond as well to lithium as the more "typical" manic-depressive
patients.41415
Prior to the availability of lithium salts, the phenothiazines were the major drug treatment available for mania. The willingness of physicians to use a new, potentially toxic drug requiring careful monitoring suggests that the existing treatments for mania, including phenothiazines, were inadequate for many, if not most, patients. The increasing tendency for clinicians to use lithium in the treatment of mania, rather than to persist in using the
"established," easily available neuroleptic drugs is consist¬
ent with the empirical observation that lithium has an overall advantage over phenothiazines in the treatment of mania. Except for the results regarding the "highly active" patients in the VA-NIMH study, the results of controlled
studies are generally consistent with those clinical observa¬ tions advocating the superiority and specificity of lithium over chlorpromazine in the treatment of mania. This does not imply that neuroleptics have no place in the treatment of acute mania. As already discussed, chlorpro¬ mazine appears to be at least equal to and possibly superior to lithium in the initial control of increased psychomotor activity. It is unfortunate that comparisons of lithium with neuroleptics have been limited primarily to chlorproma¬ zine. Preliminary evidence suggests that other neurolep¬ tics, with pharmacological profiles more specific than chlorpromazine, may be particularly useful when rapid control of increased psychomotor activity and unmanagea¬ ble behavior is desired. Thus, haloperidol, a fairly potent dopamine receptor blocker, was shown by Shopsin et al21 to decrease rapidly (sooner than either lithium or chlorproma¬ zine) the BRPS scores for items such as hostility, excite¬ ment, grandiosity, and suspiciousness. Rapid control of manic symptomatology and behavior has been also
observed with pimozide, a rather specific dopamine recep¬ tor blocker (R. M. Post, MD, D. C. Jimerson, MD, W. E. Bunney, Jr, MD, et al, unpublished observations, December 1978); in the pimozide study, the onset of therapeutic effect was within 24 hours for pimozide, compared to five days for lithium. The effects of these drugs on increased psychomo¬ tor activity and on psychotic disorganization may often be vital to the rapid control of the highly agitated manic patient during the first few days. It is common practice among experienced clinicians either to initiate treatment with a neuroleptic or to combine lithium and a neuroleptic during the first few days and then gradually reduce the dosage of the latter to allow the specific ameliorating effects of lithium on mood and ideation to become appar¬ ent. It is now well established that neuroleptics can be safely coadministered with lithium (see article by Reisberg and Gershon, 879 this issue). References 1. Cade JFJ: lithium salts in the treatment of psychotic excitement. Med J Aust 2:349-353, 1949. 2. Noack CH, Trautner EM: The lithium treatment of mania and psychosis. Med J Aust 38:219-222, 1951. 3. Glesinger B: Evaluation of lithium in the treatment of psychotic excitement. Med J Aust 41:277-283, 1954. 4. Schou M, Juel-Nielson N, Stromgren E, et al: The treatment of manic psychoses by the administration of lithium salts. J Neurol Neurosurg Psychiatry 17:250-260, 1954. 5. Schou M: Lithium in psychiatric therapy: Stock-taking after ten years. Psychopharmacologia 1:65-78, 1959. 6. Kingstone E: The lithium treatment of hypomanic and manic states. Compr Psychiatry 11:317-320, 1960. 7. Wharton RW, Fieve RR: The use of lithium in the affective psychoses. Am J Psychiatry 123:706-712, 1966. 8. Schlagenhauf G, Tupin J, White RB: The use of lithium carbonate in the treatment of manic psychoses. Am J Psychiatry 123:201-207, 1966. 9. Blinder MG: Some observations on the use of lithium carbonate. Int J Neurol 4:26-27, 1968. 10. Van der Velde CP: Effectiveness of lithium carbonate in the treatment of manic-depressive illness. Am J Psychiatry 127:345-357, 1970. 11. Maggs R: Treatment of manic illness with lithium carbonate. Br J Psychiatry 109:56-65, 1963. 12. Goodwin FK, Murphy DL, Bunney WE Jr: Lithium carbonate treatment in depression and mania: A longitudinal double-blind study. Arch Gen Psychiatry 21:486-496, 1969. 13. Stokes PE, Stoli PM, Shamorian CA, et al: Efficacy of lithium as acute treatment of manic-depressive illness. Lancet 1:1319-1325, 1971. 14. Goodwin FK, Zis AP: Lithium in the treatment of mania: Comparisons with neuroleptics and the issue of specificity, in Cooper TB, Gershon S, Kline NS, et al (eds): Lithium: Controversies and Unresolved Issues. Amsterdam, Excerpta Medica, to be published. 15. Johnson G, Gershon S, Hekimian LJ: Controlled evaluation of lithium and chlorpromazine in the treatment of manic states: An interim report. Compr Psychiatry 9:563-573, 1968. 16. Johnson G, Gershon S, Burdock El, et al: Comparative effects of lithium and chlorpromazine in the treatment of manic states. Br J Psychiatry 119:267-276, 1971. 17. Spring G, Schrveid D, Gray C, et al: A double-blind comparison of lithium and chlorpromazine in the treatment of manic states. Am J Psychiatry 126:140-144, 1970. 18. Platman SR: A comparison of lithium carbonate and chlorpromazine in mania. Am J Psychiatry 127:351-353, 1970. 19. Prien RF, Caffey EM Jr, Klett CJ: Comparison of lithium carbonate and chlorpromazine in the treatment of mania. Arch Gen Psychiatry 26:146-153, 1972. 20. Takahashi R, Sakuma A, Itoh K, et al: Comparison of efficacy of lithium carbonate and chlorpromazine in mania. Arch Gen Psychiatry 32:1310-1318, 1975. 21. Shopsin B, Gershon S, Thompson H, et al: Psychoactive drugs in mania: A controlled comparison of lithium carbonate, chlorpromazine, and haloperidol. Arch Gen Psychiatry 32:32-42, 1975. 22. Mayer-Gross W: Clinical Psychiatry, ed 3, Slater E, Roth M (eds): Baltimore, Williams & Wilkins Co, 1969. 23. Diagnostic and Statistical Manual of Mental Disorders, ed 2 (DSM II). The Committee on Nomenclature and Statistics of the American Psychiatric Association. Washington, DC, American Psychiatric Association, 1968.
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With
Neuroleptics
Frederick K. Goodwin, MD, Athanasios P. Zis, MD, FRCP(C)
the original discovery of the antimanic properties of lithium nearly 30 years ago,1 a large number of studies, as well as extensive clinical experience, have confirmed the efficacy of this drug for the treatment of the manic phase of manic-depressive illness. The recent focus of questions concerning the role of lithium in the treatment of mania has shifted from efficacy per se to comparisons with other drug treatments and the related issue of specificity. This review will, therefore, focus on controlled studies comparing lithium with neuroleptics, following a brief historical review of the earlier studies. The studies comparing lithium with neuroleptics are of special importance not only from a practical point of view but also theoretically, in that they bear on the question of the specificity of lithium against the manic syndrome\p=m-\a question with implication for the underlying pathophysiology of mania.
Since
OPEN SINGLE-BLIND STUDIES
Table 1 summarizes the major uncontrolled and singleblind studies of lithium's effectiveness in acute mania.1-10 In general, these open studies represent the early clinical trials of lithium, and they do not utilize a double-blind design or placebo group comparison. Non-blind studies in
uninterpsychopharmacology frequently pretable. However, clinical experience suggests that mania, a major psychotic illness, is not particularly respon¬ sive to the subtle environmental and interpersonal factors that contribute to high placebo response rates. A greater difficulty in the interpretation of these open trials derives from the fact that mania is a cyclic phenomenon which, in the absence of intervention, will generally remit sponta¬ neously. However, it is unusual for this to occur over a period of time of several days to several weeks, ie, the time period within which most of the antimanic responses to lithium occurred. Thus it is quite unlikely that the rapid disappearance of manic symptoms during the first week of lithium therapy in the large majority of patients would be due to chance or to a placebo effect. are
dismissed
as
CONTROLLED STUDIES Lithium vs Placebo The first controlled study of the lithium treatment of acute mania was done by Schou et al in 1954.' Table 2 summarizes the four placebo-controlled studies of lithium in the treatment of acute mania.'11" Although each of From the Clinical Psychobiology Branch, National Institute of Mental Health, Bethesda, Md.
these studies comparing lithium with placebo in the treat¬ ment of mania has its own methodological strengths and shortcomings, reviewed in detail elsewhere," it can be said that, despite the methodological differences, the results are remarkably concurrent; that is, lithium is clearly superior to placebo in the acute treatment of the great majority of cases of mania. Lithium vs Neuroleptics: Review and Clinical Implications
In recent years, studies of lithium in mania have focused comparisons with chlorpromazine and other neurolep¬ tics (see Table 3). These studies could be said to represent a clinically more realistic test of the efficacy of lithium in mania since it is being compared with other drugs that were and still are widely used in the treatment of mania. Johnson et al" studied 29 manic-depressive patients treated with lithium and chlorpromazine and compared their response with a second group of 17 excited schizoafon
Table 1.—Lithium in Mania: and Single-Blind Studies
Open
Improve¬
ment, %*
Source, yr Cade,' 1949
100
Comments Individual case reports
presented reported
30
83
2
21
71
30
90
No case reports; lithium citrate used 12 "definite" responders; 15 "possible" respond¬ ers: ratings used and diagnostic criteria
119
76
Includes "typical" and "mixed" manic syn¬
Klngstone,·
17
94
3
Wharton and Fieve.'t 1960
25
68
Schlagenhauf
68
90
Single-blind ratings; diag¬ nostic criteria specified Some patients subsequently received other
Blinder,9 1968
22
95
medication Patients described
73
"hypomanic" Diagnostic criteria speci¬
Noack and
Trautner,'
cases
1951
Glesinger,3
1954
Schou et al,* 1954
specified Schou,s 1959
dromes cases
1960
et
al,» 1966
Van der
Velde,'
75
as
fied
1970
"The overall response for
reported
improvement in the studies is 81%. are reported as number of episodes of mania.
tThe data from this study were 19 patients in the trial.
There
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Table 2—Lithium in Mania: Placebo-Controlled Studies Response Rate, %·
Comments
90 63
Definite, 40%; possible, 50% Definite, 25%; possible, 37%
Source, yr Schou et al,' 1954
Method Random crossover!
Maggs," 1963
Random
Goodwin et al,'2 1969
Nonrandom
crossover
12
75
superior to placebo Complete, 67%; partial,
Stokes et al," 1971
Nonrandom
crossover
38
75§
Improved
30-Typical 8-Atyplcal
4
28
crossover
Lithium
•The overall response rate in the studies is 76%.
tMethod not applied to all
tlnformation
8%
Modified
Bunney-Hamburg Scale
Quantification of NOSIEII
rate derived from number of episodes. Observation Scale for Inpatlent Evaluation.
§Response
||Nurses'
cases.
could not be ascertained from
Wlttenborn Scale
placebo, 40%
on
Assessment Method Clinical impression
original reference. Table 3.—Lithium
vs
Neuroleptics
In Mania*
Qualitative Differences Marked
Source, yr Johnson et al,'s 1968 Johnson et al,,e 1971
Improvement
Drug LI CPZ LI
or
18 11
Remission 78% 36%
13 89%
CPZ LI
13
Prien et al," 1972
CPZ LI CPZ
10 59 1 66 I
50% Most None
LI
Takahashl et al,201975
CPZ LI CPZ
69 1 61 I 37 34
LI
10
70%
CPZ HAL
10 10
10% 20%
et al," 1970
Platman," 1970
Shopsin
et
al,!' 1975
>
LI
CPZ
>
LI
LI > CPZ
BPRS, CGI, NOSIE, TRAM, SCI
LI
CPZ
LI
Target symptom assessment;
Hyperactivity
Comments Clinical impression
CPZ LI
Spring
CPZ
Normalization of Mood and Ideation LI > CPZ
Decreased
>
LI
CPZ
>
LI
> >
CPZ
CPZ CPZ >
LI
CPZ> LI
Ll> CPZ
CPZ
LI
MA
in¬
cludes the crossover trials Quantified behavioral ratings
Multihospital study; BPRS, IMPS, PIP; HA group had higher dropout rate with LI MA group had higher dropout rate with CPZ
32% 12%
HAL
>
>
LI
LI
>
LI
CPZ
>
>
CPZ
HAL
>
CPZ
Multihospital study; Special Rat¬ ing Scale; 5-wk study; in¬ creased incidence of depres¬ sion with CPZ BPRS, CGI, SCI, NOSIE
'Except as indicated, all studies were double-blind, random assignment, three-week studies. Abbreviations are as follows: LI, lithium carbonate; CPZ, chlorpromazine; HAL, haloperidol; BPRS, Brief Psychiatric Rating Scale, CGI, Clinical Global Impression; NOSIE, Nurses' Observation Scale for Inpatlent Evaluation; TRAM, Treatment Response Assessment Method; SCI, Structured Clinical Interview; IMPS, Inpatient Multidimensional Psychiatric Scale; PIP, Psychotic Inpatient Profile; HA, highly active; MA, mildly active. Ellipses in the table indicate that information could not be ascertained from original reference.
fective patients. Patients were randomly assigned to ei¬ ther drug following a washout period of five days (aver¬ age). The lithium blood level obtained was 1.0 mEq/L or greater. Chlorpromazine was given in doses ranging from 200 to 1,800 mg/day. The diagnosis of manic-depressive illness, manic phase, was based on the criteria detailed in the Mayer-Gross textbook of psychiatry."- Schizoaffective patients were characterized by "psychomotor excitation and heightened affect in association with clear-cut schizo¬ phrenic symptoms, such as formal thought disorders, inap¬ propriate behavior, incongruity of affect and ideation, systematized delusions and hallucinations of more than transient nature." Of the 18 manies treated with lithium, marked improve¬ ment or remission was observed in 14; while only four of the 11 manies treated with chlorpromazine showed marked improvement. None of the ten schizoaffective patients became worse on chlorpromazine, and three exhibited marked improvement. In addition to those global impres¬ sions suggesting the superiority of lithium over chlorpro¬ mazine in the treatment of the manic phase of manic-
depressive illness, the authors also noted qualitative differ¬ ences between the two drugs. Although both drugs decreased psychomotor activity, this occurred earlier with chlorpromazine. On the other hand, normalization of affect and ideation
was
obtained consistently earlier with lithium
to two weeks after initiation of therapy) and was maintained at a lithium dose level that did not produce
(one
major side effects. With chlorpromazine, normalization of
affect and ideation was less consistent and slower to evolve (two to three weeks after initiation of therapy), and was maintained only at dose levels inducing considerable inter¬ ference with alertness and psychomotor performance. In another report, Johnson et al" presented data on 21 manic patients treated with lithium or chlorpromazine and compared the results with treatment results of 13 schizoaf¬ fective patients in an excited phase. It is unclear how many of the patients in this study were included in the earlier
report by the criteria and
changes
behavior
investigators. Similar patient selection design were used in both studies. Clinical same
were was
assessed in several different ways. Ward
quantified by use of the Nurses' Observation
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Inpatient Evaluation (NOSIE). Independent psychological assessments were made prior to medication and at several points after medication by the Structured Clinical Interview (SCI). The Brief Psychiatric Rating Scale (BPRS), Treatment Response Assessment Method (TRAM), and Clinical Global Impression (CGI) were also Scale for
used. On the BPRS and CGI, significant improvement was noted in all groups with the exception of the schizoaffec¬ tive patients treated with lithium. On the TRAM scale, only the lithium-treated manic-depressives had signifi¬ cantly improved at termination, whereas on the NOSIE, the results indicated no significant improvement for any of the treatment groups from baseline to termination. The analysis of the SCI scores showed that both lithium and chlorpromazine decreased the mean level of psychopathology in the manic and schizoaffective patients; the manic patient scores were decreased to within the normal range with both treatments, whereas schizoaffective patients continued to show a significant amount of abnormality after either treatment. However, it is noted that schizoaf¬
fective patients had a higher initial level of psychopathology than manic patients. Spring et al'7 reported a double-blind study comparing the effectiveness of lithium carbonate vs chlorpromazine in 14 patients with acute mania, the condition diagnosed independently by three psychiatrists. The following symp¬ toms were required for a diagnosis of mania: euphoria, expansiveness, grandiosity, flight of ideas, distractibility, pressured speech, accelerated motor activity, and sleep disturbance. Although positive criteria for the diagnosis of mania are carefully detailed, the authors do not define their criteria for excluding schizoaffective patients. Clini¬ cal response was quantified by having two psychiatrists rate the patients twice a week on a 0 to 3 scale for each of the target symptoms used to diagnose mania. The 14 patients were assigned randomly to a lithium or chlorpro¬ mazine treatment group for a three-week period. The lithium carbonate dosage was 1,800 mg/day for the first week, which could then be increased to a maximum of 3,000 mg/day, depending on the response. The maximum dose of chlorpromazine was 1,600 mg/day, depending on the sever¬ ity of mania. Six of the seven patients who initially received lithium responded to the drug, compared to three out of five who initially received chlorpromazine. The two patients who failed to respond to chlorpromazine were crossed over to lithium carbonate and both had a remission, while the one patient who failed to respond to lithium was crossed over to chlorpromazine and again no response was noted. Thus, in terms of total drug trials, responses to lithium were noted eight out of nine times, whereas responses to chlorpromazine occurred three out of six times. The authors' treatment of the data is somewhat confusing in that they do not define how they determined whether a patient had responded or not. A comparison of "mean relative improvement" of target symptoms in each group shows that the target symptoms of flight of ideas, euphoria, expansiveness, pressured speech, and motor hyperactivity respond more to lithium than to chlorproma¬ zine. However, if the "mean relative improvement" for each target symptom is summed and the data analyzed by the Mann Whitney test, the difference does not achieve
statistical significance. The sample in this study is small and may be skewed by the fact that the two patients who dropped out were both receiving lithium initially. Platman" compared the effects of lithium carbonate with chlorpromazine in 30 patients admitted to a research unit in the "manic phase of manic-depressive illness"; however, specific diagnostic criteria were not described. Patients were randomly assigned to three weeks of lithium or chlorpromazine therapy, in each case preceded by a two-week placebo period. The mean dose of lithium carbon¬ ate was 1,800 mg/day, with plasma levels maintained at a mean of 0.8 mEq/L; the mean chlorpromazine dose was 870 mg/day. Clinical change was quantified by the Psychiatric Evaluation Form completed by the ward staff, who were blind to medication. The scales used were belligerencenegativism, somatic complaints, grandiosity, denial, sleep, and severity of illness. Thirteen patients were eventually treated with lithium, ten with chlorpromazine, and seven were withdrawn from the study. By the third week of treatment, lithium was superior on all scales, but these differences did not reach statistical significance. The majority of patients receiving lithium were discharged on a regimen of it, while none of the patients were able to be discharged on a regimen of chlorpromazine. The author concludes that lithium carbonate is superior to chlorproma¬ zine in the treatment of mania, but that the difference is not marked. He also points out the difficulties in doing a true double-blind study comparing the two drugs, consider¬ ing the somewhat contrasting clinical pictures they
produce.
Prien et al"1 reported the results of the Veterans Admin¬ istration-National Institute of Mental Health (NIMH) collaborative study involving 18 VA hospitals and designed to compare lithium carbonate with chlorpromazine in newly admitted manic and schizoaffective patients. A consensus on diagnosis had to be reached by two psychiatrists who independently interviewed the patients. The diagnoses of manic-depressive psychosis, manic type, and schizoaffective psychosis, manic type, were based on the clinical descriptions of Mayer-Gross and also the American Psychiatric Association's (APA) Diagnostic and Statistical Manual of Mental Disorders, ed 2 (DSM II).23 After a baseline period of three to five days, patients were randomly assigned to lithium carbonate or chlorpromazine for three weeks of treatment with individualized dosages. Clinical change was measured by the BPRS completed by a psychiatrist on the basis of an interview before and after treatment, the Inpatient Multidimensional Psychiatric Scale (IMPS) completed before and after treatment by two psychologists on the basis of an interview, and the Psychot¬ ic Inpatient Profile (PIP) completed before treatment and twice weekly during treatment by two nurses on the basis of ward behavior. The total number of manic patients included in the study was 255. A large number of patients (n 45) were withdrawn from the study before completion of the three-week treatment period because of uncoopera¬ tive behavior, toxicity, or poor clinical response. Among those patients defined as "highly active" on the basis of their pretreatment IMPS profile, both lithium and chlorpromazine produced significant improvement in a wide range of symptom areas, but 38% of patients receiv¬ ing lithium failed to complete the study, as compared with =
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only 8% of patients receiving chlorpromazine. Among those who completed the three-week trial, there were no major differences between the lithium and the chlorpromazine groups. For the "mildly" active patients, there was no appreciable difference in incidence of early termination: 10% of patients receiving lithium and 20% of patients receiving chlorpromazine were withdrawn before three weeks. Again, both drugs produced significant improve¬ ment over the three-week period. The relatively high withdrawal rate from the study raises some questions; for example, it is not clear why there were almost as many terminators among the "mildly active" patients (n 19) as there were among the "highly active" patients (n 26). Chlorpromazine acted more quickly in controlling the manic behavior of the highly active group—not simply motor activity, but excitement, grandiosity, hostility, and psychotic disorganization. It also produced a sharp decrease in the amount of ward supervision required by the patient within the first week, while lithium did not. The authors of the VA-NIMH collaborative study conclude that chlorpromazine is superior to lithium in the initial treat¬ ment of highly active patients; in addition, they found no difference in the efficacy of the two drugs in this group at the end of three weeks. Among the "mildly active" patients, lithium appeared to be slightly better because it did not make the patient feel as "sluggish and fatigued." Takahashi et al20 reported a double-blind multi-institu¬ tional study conducted in Japan that compared lithium to chlorpromazine in the treatment of acute mania. Criteria for the diagnosis of the manic cycle, on which patient selection was based, are not reported. Following a oneweek washout period, 80 patients (71 completed the study) were randomly assigned to either drug. Lithium carbonate dosage ranged from 600 to 1,800 mg/day with a mean serum lithium level of 0.57 mEq/L. The chlorpromazine dosage ranged from 150 to 450 mg/day, with an average of 256 mg/day. These doses (and the resulting serum levels) =
=
are well below those used in the studies conducted in the West (eg, in the VA-NIMH collaborative study, the median lithium concentration was 1.4 mEq/L for the highly active group and 1.2 mEq/L for the mildly active group, and the mean chlorpromazine dose was 1,000 mg/day). Patients were rated weekly on a 5-point scale by the attending physician. A rating scale for mania developed by the Clinical Psychopharmacology Research Group (CPRG) in Japan was used to quantify changes in behavior. Marked improvement at the end of the study (five weeks) was noted in 32% of the patients receiving lithium and in 12% of those receiving chlorpromazine. In addition, the onset of the therapeutic effect was evident earlier with lithium than it was with chlorpromazine. As for target symptoms, the CPRG-derived data indicated that "lithium was characteristically effective in ameliorating basic mood, speech and voice, expression, attitude, sleep and within-day changes," whereas "chlorpromazine proved as effective as lithium carbonate against increased psychomo¬
tor
activity."
The study of Shopsin et al2' is of particular interest since lithium carbonate is compared (in a double-blind design) not only with chlorpromazine but also with haloperidol. Anecdotal reports had suggested that haloperidol, a butyrophenone, was particularly effective in the treatment of
acute mania. A total of 30 manic patients (ten in each group) were randomly assigned to either lithium, chlor¬ promazine, or haloperidol following a seven-day washout period. Patients were rated by two psychiatrists using the
CGI and the BPRS. The SCI was administered by a research psychologist, and the nursing staff rated ward behavior using the NOSIE. Seven of the ten patients treated with lithium were well enough to be discharged at the end of three weeks of treatment, as compared with two of the ten patients receiving haloperidol and one of the ten patients receiving chlorpromazine. All three drugs induced significant improvement as measured by both the CGI and the BPRS. Both scales revealed that the greatest improvement was obtained with either lithium or haloperidol as compared with chlorpromazine. In addition, the BPRS scale showed haloperidol to be faster acting than either lithium or chlorpromazine, since significant changes from baseline were obtained within one week from the start of treat¬ ment. Although comparison of baseline and termination SCI profiles indicated that all three drugs induced signifi¬ cant improvement, improvement was greatest for lithium. On the NOSIE, significant improvement for the "irritabil¬ ity" and "manifest psychosis" items occurred only in the lithium and chlorpromazine groups. In their discussion, the authors point out that the rating scales do not reflect accurately the qualitative differences between lithium and either neuroleptic. Thus, while halo¬ peridol rapidly improved hyperactivity without marked sedation and lithium appeared to act more evenly on all symptoms of mania, chlorpromazine had an "insignificant effect on manic ideation or behavior." These qualitative differences were reflected in the differential discharge rates (favoring lithium) rather than in improvement scores on the various rating scales. COMMENT With the exception of the Japanese study (in which relatively low doses were used), lithium treatment was associated with marked improvement or remission or both in at least 70% of the patients. This is in good agreement with the percentage of marked improvement reported in
the controlled studies of lithium alone (Table 2) and the open or single-blind studies (Table 1). Furthermore, with the exception of the VA-NIMH study, lithium was found superior to chlorpromazine in the treatment of acute mania, as judged by the overall percentage of patients showing marked improvement or remission. In addition, the available evidence strongly suggests that lithium appears to be particularly effective in ameliorating those affective and ideational symptoms that in a sense consti¬ tute the core phenomenology most specific to the manic syndrome. Chlorpromazine, on the other hand, appears to be at least equal to and probably superior to lithium in the initial control of increased psychomotor activity; the contribution of nonspecific sedation to this antihyperactivity effect is not clear. According to the VA-NIMH study, chlorpromazine was superior in the treatment of "highly active" patients, whereas the differences between lithium and chlorproma¬ zine treatment were less pronounced among "mildly active" patients, the results tending to favor lithium. The
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conclusion that chlorpromazine is superior to lithium in "highly active" patients was based on both the higher dropout rate with lithium, as well as on the results obtained on the various rating scales. Neither discharge rates nor overall improvement rates are reported. In this regard, it is worthwhile emphasizing that in the other studies it is precisely the differences in discharge rate and clinical impression (not the various rating scales) that differen¬ tiate between the two treatments.15'17·20·21 Furthermore, some of the rating instruments (eg, NOSIE) failed to demonstrate significant improvement with either drug.16 In the interpretation of dropout rates, it must be kept in mind that a dropout can reflect limitations in clinical management, not just an inherent limitation of the drug in question. That such issues must be taken into account in interpreting the VA-NIMH study is suggested by the 31% rate of severe side effects with lithium. Diagnosis, again, is a critical issue; Prien and his associates19 refer to the Mayer-Gross textbook and to the APA Diagnostic Manual as their diagnostic guidelines, but do not specify how the differential diagnosis was made between manic phase, manic-depressive illness and manic phase, schizoaffective psychosis. The "highly active" patients were noted to be more disturbed and disorganized than the "mildly active" group and conceivably might be diagnosed as schizoaffec¬ tive or "atypical" by other investigators. The available evidence suggests that these patients do not respond as well to lithium as the more "typical" manic-depressive
patients.41415
Prior to the availability of lithium salts, the phenothiazines were the major drug treatment available for mania. The willingness of physicians to use a new, potentially toxic drug requiring careful monitoring suggests that the existing treatments for mania, including phenothiazines, were inadequate for many, if not most, patients. The increasing tendency for clinicians to use lithium in the treatment of mania, rather than to persist in using the
"established," easily available neuroleptic drugs is consist¬
ent with the empirical observation that lithium has an overall advantage over phenothiazines in the treatment of mania. Except for the results regarding the "highly active" patients in the VA-NIMH study, the results of controlled
studies are generally consistent with those clinical observa¬ tions advocating the superiority and specificity of lithium over chlorpromazine in the treatment of mania. This does not imply that neuroleptics have no place in the treatment of acute mania. As already discussed, chlorpro¬ mazine appears to be at least equal to and possibly superior to lithium in the initial control of increased psychomotor activity. It is unfortunate that comparisons of lithium with neuroleptics have been limited primarily to chlorproma¬ zine. Preliminary evidence suggests that other neurolep¬ tics, with pharmacological profiles more specific than chlorpromazine, may be particularly useful when rapid control of increased psychomotor activity and unmanagea¬ ble behavior is desired. Thus, haloperidol, a fairly potent dopamine receptor blocker, was shown by Shopsin et al21 to decrease rapidly (sooner than either lithium or chlorproma¬ zine) the BRPS scores for items such as hostility, excite¬ ment, grandiosity, and suspiciousness. Rapid control of manic symptomatology and behavior has been also
observed with pimozide, a rather specific dopamine recep¬ tor blocker (R. M. Post, MD, D. C. Jimerson, MD, W. E. Bunney, Jr, MD, et al, unpublished observations, December 1978); in the pimozide study, the onset of therapeutic effect was within 24 hours for pimozide, compared to five days for lithium. The effects of these drugs on increased psychomo¬ tor activity and on psychotic disorganization may often be vital to the rapid control of the highly agitated manic patient during the first few days. It is common practice among experienced clinicians either to initiate treatment with a neuroleptic or to combine lithium and a neuroleptic during the first few days and then gradually reduce the dosage of the latter to allow the specific ameliorating effects of lithium on mood and ideation to become appar¬ ent. It is now well established that neuroleptics can be safely coadministered with lithium (see article by Reisberg and Gershon, 879 this issue). References 1. Cade JFJ: lithium salts in the treatment of psychotic excitement. Med J Aust 2:349-353, 1949. 2. Noack CH, Trautner EM: The lithium treatment of mania and psychosis. Med J Aust 38:219-222, 1951. 3. Glesinger B: Evaluation of lithium in the treatment of psychotic excitement. Med J Aust 41:277-283, 1954. 4. Schou M, Juel-Nielson N, Stromgren E, et al: The treatment of manic psychoses by the administration of lithium salts. J Neurol Neurosurg Psychiatry 17:250-260, 1954. 5. Schou M: Lithium in psychiatric therapy: Stock-taking after ten years. Psychopharmacologia 1:65-78, 1959. 6. Kingstone E: The lithium treatment of hypomanic and manic states. Compr Psychiatry 11:317-320, 1960. 7. Wharton RW, Fieve RR: The use of lithium in the affective psychoses. Am J Psychiatry 123:706-712, 1966. 8. Schlagenhauf G, Tupin J, White RB: The use of lithium carbonate in the treatment of manic psychoses. Am J Psychiatry 123:201-207, 1966. 9. Blinder MG: Some observations on the use of lithium carbonate. Int J Neurol 4:26-27, 1968. 10. Van der Velde CP: Effectiveness of lithium carbonate in the treatment of manic-depressive illness. Am J Psychiatry 127:345-357, 1970. 11. Maggs R: Treatment of manic illness with lithium carbonate. Br J Psychiatry 109:56-65, 1963. 12. Goodwin FK, Murphy DL, Bunney WE Jr: Lithium carbonate treatment in depression and mania: A longitudinal double-blind study. Arch Gen Psychiatry 21:486-496, 1969. 13. Stokes PE, Stoli PM, Shamorian CA, et al: Efficacy of lithium as acute treatment of manic-depressive illness. Lancet 1:1319-1325, 1971. 14. Goodwin FK, Zis AP: Lithium in the treatment of mania: Comparisons with neuroleptics and the issue of specificity, in Cooper TB, Gershon S, Kline NS, et al (eds): Lithium: Controversies and Unresolved Issues. Amsterdam, Excerpta Medica, to be published. 15. Johnson G, Gershon S, Hekimian LJ: Controlled evaluation of lithium and chlorpromazine in the treatment of manic states: An interim report. Compr Psychiatry 9:563-573, 1968. 16. Johnson G, Gershon S, Burdock El, et al: Comparative effects of lithium and chlorpromazine in the treatment of manic states. Br J Psychiatry 119:267-276, 1971. 17. Spring G, Schrveid D, Gray C, et al: A double-blind comparison of lithium and chlorpromazine in the treatment of manic states. Am J Psychiatry 126:140-144, 1970. 18. Platman SR: A comparison of lithium carbonate and chlorpromazine in mania. Am J Psychiatry 127:351-353, 1970. 19. Prien RF, Caffey EM Jr, Klett CJ: Comparison of lithium carbonate and chlorpromazine in the treatment of mania. Arch Gen Psychiatry 26:146-153, 1972. 20. Takahashi R, Sakuma A, Itoh K, et al: Comparison of efficacy of lithium carbonate and chlorpromazine in mania. Arch Gen Psychiatry 32:1310-1318, 1975. 21. Shopsin B, Gershon S, Thompson H, et al: Psychoactive drugs in mania: A controlled comparison of lithium carbonate, chlorpromazine, and haloperidol. Arch Gen Psychiatry 32:32-42, 1975. 22. Mayer-Gross W: Clinical Psychiatry, ed 3, Slater E, Roth M (eds): Baltimore, Williams & Wilkins Co, 1969. 23. Diagnostic and Statistical Manual of Mental Disorders, ed 2 (DSM II). The Committee on Nomenclature and Statistics of the American Psychiatric Association. Washington, DC, American Psychiatric Association, 1968.
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