In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Dramatic changes have recently occurred in the availability of treatment options for bipolar illness. Second generation mood stabilizing anticonvulsants carbamazepine and valproate are now widely used as alternatives or adjuncts to lithium. High potency benzodiazepines are also used as alternatives to typical neuroleptics, and now atypical neuroleptics are demonstrating efficacy and better side-effects profiles than the typicals.
Thyroid augmentation strategies and dihydropyridine L-type calcium channel blockers require further clinical trials to define their role. Putative third generation mood stabilizing anticonvulsants lamotrigine, gabapentin, and topiramate have unique mechanisms of action and deserve further systematic study, as does the potential role for nonconvulsive brain stimulation with repeated transcranial magnetic stimulation rTMS. These and a host of other potential treatment options now require a new generation of clinical trials to help identify clinical and biological markers of response and optimal use alone and in complex combination therapeutic regimens.
Some bipolar patient subtypes are particularly prone to lithium nonresponsiveness; among these are patients with dysphoric mania and rapid cycling; a negative family history for bipolar illness in first-degree relatives; the episode sequence pattern of depression-mania-well interval i. In addition, it is recognized that patients with initial excellent responses to lithium can begin to develop breakthrough episodes in subsequent extended years of follow-up Maj et al.
In our series of 66 lithium-refractory patients, 23 Another recently described route to refractoriness has been found in patients who were excellent responders to lithium, but then discontinued treatment on the basis of either noncompliance or physician acquiescence , experienced a relapse, and then failed to re-respond once lithium was reinstituted Post et al. This type of lithium discontinuation-induced refractoriness can be quite malignant, with patients failing to re-respond, even when lithium is augmented with a variety of the other alternative treatments described below; or more mild, and just require greater neuroleptic augmentation.
Thus, lithium shows parallels to the role of penicillin in the treatment of infectious diseases. Penicillin was initially heralded as a miracle drug which it was , until patterns of nonresponse or treatment-resistance emerged, and a variety of alternative treatments were required. In cases of tuberculosis or AIDS-related opportunistic infections, for example, patients can require complex combination therapy to bring these more malignant infections under control.
A similar sequence of adjuncts and alternatives to lithium treatment is now required for many patients with lithium nonresponsive affective illness. Some of these emerging alternatives are described below, two of which the mood-stabilizing anticonvulsants carbamazepine and valproate have already gained wide acceptance in clinical practice.
Valproate recently has been FDA-approved for first-line treatment of acute mania. Many of the other promising approaches are more investigational, but, in many instances, clinical practice is again ahead of more formal controlled clinical trials. Perhaps most revealing is the clear documentation of responsivity in individual patients using double-blind, placebo substitution designs that demonstrate efficacy, reconfirmed with placebo-related exacerbation and re-responsiveness after drug institution on a blind basis Ballenger and Post ; Post et al.
Antidepressant effects are much less well documented and require further controlled study Post et al. Although many of these double-blind studies have been criticized on methodological grounds, other designs used, such as mirror image designs in treatment-refractory patients and B-A-B-A designs, have been cited by Prien and Gelenberg as more convincing.
As with lithium, a subgroup of patients who are initially responsive to carbamazepine alone or with adjunctive treatment with other agents seems to lose efficacy with the development of tolerance Post et al. Loss of responsiveness may have accounted for the large drop-out rate in the follow-up study of Frankenburg et al. This high percentage may be unrepresentative of the general population because of the relatively treatment-refractory and rapid-cycling nature of the patients who were started on carbamazepine in the acute inpatient phase of this study.
However, it would seem that at least a subgroup of patients may develop tolerance to carbamazepine in the treatment of bipolar illness, similar to the even higher percentage of tolerance development using carbamazepine in the treatment of trigeminal neuralgia Fromm and Terrence Weiss et al. These data suggest that tolerance to carbamazepine is pharmacodynamic rather than pharmacokinetic and may represent the loss of illness-induced adaptations during carbamazepine treatment.
As such, these preclinical data would suggest the potential utility of switching to drugs with different mechanisms of action or returning to carbamazepine after a time-off period. Several cases studies support the possibility of the usefulness of such a maneuver Pazzaglia and Post ; and unpublished data , although larger long-term prospective studies are required in order to develop the optimal intervention paradigms for the treatment of carbamazepine tolerance.
In patients who remain successfully treated with carbamazepine, there does not seem to be a very high rate of discontinuation-related refractoriness as observed with lithium; all 10 patients re-responded during a second double-blind trial. However, one schizoaffective patient who showed a rapid antimanic re-response remained psychotic for a longer period Post et al.
On this issue, as well, longer-term studies in a larger number of patients are required in order to assess this potential liability more definitively across different psychotropic medications. The clinical predictors of response to carbamazepine have not been adequately delineated.
However, there is preliminary evidence that, as in lithium treatment, rapid-cycling patients do not respond as well to carbamazepine monotherapy as do nonrapid-cycling patients Okuma ; Denicoff et al. In the study of Denicoff et al. Ketter et al. It is these latter patients with the typical depressive pattern of frontal hypometabolism who seem more responsive to the dihydropyridine L-type calcium channel blocker nimodipine.
Valproate is now FDA-approved for the treatment of acute mania based on several placebo-controlled clinical trials demonstrating efficacy Pope et al. However, in the study of Bowden et al. These data indicate that although valproate is highly effective as compared with placebo, many patients remain inadequately responsive and require adjunctive medications in order to optimize either the time frame or completeness of clinical response. In this regard, Keck et al. This is convergent with the data of Bowden et al.
Open studies by a variety of investigators indicate that valproate has prophylactic effects against recurrences of both acute mania and acute depression in a variety of patients subgroups, including those with dysphoric mania, rapid cycling, and a variety of other traditionally inadequately treated subgroups of bipolar patients Lambert ; Emrich et al. In particular, we and others have noted many patients with excellent responses to valproate who previously were unresponsive to both lithium and carbamazepine.
Conversely, we have observed some patients who responded to carbamazepine but failed valproate Post et al. In our initial series of 27 patients followed for an average of 5. Clinical predictors and therapeutic maneuvers remain to be more definitively delineated. A substantial, but partially mixed, literature review supports the use of verapmil in acute mania Table 3 , although several recent studies do not support this perspective Janicak et al. Even the positive double-blind series of Hoschl and Kozeny in acute mania was unable to demonstrate significant acute antidepressant effects.
In light of this ambiguous profile and less than satisfactory response in acute depression, we elected to study a different calcium channel blocker with a different profile of physiochemical and biochemical properties—the dihydropyridine L-type calcium channel blocker nimodipine. Nimodipine has greater lipid solubility and better penetration into the central nervous system Freedman and Waters and is reported to be problematic with tolerance in the treatment of migraine as compared with other calcium channel blockers.
Moreover, nimodipine has a different profile of anticonvulsant effects in animal models and, in contrast to verapamil, blocks cocaine-induced hyperactivity and its associated dopamine overflow Pani et al. Five of the first 12 patients treated with nimodipine showed clinically relevant improvement using a double-blind B-A-B, and in some instances, B-A-B-A placebo-substitution design Pazzaglia et al.
Using this design, response could be confirmed in patients with very different cycle frequencies, and appropriate statistical techniques could be applied in single-case analyses, as described by McDermut et al.
In an extension of the original study of Pazzaglia et al. Ten of these patients showed clinically relevant degrees of response as rated by marked to moderate response on the clinical global impressions scale CGI and confirmed by appropriate within-patient statistical analyses Pazzaglia et al.
Fourteen patients with an incomplete or inadequate response to nimodipine monotherapy were given a trial of blind carbamazepine augmentation. Four of these showed a clinically significant degree of improvement with the addition of carbamazepine as rated by the CGI change score and confirmed with t -tests.
Many of the responsive patients had failed multiple clinical trials of more traditional treatments, including lithium and a variety of other mood-stabilizing and antidepressant modalities. Among these were several patients with ultrarapid and ultra-ultrarapid ultradian cycling and several patients with recurrent brief depression.
Several of the bipolar patients on either nimodipine monotherapy or combination therapy with carbamazepine were switched from the dihydropyridine nimodipine to the phenylalkylamine verapamil on a blind basis and failed to maintain their same degree of clinical improvement. On a blind basis, they re-responded to nimodipine and continued to maintain this degree of improvement with the transition to another dihydropyridine, isradipine.
These data suggest that, at least in these few bipolar patients, there may not be a cross responsivity among all of the L-type calcium channel blockers. The dihydropyridines, with their different site of action inside the calcium channel and different biochemical properties Triggle , may be preferable to the phenylalkylamines.
However, a more formal comparable clinical trial in larger numbers of patients is required to confirm these differential preliminary observations in a few patients with confirmed responses. This newly approved anticonvulsant for adjunctive therapy in refractory epilepsies has received attention in the treatment of bipolar illness. Lamotrigine has interesting clinical properties including inhibition of excitatory amino acid release and blockade of sodium channels Messenheimer However, evidence indicates that lamotrigine may possess other actions not shared by carbamazepine Brodie et al.
Relatively similar degrees of response have been observed by Frye et al. Subsequently, he reported on beneficial effects of treating ten patients with lithium carbonate a medically accepted, though unproved, treatment for gout for mania and on risks of discontinuing such treatment Cade These encouraging initial results are now widely considered a revolutionary discovery, although this innovative and effective treatment was not immediately adopted by psychiatry. In addition, several cases of severe, acute intoxication associated with use of lithium salts as a substitute for table salt sodium chloride were reported in , and some experience was required to learn how to use lithium safely.
This could be achieved by measuring its concentration in blood Amdisen ; Baldessarini ; Bauer and Gitlin Schou not only did so but pursued the study of lithium to contribute in a major way to establishing its safe and effective clinical use for the treatment of manic-depressive illness.
His research in collaboration with another Danish psychiatrist, Poul Baastrup — , established the most important effect of lithium—its ability to prevent recurrences of manic-depressive illness Baastrup ; Baastrup and Schou In Zurich, Jules Angst born and his collaborators confirmed the prophylactic benefits of lithium treatment Angst et al.
In addition, Angst with Paul Grof born and other colleagues proposed methods of clinical trial-design suitable for testing for long-term, prophylactic effects of a treatment such as lithium Grof et al. Gradually lithium became accepted in clinical practice around the world, though not without some resistance.
There was, in fact, a strong skepticism about its long-term efficacy, based on reasonable considerations Blackwell and Shepherd These included the requirement for evidence from blinded, randomized, controlled trials. The first of these helped to convince the scientific and clinical community Baastrup et al. Lithium treatment finally received regulatory approval by the US Food and Drug Administration FDA in for treatment of acute mania, and in as the first—and for many years, the only—approved treatment for prevention of recurrences in bipolar disorder.
In addition to its potentially toxic effects, lithium being an unpatentable natural product with limited commercial interest had difficulties in attracting extensive support for research or clinical promotion by pharmaceutical corporations. Clinical applications of lithium were made feasible by introducing sensitive, reliable, quantitative methods of monitoring lithium concentrations in serum, initially with flame spectrophotometry and later with atomic absorption, electrochemical, and other detection methods.
These established circulating concentrations of lithium required for safe and effective clinical dosing Amdisen ; Bauer and Gitlin Indeed, lithium remains unique in not being dosed adequately by the mg dose of drug given per day, but instead by achieving serum concentrations 10—14 h after the last taken dose most stable range of the day on the range of 0.
It also has evidence of effectiveness for preventing suicidal behavior in patients with bipolar or major depressive disorder.
However, it has gradually become less widely utilized, particularly for mania, mainly due to more vigorously promoted and more rapidly effective alternatives which do not require blood tests. These alternatives include drugs developed for other purposes, including certain anti-epilepsy agents carbamazepine, lamotrigine, sodium valproate and most antipsychotics.
Their adverse effects include metabolic syndrome weight-gain with diabetes, high blood pressure, and increased lipids in the blood , insulin resistance, abnormal movements, and cognitive dulling with antipsychotics, as well as markedly increased risks of birth defects including spina bifida and severe cardiac anomalies during pregnancy in association with valproate and carbamazepine Patel et al. Concerns about the safety of lithium have not entirely disappeared, despite long-established standards for its safe use with monitoring of its serum concentrations.
Fears about lithium treatment currently are most often directed to putative renal toxicity with its long-term use. In fact, such effects are uncommon and usually can be anticipated by rising serum concentrations of creatinine or declining creatinine clearance McKnight et al.
This adverse effect of lithium is modest, and greatly overlaps with age-associated declining renal function Nielsen et al. In some countries, particularly in the US, vigorous promotion of alternative and patented treatments, sometimes more rapidly acting against mania, have led to substantial displacement of lithium for acute mania. Nevertheless, lithium continues to hold a major position among treatments for bipolar disorder internationally, especially for long-term prophylactic treatment, and it tends to be used for longer times than most alternatives Baldessarini et al.
Satisfactory mood-stabilization over 6—12 months can be attained by about two-thirds of lithium-treated bipolar disorder patients, and an excellent response e. Recent comprehensive reviews considered the benefits of various proposed mood-stabilizing treatments, including lithium, against recurrences of mania and depression in bipolar disorder patients, in more than a dozen placebo-controlled, randomized, long-term trials carried out for an average of 1.
Such studies found that long-term risk of new manic or depressive episodes was lower with lithium than with placebo, although the benefit was greater against new episodes of mania than of depression.
Indeed virtually all available treatments for bipolar disorder, including lithium, anticonvulsants, and antipsychotics are notably limited in their effectiveness against recurrences or acute episodes of bipolar depression and their long-term recurrences, with the exception of lamotrigine for long-term treatment Geddes et al.
However, some randomized, double-blind trials from the s and several recent studies found that long-term treatment with lithium also may reduce recurrences in unipolar major depressive disorder Abou-Saleh et al. In addition, lithium appears to have value in augmenting antidepressant treatment, especially during episodes of unipolar major depression that respond unsatisfactorily to antidepressant treatment.
Most studies supporting this application have involved older, tricyclic antidepressants, but similar effects may occur with modern antidepressants as well Austin et al. Finally, it has been suggested that lithium occurring naturally in drinking water may lower the incidence of dementia, but this finding needs to be verified Kessing et al. This association with the type of illness-course is consistent with the view that depression-prone bipolar disorder patients, generally, respond less favorably to treatment than mania-prone patients Vieta et al.
Of interest, both the DMI versus MDI recurrence pattern, as well as the tendency to a long-term excess of mania over bipolar depression may be identifiable very early on the illness history, possibly from the first-lifetime episode or cycle Baldessarini et al. Responsiveness to lithium and alternative treatments has been inferior among patients with relatively complicated forms of bipolar disorder, such as with rapid-cycling, psychotic features, co-occurring anxiety syndromes or substance-abuse, as well as in depression-prone cases or those following the DMI course pattern, and lithium is less effective in preventing recurrences of bipolar depression than mania.
Importantly, the same limitations hold true for alternative treatments, including anticonvulsants and modern antipsychotics Baldessarini et al. Moreover, as for all maintenance treatments, a favorable clinical response is associated with faithful adherence to the treatment regardless of current lack of symptoms, absence of early or current adverse life events, adult age at onset, good social support, and absence of substance abuse or other co-occurring psychiatric disorders including personality disorders Yatham et al.
Whether indefinitely continued maintenance treatment should be started routinely after an initial manic episode lacks clear consensus. A conservative view would initiate long-term treatment after a second episode of mania since the first might be followed by another only after several years or may be of only moderate severity and duration.
Typically, patients are continued on lithium or an alternative treatment for at least some months following recovery from an acute episode of mania or bipolar depression, with reassessment of the need to continue thereafter.
Lithium probably should be started after a first manic episode presenting with severe symptoms, required hospitalization, or involved suicidal risk or prolonged duration.
Because of the frequent lack of timely recognition and diagnosis of bipolar disorder, especially of type II, initiation of long-term treatment with lithium or other mood-stabilizing treatments typically does not occur for 5—10 years from illness-onset, and even longer following juvenile onset Post et al. Such delay, with associated morbidity, contribute considerably to disability and risk of suicide.
Nevertheless, some studies have found that neither such delays nor the number of recurrences before treatment had a measurable impact on the likelihood of responding once mood-stabilizing treatment was initiated Baethge et al.
Before starting treatment with lithium, and once or twice a year thereafter, we recommend measuring blood concentrations of a creatinine and urea-nitrogen BUN to evaluate kidney function, b sodium, potassium, calcium, and c thyroid and parathyroid hormones, as well as obtaining an electrocardiogram—all of which can be affected by lithium.
Discontinuing long-term lithium treatment of mood disorder patients leads to a substantial risk of illness-recurrences, need for hospitalization, and of suicidal behavior, especially if the discontinuation is rapid or abrupt.
The risk is especially high in the 6—12 months after discontinuation Faedda et al. This effect not only reflects lack of treatment but may be a response to treatment-discontinuation itself as a major stressor Baldessarini and Tondo Suicide is far more likely in depressive, and especially dysphoric-agitated or mixed, phases of bipolar disorder than in manic periods, and is rare in hypomania Swann et al.
This ratio indicates greater lethality of means and intent in major mood disorder patients with a similar risk of suicidal behavior in types I and II bipolar disorder Tondo et al. Initial considerations that lithium treatment might contribute to suicide prevention date to the early s Barraclough , followed by important contributions supporting this hypothesis over the next two decades Coppen et al. An early case—control study of suicidal risk in 68 patients with various major affective disorder diagnoses and at least one suicide attempt, found a rate of suicides or attempts during 8.
In type I or II bipolar disorder patients before, during, and following discontinuation of long-term lithium monotherapy, rates of suicide and life-threatening attempts were 6. The risk of suicidal acts increased fold within several months after discontinuing lithium maintenance treatment, but later fell back to the same level encountered before lithium treatment had started Tondo et al. Moreover, early suicidal risk following discontinuation of long-term treatment with lithium was twice-higher following abrupt or rapid versus more gradual discontinuation of lithium over at least 2-weeks.
In a systematic review of 12 studies, the pooled rate of suicides and attempts was 8. Similar effects on suicidal behavior have not been achieved with several proved or putative mood-stabilizing anticonvulsants including carbamazepine, lamotrigine, and valproate Thies-Flechtner et al.
Antipsychotic drugs have not been tested for such effects in bipolar disorder patients. An association of reduced suicidal risk during long-term treatment with lithium in bipolar disorder patients is supported by several studies and quantitative reviews Angst et al.
Overall, the findings summarized here, appear to provide strong and quite consistent support for the hypothesis that lithium treatment may have a special role in reducing suicidal risks. Although these findings are encouraging and unusual, it must be emphasized that such an effect of lithium treatment has not yet been definitely proved in prospective, randomized trials in which suicidal behavior is an explicit outcome.
Largely for that reason, lithium has not been accepted by the FDA as a specific indication to prevent suicidal ideation or behavior. Frederick Goodwin and Ross J. This included data from several randomized, controlled trials in which suicidal acts were cited as adverse outcomes. However, no pharmaceutical company is likely to underwrite studies or to make formal application to the FDA for such an indication.
The only randomized and controlled study in patients who have attempted suicide, with suicidal behavior as an explicit outcome, found a significantly lower number of suicides in the lithium group compared to placebo 0 vs. The following guidelines for managing lithium treatment are based on several recent publications and the extensive clinical experience of the authors Baldessarini ; Bauer and Gitlin ; Haussmann et al.
As noted, lithium is used mostly as a long-term treatment to prevent mood-disorder recurrences. Its place in the treatment of acute mania has largely been displaced in favor of some anticonvulsants and modern antipsychotic drugs, which act more rapidly and whose target doses can be reached within a few days.
In particular, the most common current treatment for a manic episode is with modern antipsychotic agents for several months, with lithium introduced adjunctively or continued long-term by itself as a preventive treatment Yatham et al. Lithium should be taken regularly as prescribed. A daily single dose after the evening meal is convenient, preferably with slow-release formulations in relatively young, otherwise healthy patients.
This practice can support critically important, long-term treatment-adherence Malhi et al. For older or infirm patients, and users of high daily doses over mg of lithium carbonate [32 mEq] , divided daily doses may be safer.
If a dose is missed it is not safe to double the next dose. If the brand or salt-form of lithium needs changing, this should be done by gradually discontinuing the first preparation as the second is introduced and gradually increased. The optimum amount of lithium to be taken is based on clinical response and measured blood levels of lithium which guide the dose of lithium.
Blood assays of lithium usually are obtained at 1 week after the start of lithium treatment, then monthly in the first 3 months.
Subsequently, when the patient is considered stable, blood tests may be done every 6 months depending on age, general health, and response to treatment. Blood should be drawn at a consistent interval, at 10—14 optimally, 12 hours after the last intake.
If a dose is changed, 5—7 days should pass before measuring the blood level to allow tissue distribution to stabilize. Optimal daily trough blood concentrations of lithium for long-term treatment usually are between 0.
Lithium is an effective treatment for acute mania. Lithium was more effective than a placebo or the anti-epileptic drug topiramate. There was some evidence that lithium may be less effective than the antipsychotic drug olanzapine, but this needs further investigation.
There was no evidence that lithium was better or worse at treating mania than any of the other drugs, and not enough evidence to draw a conclusion for ECT.
There was not enough evidence to provide a definite answer as to which treatment for mania has the fewest side effects. It is probable that more people will develop a mild tremor when treated with lithium than other treatments.
Participants were not more likely to withdraw from a study if they were treated with lithium compared to another treatment. Unanswered questions remain, and these would be best resolved by further large, well-designed studies comparing lithium to other treatments for acute mania. This systematic review indicates that lithium is more effective than placebo as a treatment for acute mania but increases the risk for somnolence and tremor.
Limited evidence suggests little or no difference between lithium and other mood stabilisers valproate, carbamazepine or antipsychotics risperidone, quetiapine, haloperidol. Olanzapine may be an exception, as it is probably slightly more effective than lithium. There is uncertain evidence that risperidone may also be more effective than lithium. Lithium is probably more effective at treating acute mania than topiramate. When compared to placebo, lithium was more likely to cause adverse events.
However, when compared to other drugs, too few studies provided data on adverse effects to provide high-certainty evidence. More, rigorously designed, large-scale studies are needed to definitively conclude if lithium is superior to other interventions in treating acute mania.
The serum lithium level was unchanged. ECT sessions 3 and 4 were uneventful, with no post-treatment delirium. Seizure duration for Treatment 4 was 58 seconds. After Treatment 4, Mrs. Repeat CT of head, after Treatment 4, was unchanged from baseline. What is the role of lithium?
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