6belm.mp

The new england journal of medicine m e d i c a l p r o g r e s s
ipolar disorder is one of the most distinct syndromes in psy- Gurion University of the Negev, Beersheba, chiatry and has been described in numerous cultures over the course of histo- Israel. Address reprint requests to Dr. Bel- ry.1 The unique hallmark of the illness is mania. Mania is, in many ways, the maker at the Beersheba Mental Health Cen-ter, P.O. Box 4600, Beersheba, Israel, or at opposite of depression. It is characterized by elevated mood or euphoria, overactivity with a lack of need for sleep, and an increased optimism that usually becomes so ex-treme that the patient’s judgment is impaired. For example, a person with mania may N Engl J Med 2004;351:476-86.
Copyright 2004 Massachusetts Medical Society. decide to purchase 500 television sets if he or she believes that their price will go up.
Drives such as sexual desire are also enhanced; manic patients are disinhibited in theirspeech about sexual matters, joking or talking about subjects not normally allowed intheir culture. Manic patients are sometimes disinhibited in their sexual actions as well,and they may endanger their marriage or relationship as a result. A key point is thatmanic behavior is distinct from a patient’s usual personality, but its onset may be grad-ual with weeks or months passing before the syndrome becomes full-blown. In the ab-sence of effective treatment, a manic episode, although ultimately self-limited, couldlast months or years.2 Before effective treatment was available, even after a long manicepisode, patients were known to recover to a state closely approximating, if not identi-cal with, their personality before the illness developed.3 The depression that alternates with manic episodes (bipolar depression) is charac- terized by more familiar symptoms (Table 1). A single manic episode is sufficient forthe diagnosis of bipolar illness, as long as the manic symptoms are not due to a generalmedical condition such as amphetamine abuse or pheochromocytoma.4 Some patientsmay have one manic episode at a young age and frequent depressive episodes there-after, others may have alternating episodes of mania and depression on a yearly basis,and still others may have a manic episode every five years but never have a depressiveepisode.
Mania can be of varying severity. Mild episodes without psychotic symptoms and with-out symptoms of being dangerous to oneself or to others are called hypomania.5 Hy-pomanic episodes can occur in patients with diagnosed bipolar illness, but they canalso occur in patients with a history only of depression. The syndrome of major depres-sive episodes and hypomanic episodes has been called bipolar II disorder, to distin-guish it from the full-blown bipolar illness called bipolar I disorder. However, the reli-ability of the diagnosis of bipolar II disorder is lower than for bipolar I disorder, anddrug response and family history do not convincingly indicate that bipolar II is trulya milder version of the disorder.5 Bipolar illness (classically defined bipolar I disorder) affects approximately 1 percent of the population worldwide.6 Bipolar II disorder is reported to be much more preva-lent, and a spectrum of bipolar disorder has been described that includes states of chron-ic mild hypomania.7 However, the use of the concept that bipolar illness covers a wide Downloaded from www.nejm.org at ICHILOV / SOURASKY MEDICAL CTR on September 21, 2008 . Copyright 2004 Massachusetts Medical Society. All rights reserved. Table 1. Features of Bipolar Disorder.
Hypomania
Depression
Severity of disorder Severity requires hospitaliza- ferent from usual personality, causing notice-able impairment in social, occupational, and other areas of functioning Euphoria or irritable mood; de- Same as in mania creased interest in sexual activity and in other plea-surable activities spectrum may result in labeling patients as having ery do not have the good prognosis characteristicthis disorder and may result in clinicians’ overpre- of mild depressive postpartum symptoms. Alcoholscribing drugs and framing psychosocial issues as abuse and drug abuse frequently complicate themedical.
treatment of patients with bipolar disorder and the Patients who have four or more episodes of clinical course of the disease, because patients in mania or depression per year are considered to be the depressive phase may use alcohol or drugs as“rapid cyclers,” and rapid cycling is difficult to treat. self-medication and patients in the manic phaseAlthough some experts have advocated specific may crave them as part of the arousal characteristicpharmacologic treatment, a recent large, controlled of this phase. The extent of substance abuse in pa-study showed that valproate was not superior to tients with bipolar disorder varies greatly accord-lithium in the treatment of these patients.8 Further- ing to culture, country of residence, and socioeco-more, there are few life-course studies, and many nomic class.
clinicians have observed that in some patients a pe- Figure 1 presents a life chart of a patient with riod of a few years of rapid cycling occurs, with a lat- bipolar disorder and shows the episodes of ma-er transition to a period of less frequent episodes, nia and depression that affected the patient’s life,and vice versa.9 ruining several potential careers and leading to three The lifetime incidence of about 1 percent for bi- divorces. In the healthy intervals, the patient clearly polar disorder contrasts by an order of magnitude regretted some of his behavior during the periodswith estimates of the prevalence of unipolar depres- of depression and mania; when well, he saw suchsion, which is far more common in the general pop- behavior as not part of himself.
ulation. However, bipolar disorder, especially in the Many famous musicians, writers, and leaders manic phase, is so destructive to the patient’s abili- of society have had bipolar disorder.11 Many ofty to work and to the function of the family that it these people — and some of their physicians —constitutes a substantial public health problem even have been concerned that the pharmacologic treat-in comparison with the more common unipolar de- ment of their mood swings might reduce theirpression.10 creativity. However, there is considerable evidence For women with bipolar disorder, the postpar- that people with bipolar disorder are more cre- tum period is a time of considerable risk, and this ative when effectively treated than when they arefact should be discussed when counseling female not treated. Only the early phases of mania appearpatients about the risk of pregnancy. Bipolar ill- to contribute to creativity, whereas full-blown ma-ness may also have its onset post partum, and man- nia usually becomes destructive to creativity andic symptoms that appear in the weeks after deliv- productivity.12 Downloaded from www.nejm.org at ICHILOV / SOURASKY MEDICAL CTR on September 21, 2008 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Depression
Year and Duration (months)
Figure 1. Life Chart of a Patient with Bipolar Illness.
The patient was a 43-year-old man who had a first episode of mania at the age of 23 and a first episode of depression at the age of 27. Orange denotes mania, and blue depression. Positive scores indicate mania and negative scores de-pression, with higher scores indicating a greater severity of illness and zero indicating no illness.
genomic medicine offers the hope that specific genes that confer an elevated risk of bipolar illness About 50 percent of patients with bipolar illness will be found.16have a family history of the disorder, and in some Genetic counseling of families with bipolar ill- families, known as multiplex families, there are ness may be helpful, but of necessity, such counsel-many members with the disease across several gen- ing is based on premolecular and family studies.
erations. Studies of twins suggest that the concor- On the basis of family studies, the risk of bipolardance for bipolar illness is between 40 percent disorder in the child or sibling of a person with theand 80 percent in monozygotic twins and is lower disease is about 10 percent.13 Such information(10 to 20 percent) in dizygotic twins, a difference may be helpful for life planning, though even a riskthat suggests a genetic component to the disor- of 10 percent may lead some potential life partnersder.13 There is no mendelian pattern, however, and to think twice about continuing a relationship.
statistical analysis suggests polygenic inheritance.
The advent of molecular genetics opened a new era in genetic studies of bipolar disorder. DNA
markers have been sought throughout the genome acute mania
in large pedigrees in which many family members Acute mania is a medical emergency. If a manic pa-
have the illness and, with the use of the transmis- tient is not treated rapidly, he or she is liable to en-
sion disequilibrium test, in patients with bipolar gage in activities that may endanger the patient’s
disorder and their parents. Linkage studies have marriage or job and possibly the patient’s life. Acute-
identified markers, which have been replicated in ly manic persons may appear rational at one mo-
more than one study, particularly on chromosomes ment and yet be out of control the next. For exam-
18 and 22.14 However, no single locus has been ple, a manic person who is driving at 110 miles an
consistently replicated, and the contribution of hour through the city may just have had a rational
any identified locus appears small.15 Progress in conversation with the family physician in which
Downloaded from www.nejm.org at ICHILOV / SOURASKY MEDICAL CTR on September 21, 2008 . Copyright 2004 Massachusetts Medical Society. All rights reserved. the patient denied having delusions or hallucina- inhibitors, and monoamine oxidase inhibitors.33tions and seemed pleasant, even if speaking unusu- The length of time before a response in a patientally rapidly. It is critical to obtain collateral infor- with bipolar depression is similar to that seen inmation from relatives, friends, and coworkers about those with unipolar depression, three to six weeks.
such a patient’s behavior in recent days to supple- However, treatment for bipolar depression must bement the clinical interview. Identified behavioral carried out in the knowledge that antidepressantdangers are as much an indication for involuntary drugs may induce a switch from depression to ma-hospitalization of a patient as the patient’s verbal nia. A patient with a history of at least one danger-expression of violent hallucinations or delusions.
ous episode of mania that put the family or the pa- Numerous effective treatments exist for acute tient’s job at risk should probably not be treated mania (Table 2). Neuroleptic (antipsychotic) drugs with antidepressants, even if the patient continuesare clearly effective in acute mania.30 These drugs to have residual low mood or low energy. However,are not recommended for long-term prophylaxis patients who have had one diagnosed moderatebecause of the danger of tardive dyskinesia. In the episode of mania in which neither self-injury noracutely manic patient, these medications have the damage to the family occurred but who have hadadvantages of readily available parenteral as well as recurrent, crippling depression after the single man-oral forms and of rapid onset of psychomotor in- ic episode will probably benefit from an antidepres-hibition, which may be lifesaving in the case of a vi- sant without sustaining undue risk.33olent or psychotic patient. These medications are Some studies have suggested that relatively new generally detested by patients with milder disease, antidepressants such as the selective serotonin-who often are more compliant with a regimen than reuptake inhibitors and bupropion are less likelyare patients with severe mania. The new, atypical than older agents to induce mania in persons withantipsychotic drugs (those without extrapyramidal bipolar depression,34 but these studies have oftenside effects) are effective in compliant patients and been restricted to data on patients with very mildalso may pose lower risks of inducing depression mania (bipolar II disorder), and the data shouldthan is the case with classic neuroleptic drugs. Par- not be extrapolated to all patients with bipolar ill-enteral preparations of the atypical antipsychotic ness.35,36 The n¡3 fatty acids have been experi-drugs are becoming available. Some worrisome mentally reported to be antidepressant in prelimi-adverse effects of these drugs include weight gain, nary studies37 and may represent a new directionchanges in lipid levels, and abnormalities in glucose for the treatment of bipolar disorder. Inositol is an-tolerance.31 Thus, a patient who had a good re- other natural substance that has been studied in bi-sponse to a classic neuroleptic in the past should polar depression.38probably be treated with the same drug when a re-current manic episode occurs.
m o o d s t a b i l i z e r s a n d p r o p h y l a x i s
Research studies have shown that lithium, val- Lithium is the quintessential and classic mood sta- proate, and carbamazepine have established effi- bilizer.39 Lithium was developed when the regula-cacy in the treatment of acute mania and are ef- tions of the Food and Drug Administration (FDA)fective in clinical practice as monotherapy for were less stringent than they are now, and the newoccasional episodes of mild mania in unusually agents to treat mania may be promoted as the onlycompliant patients. Surveys of clinicans, however, treatments that satisfy the current, more stringenthave suggested that these drugs work too slowly in standards of proof in clinical trials. However, forthe great majority of patients with acute mania.32 the past 50 years lithium has been shown to haveTreatment should generally be initiated, then, with antimanic efficacy, prophylactic efficacy in bipolareither a typical or an atypical neuroleptic drug, with disorder, and some efficacy in prophylaxis againstthe addition of a mood stabilizer such as lithium, bipolar depression.23 The drug has a narrow thera-valproate, or carbamazepine as soon as compliance peutic index, and the blood levels in patients takingwith oral therapy is assured.
lithium must be monitored. Severe toxic effectsand sometimes death can occur when renal excre- b i p o l a r d e p r e s s i o n
tion is impaired, even by such apparently innocent Bipolar depression (depressive episodes in a pa- changes as the onset of diuretic treatment for hy-tient with bipolar illness) generally responds to tri- pertension. Progressive renal failure after decadescyclic antidepressants, selective serotonin-reuptake of lithium use has been reported,40 although some Downloaded from www.nejm.org at ICHILOV / SOURASKY MEDICAL CTR on September 21, 2008 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 2. Drug Treatments for Mania and Bipolar Disorder.
Side Effects
Indication
Effectiveness
Highly effective but pos- Licht,17 Littlejohn Atypical neuroleptics Diabetes and weight Established for moderate Sanger et al.,20 Noncompliance with Highly effective but pos- Littlejohn et al.18 Rare hepatotoxic effects, Good compliance Highly effective, slow on- Bowden et al.,25 Rare hepatotoxic effects, Good compliance Anxiety, psychomotor Questionable for core have questioned the specificity of lithium as the controlled. However, when a U.S. pharmaceuticalcausative agent in these cases.41 company, Abbott, reached an agreement with the Carbamazepine was the anticonvulsant drug FDA to patent a new formulation of valproic acid, reported to be useful in the treatment of bipolar ill- a large-scale, controlled study was carried out,25ness in the 1980s42 — it was estimated that as much leading to a profitable compound, divalproex so-as half the sales of carbamazepine were for bipo- dium. Although some have viewed divalproex sodi-lar illness. Throughout that decade, many small um as having a dubious pharmacologic advantagestudies reported on the therapeutic efficacy of car- over valproic acid, and despite heavy advertisingbamazepine as prophylaxis against mania, bipolar and promotion of its use, lithium still controls adepression, and bipolar disorder, as monotherapy large market share in the treatment of bipolar dis-sometimes but often in addition to other treatment. order, a situation that suggests either that psychi-This literature has lately been reevaluated in the atrists are a stubborn lot or that lithium may havelight of the FDA’s standards for the licensing of new greater efficacy in the treatment of bipolar disor-anticonvulsant agents for use in the treatment of der than commercially sponsored studies wouldbipolar disorder, and the literature has sometimes suggest.44 A recent large study has suggested thatbeen found wanting. However, a clinician must take lithium prophylaxis is much more effective thaninto account the relatively long and successful clin- valproate prophylaxis in the prevention of suicideical use of this compound.27 The first studies of valproate (valproic acid), an- The success of carbamazepine and valproate other anticonvulsant agent, in treating bipolar ill- and the development of new antiepileptic agentsness came from outside the United States,43 as was have led to the use of these drugs in treating bipo-the case with carbamazepine. These early studies lar disorder as well. Case reports and small stud-were criticized by U.S. physicians as being poorly ies have suggested that topiramate is effective in Downloaded from www.nejm.org at ICHILOV / SOURASKY MEDICAL CTR on September 21, 2008 . Copyright 2004 Massachusetts Medical Society. All rights reserved. bipolar illness, although a large study sponsored through depression present at referral centers. Theby Janssen Cilag found no difference in efficacy be- effectiveness of a polypharmacy approach — lithi-tween topiramate and placebo, perhaps because um plus anticonvulsant, two anticonvulsants, lithi-mild, antidepressant-induced manias subsided in um plus an atypical neuroleptic, and occasionallya large number of patients in the placebo group.46 lithium plus an antidepressant — is supported byLamotrigine has also been reported to have a posi- some research data.50tive effect in bipolar illness, particularly in the de- The design of drug trials for bipolar illness has pressive phase. Clinicians have for many years re- engendered an ethical controversy that will affectgarded lithium, valproate, and carbamazepine as future trials.51 A manic episode can be life-threat-more successful in controlling the manic phase of ening to the patient, and it is the view of many psy-bipolar disorder than the depressive phase, and a chiatrists and physicians that, given that effectiveneed exists for a drug to treat depression for use in treatment exists, patients with this illness shouldthis disorder. A large, company-sponsored study not be recruited for placebo-controlled trials. How-suggested that lamotrigine was more effective as ever, in most cases the FDA has insisted on place-prophylaxis against bipolar depression than lithi- bo-controlled monotherapy trials for the registra-um or placebo.47 However, the size of the effect was tion of new compounds for use in psychiatry. Somesmall, and there was concern about whether a large statisticians support the FDA’s position, calculat-number of patients who had not had a good re- ing that without the use of a placebo control group,sponse to lithium had been attracted to the study.
many patients would be exposed to poor treatment Benzodiazepines act on the benzodiazepine because a very large number of subjects would be receptor of the g-aminobutyric acid–benzodiaz- needed to prove lack of efficacy of a new treatmentepine complex and are effective in status epilepticus, as compared with the efficacy of an active controland they may be useful adjuncts in the treatment medication such as lithium.52 These statistical cal-of mania because they reduce tension and improve culations do not take into account the distortionssleep. However, they do not seem to have true an- that may be induced by the use of unrepresentativetimanic efficacy.28,29 Gabapentin has not been ef- patient populations in placebo-controlled studies.
fective against mania in well-designed trials, despite One example is a large, rigorous study that com-early reports suggesting such an effect.48 Zonisa- pared the efficacy of valproate, lithium, and placebomide and felbamate, also new anticonvulsants, have in three randomized groups of patients with bipo-been shown in some case reports to have efficacy lar illness and showed no significant differences be-in bipolar illness but have not yet been studied in tween the groups, apparently because only patientsa controlled fashion.48 with mild forms of the disorder were recruited.26 Dopamine receptor–blocking drugs (neuro- leptics) that are used in schizophrenia are also ther- apeutic in acute mania. A few studies have foundthese drugs efficacious in prophylaxis against bi- Surprisingly, studies have not identified a clearpolar disorder as well, but the risk of tardive dyski- personality trait specific to patients with bipolarnesia has limited their use. Atypical neuroleptic manic–depressive illness. Intuition may suggest thatdrugs such as clozapine, olanzapine, risperidone, patients are labile, unstable, or perhaps seekers ofand ziprasidone have efficacy49 in at least some novelty even when they are not manic or depressed.
phases of bipolar disorder. Such efficacy blurs the However, there is little evidence of specific person-distinction between therapy with neuroleptic drugs ality characteristics.53 Evidence suggests that theto treat schizophrenia and mood-stabilizing thera- first episode of bipolar disorder often is associat-py. Future studies of prophylaxis with atypical anti- ed with stress in the life of the patient — the clas-psychotic drugs may lead to an entirely new classi- sic stressful event may be a first love relationship.54fication of mood-stabilizing agents, in comparison However, most studies agree that subsequent man-with antipsychotic agents.
ic episodes often tend to be unrelated to external Although treatment with lithium or an anti- events in the patient’s life.
convulsant agent provides remarkable prophylaxis Most clinicians and some research data support over many years for many patients with bipolar ill- the idea that sleep disturbance can trigger manicness, large numbers of patients with breakthrough and depressive episodes in patients with bipolar ill-episodes of mania and, even more common, break- ness,55 although in one controlled study no thera- Downloaded from www.nejm.org at ICHILOV / SOURASKY MEDICAL CTR on September 21, 2008 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine peutic effect of social rhythms therapy was shown.56 malities that precede the manifestation of symp-Clinicians generally advise patients with bipolar dis- toms of the illness. Such markers are also less like-order to avoid late work shifts, late-night partying, ly to be artifacts than to be secondary to changesand other events that disturb sleep.56,57 in the patient’s activity, sleep, appetite, and weight.
Until such findings can be replicated multiple timesand shown to be independent of the alterations in activity and weight that are characteristic of mania n e u r o c h e m i c a l s t u d i e s
or depression, the phenomena should not be con- The discovery that lithium, a simple ion, had a con- sidered to be established. Owing to the difficulty
siderable effect in terms of mood stabilization sug- of studying the brain in a living patient, the use of
gested that a straightforward biologic pathophysi- a specific treatment as a “pharmacologic bridge”
ology might easily be detected in manic–depressive remains a key strategy to understanding the neuro-
illness — a concept that could lead to important chemistry of bipolar disorder. The development of
biologic findings in other mental disorders and in such a pharmacologic bridge involves the selection
human behavior in general. However, 2004 arrived of a candidate neurochemical abnormality68 and
without the discovery of a biologic diagnostic test the testing of its relevance with the use of a hypoth-
or the identification of a specific pathophysiologic- esis-based clinical intervention.69
al abnormality in manic–depressive illness. In early
studies, urine and spinal fluid were examined for neuroimaging and neuroanatomical
abnormalities in metabolites of the chief mono- studies
amine neurotransmitters, neuroadrenalin, seroto- The increasing sophistication of techniques to mea-
nin, and dopamine. The findings were difficult to sure the anatomy and function of the human brain
replicate and, if replicated, turned out to be second- with the use of neuroimaging has not been ignored
ary to the hyperactivity typical of mania and the hy- in the study of bipolar disorder. Even though com-
poactivity and weight loss typical of depression.58
puted tomography and magnetic resonance imag- The techniques of postmortem neurochemical ing (MRI) are limited to structural findings, func- analysis have developed in recent years as brain tional MRI and positron-emission tomography
banks have acquired modern methods, including (PET) can provide information about function. Most
speedy removal of central nervous system tissue.59 of the imaging studies in bipolar disorder are small,
Despite the use of protocols with patients’ informed because of both the cost and the difficulty involved
consent that include antemortem diagnosis and ex- in studying patients who are either manic or de-
clude the recruitment of patients with severe sys- pressed; to date, the ability to replicate results has
temic physical illness, information about a patient’s been poor (Table 3).70 One promising report not-
mental state at time of death — whether the patient ed decreased volume of gray matter and decreased
had depression, mania, or euthymia — is rarely ob- blood flow in the subgenual prefrontal cortex of
tained. Patients with bipolar illness who die at an patients with bipolar illness, as compared with per-
advanced age are likely to have neurochemical ab- sons without this illness.67 The prefrontal cortex
normalities secondary to other brain disorders, is known to be involved in emotional responses,
including Alzheimer’s disease, or to the effects and its neurochemistry is affected by psychotro-
of long-term drug treatment. Those who die at a pic drugs. At present, neither neuronal imaging nor
younger age often have committed suicide during neurochemical studies can provide a helpful answer
a period of acute stress that was unrelated to the to the relative of a person in whom bipolar illness
specific diagnosis. Perhaps the most specific and is suspected who asks if there is a biologic test
replicable findings are those of Rajkowska et al.,60 that can establish the diagnosis.
which suggest a reduction in neuronal and glial
density in specific frontal brain regions post mor- mechanism of action of lithium and other
tem in patients with bipolar illness.
m o o d s t a b i l i z e r s
Table 3 provides a selected sample of recent neu- Lithium has a myriad of biochemical and biologic rochemical findings in the central nervous system effects, although many of them occur only at toxicin bipolar disorder. The findings of abnormalities concentrations. One way to frame the biologic ef-in the euthymic state may be particularly important, fects of lithium is to examine these effects as theybecause they have the potential to reveal abnor- came to be understood over the past half-century of Downloaded from www.nejm.org at ICHILOV / SOURASKY MEDICAL CTR on September 21, 2008 . Copyright 2004 Massachusetts Medical Society. All rights reserved. Table 3. Neurochemical and Imaging Findings in Bipolar Disorder.*
Focus of Study
Possible Implication
Increased serotonin innervation Zubieta et al.62 mus and ventral midbrain, studied with PET in vivo Postmortem brain tissue (prefron- Decrease in brain reelin Abnormality of brain extracellular Guidotti et al.63 studied with immunohisto-chemical analysis, RT-PCR, and Western blot the use of morphometric, three-dimensional cell counting Abnormal emotional responsive- Drevets et al.67 * VMAT denotes vesicular monoamine transporter, PET positron-emission tomography, RT-PCR reverse-transcriptase polymerase chain reaction, and MRI magnetic resonance imaging.
the development of neuroscience. The central fo- The principle of Occam’s razor would suggest thatcus in neuroscience has shifted repeatedly during only one of these biochemical effects will emergethis time, and lithium appears to have at least one as the mechanism for the effect of lithium on mood.
major effect according to each focus (Table 4).
However, a better understanding of how lithium Lithium inhibits the accumulation of cyclic aden- works would probably serve as a rational basis for osine monophosphate (cAMP),73 perhaps at the the development of new drugs.
level of G proteins, which act to convey the signal Mood stabilizers other than lithium include between the receptors and adenylate cyclase.78 anticonvulsants, numerous biochemical actions ofLithium may down-regulate second-messenger sys- which involve voltage-activated sodium channels,tems that are associated with cAMP–linked recep- and g-aminobutyric acid.83 Valproate shares sometors. Lithium inhibits the activity of inositol mono- reported effects with lithium — for example, thephosphatase,74 resulting in inositol depletion, an inhibition of GSK-3b and the increase in bcl-2.84effect that could down-regulate second-messen- Recently, Williams et al.85 reported that lithium, val-ger systems that are linked to the phosphatidylino- proate, and carbamazapine have common effectssitol cycle. Although these two potential actions of on neuronal growth cones that are reversible bylithium were of interest in the past, neither has led inositol — a finding that supports the classic ino-to the successful development of new drugs.79 New- sitol-depletion hypothesis.
ly proposed mechanisms for the action of lithiuminclude the inhibition of glycogen synthase kinase- 3 beta (GSK-3b),80 the inhibition of binding of se-rotonin (5–HT) to 5–HT receptors,81 effects on The evidence of a clear genetic predisposition to glutamate uptake and release,82 and an increase in bipolar illness has led to important efforts in genethe levels of the neuroprotective protein bcl-2.77 discovery, and several linkage studies have pro- Downloaded from www.nejm.org at ICHILOV / SOURASKY MEDICAL CTR on September 21, 2008 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 4. Focus of Neuroscientific Studies and the History of Understanding the Mechanism of Action of Lithium.*
Finding about Lithium
* cAMP denotes cyclic AMP, and CREB cyclic AMP–responsive element–binding protein. duced similar results. However, these results are ment for some affected patients, often with lithi-not sufficiently robust to be used in genetic coun- um or valproate, but the use of these agents in mildseling. New drugs, such as valproic acid and lamo- variants of the disorder remains unsupported bytrigine, are effective. These drugs are useful alter- strong biologic or clinical data. For this reason,natives for patients in whom adverse effects occur clinicians should be careful to avoid misdiagnos-with lithium or in whom the response to lithium ing psychological or social phenomena as bipolaris inadequate, but no drug seems more effective illness. Increasing evidence for the efficacy of newthan lithium for the majority of patients with bi- atypical antipsychotic drugs in the treatment ofpolar illness. Although the search for evidence of and prophylaxis against bipolar illness has provid-abnormalities in neurochemical and neuroimag- ed a major treatment alternative that may, in the fu-ing studies remains promising, diagnostic mark- ture, blur the diagnostic and therapeutic bound-ers that would have clinical relevance have still to aries between bipolar illness and schizophrenia.
be discovered.
However, the emerging adverse effects of these new A new diagnostic tendency to view milder con- compounds cannot be ignored.
ditions that include mood swings as variants of I am indebted to Samuel Gershon, mentor extraordinaire in the bipolar illness may lead to more effective treat- field of bipolar disorder.
r e f e r e n c e s
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