Bipolar affective disorder, when narrowly defined, has a lifetime incidence of 0.3-1.5/100.^[1] Overall, patients with severe affective disorders have a risk of completed suicide of 6% to 15%.^[2,3] Traditionally, bipolar disorder and its predecessor, manic-depressive psychosis, have been considered as intermittent disorders with good interepisode recovery.^[4] However, recently it has been shown that patients may have social, marital, occupational, and cognitive dysfunction even when supposedly recovered.^[5] A number of factors are of importance in the management of bipolar disorder, including the subtype of episode (manic, depressed, or mixed); the nature of recovery; the cycling frequency and precipitant, if any, for recurrence; and the onset and evolution of the underlying illness. On average, 4 episodes occur every 10 years; however, up to a quarter of patients develop rapid cycling disorder, which is defined as 4 or more episodes occurring within a year.^[6] Patients with bipolar disorder often have comorbid anxiety and substance abuse. Such comorbidity is associated with an earlier age at onset and worsening course of bipolar illness. Established addictive problems should be independently assessed and treated.^[7] Personality problems are also common. Kay and colleagues,^[8] after excluding patients with a history of alcohol use disorder, demonstrated axis II comorbidity in almost a quarter of euthymic bipolar patients. As with all psychiatric disorders, treatment strategies in bipolar disorder must be based on an overall management plan that incorporates both pharmacologic and psychological approaches.

Bipolar disorder is often undiagnosed or misdiagnosed as another psychiatric disorder, most commonly unipolar disorder. As mentioned above, it is also frequently comorbid with both Axis I and Axis II disorders. Mania is fundamental to the diagnosis of bipolar 1 disorder. Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for mania are as follows^[6]:

1. A distinct period of abnormally and persistent elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary).
   
   
2. During the period of mood disturbance, 3 (or more) of the following symptoms have persisted (4 if the mood is only irritable) and have been present to a significant degree:
   
   
   1. Inflated self-esteem or grandiosity
   2. Decreased need for sleep (eg, feels rested after only 3 hours of sleep)
   3. More talkative than usual or pressure to keep talking
   4. Flight of ideas or subjective experience that thoughts are racing
   5. Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli)
   6. Increase in goal-directed activity (either socially, at work, at school, or sexually) or psychomotor agitation
   7. Excessive involvement in pleasurable activities that have a high potential for painful consequences (eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments).
   
   
3. The symptoms do not meet criteria for a mixed episode.
   
   
4. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.
   
   
5. The symptoms are not due to the direct physiologic effects of a substance (eg, a drug of abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism).
   
   

Hypomania is not associated with significant functional impairment and, with major depression, defines bipolar 2 disorder. The DSM-IV definition is:

1. A distinct period of at least 4 days of elevated, expansive, or irritable mood;
2. The presence of 3 or more of 7 diagnostic symptoms (4 symptoms if the mood is only irritable);
3. An unequivocal change in functioning;
4. This change and disturbance is observable by others;
5. The episode does not meet criteria for mania; and
6. The symptoms are not due to the effects of a substance or a general medical condition.

For bipolar depression, individuals must fulfil DSM-IV criteria for a major depressive episode within the context of a bipolar disorder.

1. The criteria are met both for a manic episode and for a major depressive episode (except for duration) nearly every day during at least a 1-week period;
2. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features; and
3. The symptoms are not due to the direct physiologic effects of a substance (eg, a drug of abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism).

Delay in diagnosis occurs because the illness may start nonspecifically and the diagnosis of mood elevation is missed or symptoms are attributed to circumstances of personality disturbance.

Many authors now believe that full mania (induced by antidepressants or stimulants) should be regarded as bipolar disorder, although DSM-IV does not allow this. Alcohol abuse is the most common clinical comorbidity.

Ideally, successful treatment should treat both mania and depression, prevent recurrence, and improve quality of life between episodes.

Psychological Treatments

Enhancement of patient care may be facilitated by psychological interventions based on behavioral and cognitive psychology. In line with current practice in other areas of psychiatry, these psychological treatments should complement and inform treatment with medications rather than replace it. The components of psychological treatment include psychoeducation aimed at improving evaluation of the personal risk posed by the illness; self monitoring; self regulation, including action plans and modification of behaviour; and increased adherence to medicines. There is some evidence to suggest that use of these strategies may improve the outcome at least with respect to relapse of mania.^[9]

Lithium

Lithium has been used in bipolar affective disorder for 50 years^[10] and is one of the most extensively studied drugs in bipolar disorder. Lithium has proven efficacy in treating mania with a response rate of 60% to 80% in classic euphoric mania. The use of lithium in maintenance treatment of bipolar affective disorder is supported by randomized controlled trials (RCTs), naturalistic studies,^[11,12] and a Cochrane review.^[13] Lithium has established efficacy in the treatment of bipolar depression.^[14,15] Its use may be associated with reduced healthcare costs and mortality, including suicide.^[16,17] However, a substantial number of patients do not respond adequately to lithium, with relatively poor outcomes in mixed states and rapid cycling^[18-20] and in young males, those who are poorly compliant, those who have a history of head injury, those with severe mania, and those with comorbidity.^[21] Lithium has a significant side effect burden and a narrow therapeutic index. Abrupt withdrawal is associated with a high rate of relapse -- a phenomenon that may limit lithium's clinical usefulness.^[20]

Despite lithium's proven value as a treatment, there is a need for new treatments with increased efficacy, especially in refractory mania, mixed states, bipolar depression, and rapid cycling. Recent research has focused on drugs that may either be used as alternatives to or additional therapy with lithium.

Antipsychotics

Neuroleptics have been used as antimanics since the 1950s. Typical antipsychotics are effective antimanics, and this effect does not appear to be linked to sedation per se. A wide range of manic symptoms respond, including core symptoms such as elation. Controlled trials have compared the efficacy of lithium with antipsychotics (both typical and atypical) in acute mania, and these have yielded consistent results. Lithium exerts comparable but slower therapeutic effects but may be superior for affective symptoms than typical antipsychotics. Lithium does exert an effect against psychotic symptoms. The antipsychotics are superior to lithium for the treatment of patients with marked psychomotor agitation.^[22] In a trial comparing treatment of patients with mania and mixed states with 6 mg of risperidone, 10 mg of haloperidol, or 800-1200 mg of lithium, there were comparable improvements in all 3 groups.^[23] Antipsychotics are useful in combination with mood stabilizers and 2 small trials suggest an additive effect with lithium in schizoaffective or psychotic mania.^[24,25] Surveys of clinical practice indicate that antipsychotics are also used in the long-term treatment of bipolar disorder, despite a lack of evidence supporting this strategy.^[26,27] This is particularly important when one considers the possibility of inducing extrapyramidal side effects, neuroleptic malignant syndrome, and tardive dyskinesia. Additionally, long-term use of these drugs may reduce the risk of manic episodes at the cost of increasing the rate of depressive episodes.^[28]

Mania

The efficacy in mania of the atypical antipsychotics has been demonstrated in randomized placebo-controlled trials.^[29-31] The most robust data are for olanzapine, with 2 placebo-controlled trials involving a total of 254 patients. In the later olanzapine trial, a higher starting dose of 15 mg was used, and this was associated with a faster response. A significant improvement in Young-Mania Rating Score (Y-MRS) was reported after 1 week. When comparing the atypicals with mood stabilizers, no difference in efficacy between lithium and either olanzapine or risperidone monotherapy was noted in 2 small trials.^[23,32] The results of the acute phase of a trial by Tohen and colleagues^[33] comparing olanzapine with valproate in mania have been recently reported. After 3 weeks, the olanzapine-treated group had a greater remission and response rates and a greater mean fall in Y-MRS than the divalproex group. There are also open trials and case reports that support the use of olanzapine in mixed states.^[34,35]

The successful use of clozapine in treatment-refractory acute bipolar mania has been reported in some studies.^[36-38] There are case reports of patients with treatment-resistant manic symptoms responding to quetiapine,^[39,40] and there is an RCT of ziprasidone demonstrating efficacy in mania.^[41]

Bipolar Depression

Observational studies suggest some antidepressant potential for clozapine, risperidone, and olanzapine.^[28] In an RCT of 30 bipolar depressed patients, sulpiride was shown to be as effective as amitriptyline as augmentation to lithium.^[42]

Maintenance

Open trials suggest that clozapine monotherapy may provide effective mood stabilization in patients refractory to standard treatments. Maintenance data with most other atypicals is sparse, but open-label extensions of antimanic trials are promising, with effects possibly not confined to psychotic symptoms. There is little evidence suggestive of induction of depression, and there appears to be a low side effect profile.^[30]

Relapse Prevention

A recent Cochrane review has confirmed that lithium has efficacy in the prevention of relapse in bipolar disorder. However, the preventive action of lithium is greater for relapse into mania than depression.^[13] The efficacy of anticonvulsants (particularly preparations of sodium valproate) for relapse prevention in bipolar disorder has not been demonstrated.^[43] There has been a preliminary report of a randomized double-blind trial of olanzapine vs lithium in the prevention of relapse of bipolar disorder.^[44] In this large double-blind trial, patients were randomized from a combination of olanzapine and lithium to monotherapy with either drug for at least 1 year. Of note, the effects of lithium withdrawal were totally mitigated by monotherapy with olanzapine, suggesting that this should be a preferred treatment for patients who wish to be withdrawn from lithium. In terms of overall relapse, there was a highly significant improvement in terms of relapse into mania for the olanzapine group greater than the lithium group (28% manic relapse for lithium, 14% for olanzapine). There were no differences between these groups with respect to relapse into depression. This is a very important study that suggests that olanzapine has a role in the prevention of relapse and mania and potentially works just as well as lithium for the relapse of bipolar depression.

Antipsychotics and Mood Stabilizers

A number of studies have suggested that add-on of atypical antipsychotics to mood stabilizers may improve outcomes in bipolar disorder.^[45] A recent study has evaluated the efficacy of olanzapine in combination with valproate or lithium for the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy.^[46] This was a 6-week, double-blind, randomized, placebo-controlled trial that aimed to determine the efficacy of combined therapy of olanzapine with either valproate or lithium compared with monotherapy with either valproate or lithium alone in treating acute manic or mixed bipolar episodes. Patients with bipolar disorder (n = 344 manic or mixed) who had an inadequate response to more than 2 weeks of either lithium or valproate therapy were randomized to receive cotherapy (ie, olanzapine plus mood stabilizer or monotherapy, or placebo plus mood stabilizer). Olanzapine cotherapy improved patients' Y-MRS total scores significantly more than monotherapy, and the clinical response rates were significantly higher with cotherapy. Olanzapine cotherapy improved the 21-item Hamilton Depression (HAM-D) rating scores significantly more than monotherapy. In patients with mixed episodes with moderate to severe depressive symptoms, olanzapine cotherapy improved HAM-D 21 scores by 10.31 points compared with 1.57 for monotherapy. Extrapyramidal symptoms were not significantly changed from baseline in either treatment group. The authors concluded that compared with the use of valproate or lithium alone, the addition of olanzapine provides superior efficacy in the treatment of manic or mixed bipolar episodes.

Anticonvulsants

The use of anticonvulsants in bipolar disorder has led to the observation that processes, which appear to be similar to kindling phenomena, occur in the natural history of bipolar and unipolar affective disorders.^[47] Most anticonvulsant drugs with mood-stabilizing properties also inhibit the electrically induced kindling of seizure activity in animals. However, the mood stabilizing properties of anticonvulsants may not be mediated by the same mechanisms that mediate seizure control in epilepsy.

Sodium Valproate

Sodium valproate is the most frequently prescribed mood stabilizer in the United States and is increasingly used in Europe. It is no longer restricted to patients who have failed to respond to or are intolerant of lithium, but is increasingly being used as first-line monotherapy.

Trial evidence. The evidence mostly supports the role of sodium valproate in the treatment of acute mania, particularly with dysphoric or mixed presentations.^[48,49] Several controlled studies suggest that it has a more rapid onset than lithium and may be the better tolerated of the two.^[48] One small study comparing valproate with an antipsychotic showed similar efficacy in the reduction of affective or psychotic symptoms in the acute treatment of mania.^[50] The antimanic efficacy of valproate does not appear to be compromised by the presence of depressive features in patients with mixed states. Moreover, valproate may be effective in treating the depressive symptoms concurrently.^[49,51]

Sodium valproate's long-term efficacy in bipolar maintenance is supported by open studies.^[18] However, in a recent parallel group randomized controlled 12-month follow-up trial with placebo and lithium, no significant differences in efficacy were seen between any of the groups on the primary outcome measure of time to relapse to mania. An advantage of valproate was seen on some of the secondary measures, such as time in the study or the occurrence of depression.^[52] There are many open studies showing good response in rapid cycling disorder.^[53]

Clinical use. Valproate semi-sodium (in the United States, divalproex sodium) has been launched for the acute treatment of manic episodes associated with bipolar disorder. It is marketed as Depakote in the United Kingdom. It is a compound of sodium valproate and valproic acid in a ratio of 1 to 1. There is a widespread tendency to confuse these licensed compounds with preparations of sodium valproate used in epilepsy.

For valproate semi-sodium, a dose of 1000-3000 mg is usually associated with the best response. There is no clear relationship between plasma level and response,^[54] although therapeutic efficacy at plasma levels of less than 45 mg/L is doubtful. The optimum blood level appears to be 60-90 mg/L, with 100-120 mg/L in special circumstances. There is a greater side effect burden in doses above 125 mg/L.^[55] Side effects are gastrointestinal disturbance including nausea, weight gain, hepatic dysfunction, neurological problems including tremor and sedation, and hair loss. Accelerated oral loading at a dose of 30 mg/kg for the first 2 days followed by 20 mg/kg for the next 7 results in serum valproate levels attaining therapeutic levels more rapidly and as safely as standard dosage regimes.^[56]

Carbamazepine

The efficacy of carbamazepine in treating mania and bipolar depression and in prophylaxis has been shown in some studies, but evidence for its acute efficacy in bipolar depression and overall prophylactic efficacy is not strong.^[57] A 2-year randomized double-blind trial by Moleman and colleagues^[58] examined the efficacy in maintenance treatment and demonstrated a 40% risk of relapse per year, the overall relapse rate being nonsignificantly greater than that seen with lithium. Griel and colleagues^[59] also compared the relative efficacy of carbamazepine and lithium in maintenance of bipolar disorder. When using broad outcome criteria, they noted an overall superior efficacy of lithium. Open trials suggest a role for carbamazepine in rapid cycling and mixed states.^[60] There have been suggestions that it loses efficacy over time.^[61] It is, however, effective in the acute-phase treatment of mania, as shown by a placebo-controlled cross-over study.^[62] As noted above, comparator trials with lithium have revealed disparate results.^[22] Several small double-blind placebo-controlled studies suggest modest but statistically significant symptom reduction in bipolar depression.^[63] Additive effects have been reported with lithium.^[63-68] Side effects are common and include sedation, tremor, diplopia, weight gain, and rash. It induces liver enzymes and so enhances metabolism of other drugs, including the oral contraceptive pill and atypical antipsychotics.^[69]

Lamotrigine

Controlled trials have suggested some efficacy for lamotrigine in mania,^[70] some patients with rapid cycling disorder,^[71,72] and bipolar depression.^[73,74] In bipolar depression, Calabrese and colleagues^[73] demonstrated a dose-dependant significant improvement in response rate (50% improvement in HAM-D at week 7) compared with placebo in outpatients with bipolar depression treated with 50 or 200 mg per day of lamotrigine. Frye and colleagues^[74] compared lamotrigine monotherapy with gabapentin monotherapy and placebo in 31 patients with refractory unipolar or bipolar depression. They demonstrated significantly greater efficacy (50% improvement in Clinical Global Impression Scale) in the group receiving lamotrigine compared with both the placebo- and gabapentin-treated patients. Doses were titrated to a maximum of 500 mg of lamotrigine (mean dose, 274 mg) or 4800 mg of gabapentin (mean dose, 3987 mg). To examine the efficacy of lamotrigine in rapid cycling disorder, Calabrese and colleagues^[72] added lamotrigine to patients' existing medication and titrated to clinical effect. A total of 182 stabilized patients were tapered off other psychotropics and randomly assigned to lamotrigine or placebo monotherapy. Significantly more lamotrigine patients were stable without relapse after 6 months of monotherapy.

Lamotrigine is metabolized in the liver, and the most common adverse effects are headache, nausea, diplopia, dizziness, and ataxia. A skin rash occurs in 4% to 5% of patients early in treatment. Rashes are more common in the elderly; those on polypharmacy, particularly valproate, which inhibits the metabolism of lamotrigine; and where there has been a rapid escalation of dose. In most cases, the rash is mild and may subside spontaneously with or without drug withdrawal; but in some patients, there is an associated generalized illness with a few developing erythema multiforme, Stevens Johnson syndrome, or angioedema. Lamotrigine can be cautiously reintroduced safely in patients who have had a mild rash associated with its first introduction.^[75] However, there have been cases of fatality reported. It is therefore advisable to titrate the drug slowly and withdraw at the first signs of a rash. Lamotrigine does not induce p450 enzymes and has no significant pharmacokinetic effects on concentrations of commonly used psychotropic medication. However, carbamazepine reduces and valproate increases lamotrigine levels. Carbamazepine may also have a pharmacodynamic but not a pharmacokinetic interaction with lamotrigine, leading to neurotoxicity.^[76]

Gabapentin

Gabapentin has a high therapeutic index and a relatively benign side-effect profile. Side effects reported with gabapentin are transient and minor, the most common being somnolence, dizziness, ataxia, and fatigue.^[77] It is not associated with hepatic or haematologic problems. It has a wide dose range of 900-3000 mg/day. Gabapentin's use in rapid cycling bipolar disorder, mania, and bipolar depression was supported by open trials.^[78-80] However, disappointingly, these findings have not been replicated in RCTs, 2 of which have been negative.^[76,81]

Topiramate

Topiramate is a new antiepileptic drug that is used as adjunctive therapy for partial onset seizures. It enhances GABA activity and blocks glutamate at non N-methyl D-aspartate (NMDA) receptors. Preliminary open observations of adjunctive topiramate treatment suggest that it may have antimanic or anticycling effects in some patients with bipolar disorder, including those who are treatment resistant, and may be associated with appetite suppression and weight loss.^[82-87] There is one case report of topiramate monotherapy in maintenance treatment of bipolar disorder.^[88]

Tiagabine

Elevated brain levels of GABA have been reported in patients with euthymic bipolar disorder using nuclear magnetic spectroscopy compared with healthy controls.^[89] In theory, this may be reversed by the novel anticonvulsant tiagabine, which reduces the reuptake of GABA into neuronal and glial cells. Preliminary case reports have yielded conflicting results. The most promising report uses doses much lower than those typical for the treatment of seizures.^[90-92]

Electroconvulsive Therapy (ECT)

ECT is an effective treatment of bipolar disorder.^[93] A 50-year review suggests that 66% of manic patients respond to ECT^[94]; furthermore, there is a good response to ECT in manic patients who have failed to respond to an antipsychotic or lithium.^[95] Analysis of sequential therapeutic trials conducted over a 16-year period suggest that ECT followed by lithium maintenance is superior in efficacy to treatment with lithium or antipsychotics in hospitalized manic patients.^[96] Maintenance or continuation ECT has been shown to reduce the incidence of relapse in patients with previously refractory depressive episodes.^[97]

Transcranial Magnetic Stimulation (TMS)

There is preliminary evidence of therapeutic efficacy of TMS in bipolar disorder.^[98,99] However, there are also reports of hypomania induced by TMS.^[100,101]

Thyroid Hormones

The role of thyroid hormones in bipolar disorder continues to be of interest. Low levels of thyroxin (T₄) have been associated with more affective episodes during maintenance treatment with lithium.^[102] Whether this mood instability is causally related to low free T₄ levels and whether it can be attenuated with thyroxin replacement remains to be studied in a controlled setting. Open trials suggest efficacy for thyroxin as an augmenting agent in resistant bipolar depression and rapid cycling disorder.^[103-105]

Fatty Acids

A 4-month, double-blind, randomized, placebo-controlled trial of bipolar patients in remission has shown that augmentation with 9.6 g/day of omega 3 fatty acids prolongs the period of remission. The underlying mechanism may be the inhibition of signal transduction in neuronal membranes.^[106] This study has limitations of design, but nonetheless may represent a landmark in drug development.^[107]

Bipolar disorder is almost always recurrent.^[108] Thus, there is a need for prophylaxis, particularly in patients with recurrent episodes, severe illness, or where there is a strong family history.^[109] This need must be considered alongside the evidence of increased relapse and suicide rate after discontinuation of lithium.^[110,111] Lithium is the most frequently used initial mood stabilizer in Europe. In North America, it is now sodium valproate. Randomized, controlled trials to date have lacked sufficient power to demonstrate a difference in efficacy between these drugs. In selecting an initial mood stabilizer, the wealth of clinical experience with lithium and its possible antisuicide effect should not be overlooked. Sodium valproate should be considered, particularly for patients with poor prognostic factors for lithium such as those with mixed states or rapid cycling disorder. Recent evidence suggests olanzapine may have a role in maintenance.^[44] A combination of 2 or more mood stabilizers may be synergistic in cases of treatment resistance.^[64]

Rapid Cycling

Rapid cycling bipolar disorder is defined as at least 4 affective episodes a year and is observed in 13% to 20% of the bipolar population. It can occur sporadically at any point in the course of the illness. It is probably associated with a reduced response rate to lithium. Rapid cycling is more common in women and in those with bipolar II disorder. It may be precipitated and exacerbated by antidepressant use or minor dysfunction of the thyroid axis.^[112] The ideal long-term treatment is monotherapy with a mood stabilizer. However, because there is a high rate of lithium nonresponse,^[113] valproate is the initial mood stabilizer of choice. If monotherapy is inadequate and a rapid cycling patient develops mania, treatment options are to add a second mood stabilizer, preferably lithium or carbamazepine or an atypical antipsychotic, before combining 2 mood stabilizers with an atypical.

Bipolar Depression

The depressive phase of bipolar disorder can be very disabling. This phase is associated with the highest comorbidity, suicide risk, impairment of functioning, and reduction in quality of life.^[114,115] Active treatment is therefore appropriate. Some treatments may precipitate mania and increase cycle frequency.^[116] To facilitate appropriate treatment selection, it is very important to differentiate bipolar from unipolar depression. This is often a difficult task, and bipolar disorder may be unrecognized for many years.^[117] A family history of bipolar disorder, especially in younger patients, is an important distinguishing characteristic. The course of illness, especially early onset, and more frequent episodes also helps.^[97]

There are few data available on the treatment of bipolar depression. Young and colleagues^[118] examined combining mood stabilizers or adding an antidepressant to a mood stabilizer in a study of 27 patients and found no difference in efficacy between adding a mood stabilizer or an antidepressant. However, these authors found fewer drop outs in the antidepressant group. A recent study showed that the risk of an antidepressant precipitating mania is reduced by coadministration with a mood stabilizer.^[119] In cases of psychotic bipolar depression, a sensible initial strategy is to combine a mood stabilizer, an atypical antipsychotic, and an antidepressant. Antidepressant use without a mood stabilizer should not be undertaken lightly in bipolar disorder. Treatment strategy is influenced by factors such as patients' previous response to treatment, drug interactions, safety and tolerability profile, and lethality in overdose. Bupropion and paroxetine are recommended because of a possibly reduced risk of inducing hypomania, mania, and rapid cycling vs the tricyclics.^[120-123] Additionally, there is a role for venlafaxine for severe melancholic bipolar depression.^[109,124]

Mania and Hypomania

In treating mania, it is vital to make a clear assessment and diagnosis. Treatment setting is of great importance, with a clear need to assure safety and reduce overstimulation. The primary aim of treatment is to resolve symptoms as quickly and safely as possible. Antipsychotics are frequently used in acute and continuation treatment of (hypo)mania worldwide. The atypical antipsychotics are generally preferred over the typicals.^[109] Patients with pure uncomplicated mania respond well to all available agents. Specific poor response indicators for lithium include severe, psychotic mania with mixed or depressive features and a history of rapid cycling, numerous previous episodes, or a course in which mania follows depression.^[48,125] Treatment response should be reviewed after 3 days of valproate loading, 7-10 days of lithium, and 14 days of carbamazepine. There is little empirical evidence to support different treatment strategies for nonresponse in mania. The options include switching or combining mood stabilizers and antipsychotic drugs. If the patient is tolerating the initial drug, it would seem prudent to add rather than substitute new medication. Combinations may be synergistic and optimize results without pushing a single agent to toxic levels. Before combining medication, it is important to consider if the initial agent has been given at an adequate dose and for an adequate length of time and to consider potential pharmacokinetic interactions.^[65] There is evidence in treatment resistance to support the use of clozapine and ECT.

Mixed States

The overall incidence of mixed states in patients with bipolar disorder may be around 30% to 40%.^[126] Compared with pure states, patients in mixed states typically have higher levels of anxiety and arousal, an increased rate of psychosis and suicide,^[115] and a poorer outcome.^[127,128] It is important, though at times difficult, to distinguish mixed mania from agitated depression. Both states present with psychomotor signs of inner tension, but agitated depression does not have the goal-directed hyperactivity that is present in both pure and mixed mania.^[129] Mixed states are associated with a significant risk of substance abuse and suicide.^[130] Antidepressant therapy may worsen the inherent mood instability and, indeed, antidepressants can precipitate mixed states. Treatment should be aimed at reducing the severe increased arousal and the underlying affective dysregulation. Sodium valproate may be used; however, many clinicians prefer to use an atypical antipsychotic in order to gain rapid symptom relief.

Treatment strategies in bipolar disorder must involve consideration of the overall illness, not just the current episode. Psychological interventions should help the patient to learn about destabilizing factors and prodromes of relapse and to accept the nature of the illness. The aim of management should be recovery and responsible participation of the sufferer in treatment, not simply limited improvement and compliance. All the well-established drugs appear to be more effective in treating and preventing mania than depression. Lithium is reported to have specific antisuicidal effects, but few data are available on the antisuicidal effects of carbamazepine and valproate. Lithium has the drawback of high rates of relapse when it is stopped. The relative effects upon stoppage of other agents are unknown. Although valproate and carbamazepine may be more effective than lithium for mixed states and rapid cycling disorder, much treatment resistance remains. New medications for bipolar depression, mixed states, and rapid cycling disorder are urgently needed: new anticonvulsants and atypical antipsychotics are potential candidates that are currently being investigated. Of the atypical antipsychotics, a large number of clinical trials have been published on olanzapine. These have established olanzapine's antimanic effects and the benefits of addition of olanzapine to placebo, and recent reports suggest a preventive effect particularly for relapse into mania. For other atypicals, fewer data are available.

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