- 1 Mood Stabilizers
- 2 Anticonvulsants
- 3 Antipsychotics
- 4 Antidepressants
- 5 Related Posts
The main goal of bipolar disorder drug treatment is to establish euthymia (stable mood with a persistent sense of well-being) without inducing mania or rapid cycling (i.e., four or more mood episodes in a 12-month period). For this reason, drug treatment usually consists of an agent or, more frequently, combinations of agents that exert both antidepressant and antimanic effects. Recent studies estimate that up to 90% of bipolar patients older than 18 who are treated for Bipolar disorder are prescribed combination therapy to treat their disorder. The complexity of Bipolar disorder easily leads to the administration of combination therapies that often do not align with the recommended American Psychiatric Association guidelines. A retrospective study found that although 9% of patients diagnosed with Bipolar disorder may begin their treatment in accordance with American Psychiatric Association guidelines, the use of monotherapy declines over time and the use of four or more medications in combination increases. The study found that one-third of patients were treated with four or more medications, in combination, at some point during the year following diagnosis.
The mood stabilizer lithium (GlaxoSmithKline’s Eskalith/Liskonum/ Quilonum, Taisho’s Limas, Sanofi-Aventis’s Teralithe, generics) and the anticonvulsant valproic acid, prescribed either as monotherapy or adjunctively, are the most popular first-line therapies in most markets. Although some patients stabilize with lithium or valproic acid monotherapy, the majority of patients require combination therapy, primarily anticonvulsants, antipsychotics, and, in some cases, antidepressants.
This section summarizes the leading pharmacological therapies used to treat Bipolar disorder. It covers agents used both on- and off-label. Few agents are approved to treat Bipolar disorder: lithium (approved for manic episodes and maintenance therapy); lamotrigine (approved for maintenance therapy for Bipolar disorder I, long-term prophylactic treatment to delay relapse and recurrence of depressive episodes of patients previously treated for acute mood episodes with standard therapy); valproic acid (approved for acute mania associated with Bipolar disorder); olanzapine (approved for short-term treatment of acute mania associated with Bipolar disorder, mixed episodes associated with Bipolar disorder, maintenance treatment, for use in combination with lithium or valproate semisodium to treat acute manic episodes of Bipolar disorder I); quetiapine (approved for monotherapy or adjunctive therapy with lithium or divalproex for short-term treatment of acute manic episodes associated with Bipolar disorder I); risperidone (approved for manic symptoms associated with Bipolar disorder, monotherapy or combination therapy with lithium or valproate for short-term treatment of Bipolar disorder mania); and OFC (olanzapine/fluoxetine combination) (approved for depressive episodes associated with Bipolar disorder).
Table Current Therapies Used for Bipolar Disorder lists drugs that are used on- and off-label to treat acute mania and/or depression associated with Bipolar disorder, as well as drugs used as prophylaxis for the long-term management of Bipolar disorder in the major pharmaceutical markets (United States, France, Germany, Italy, Spain, United Kingdom, and Japan); Table Comparisons of Current Therapies for Bipolar Disorder compares monotherapies and combined therapies.
TABLE. Current Therapies Used for Bipolar Disorder
|Lithium||GlaxoSmithKline’s Eskalith/Liskonum/ Quilonum, Taisho’s Limas, Sanofi-Aventis’s Teralithe, generics||900-1,200 mg||United States, France, Germany, Italy, Spain, United Kingdom, Japan|
|Valproic acid||Abbott Laboratories’
|750-1,000 mg||United States, France, Germany, Italy, Spain, United Kingdom, Japan|
|Lamotrigine||GlaxoSmithKline’s Lamictal||50-400 mg||United States, France, Germany,Italy, Spain, United Kingdom|
|600-1,000 mg||United States, France, Germany, Italy, Spain, United Kingdom, Japan|
|Oxcarbazepine||Novartis’s Trileptal||600-2,400 mg||United States, France, Germany,Italy, Spain, United Kingdom|
|Topiramate||Ortho-McNeil’s Topamax, Janssen’s Epitomax||25-600 mg||United States, France, Germany, Italy, Spain, United Kingdom|
|Gabapentin||Pfizer’s Neurontin||900-3,000 mg||United States, France, Germany, Italy,Spain, United Kingdom|
|10-20 mg||United States, France, Germany, Italy,Spain, United Kingdom, Japan|
|Olanzapine intramuscular||Eli Lilly’s Zyprexa||10 mg||United States, France, United Kingdom|
|Risperidone||Janssen’s Risperdal/Risperdal M-Tab/Risperdal Quicklet||1-6mg||United States, France, Germany, Italy, Spain, United Kingdom, Japan|
|Risperidone depot||Janssen’s Risperdal Consta||25 mg, every 14 days||United States, Germany, Italy,Spain, United Kingdom|
|Quetiapine||AstraZeneca’s Seroquel||400-800 mg||United States, Germany, Italy,Spain, United Kingdom, Japan|
|Aripiprazole||Bristol-Myers Squibb/Otsuka Pharmaceutical’s Ability||10-15 mg||United States|
|Ziprasidone||Pfizer’s Geodon/Zeldox||80-160 mg||United States, Germany, Spain|
|20 mg||United States, Germany, Spain|
|Haloperidol||McNeil’s Haldol, Dainippon’s Serenance, generics||5mg||United States, France, Germany, Italy,Spain, United Kingdom, Japan|
|Haloperidol intramuscular||McNeil’s Haldol, Dainippon’s Serenance, generics||10mg||United States, France, Germany, Italy, United Kingdom, Japan|
|Haloperidol depot||McNeil’s Haldol Decanoate, generics||50-100 mg, monthly||United States, France, Germany, Italy,Spain, United Kingdom, Japan|
|Olanzapine-fluoxetine combination||Eli Lilly’s Symbyax||6-12/25-50 mg||United States|
|300 mg||United States(1)|
|150mg||United States, France, Germany, Italy,Spain, United Kingdom|
Dalcipran/lxel, Asahi Kasei’s Toledomin
|Paroxetine||GlaxoSmith Kline’s Paxil/Paxil||20-40 mg||UnitedStates, France, Germany, Italy, Spain, United Kingdom, Japan|
|CR/Seroxat, Novartis’ Frosinor, generics|
|Fluoxetine||Eli Lilly’s Prozac/Prozac Weekly, generics||20 mg||United States, France, Germany, Italy,Spain, United Kingdom|
|Sertraline||Pfizer’s Zoloft/Lustral/Besitran||100mg||United States, France, Germany, Italy,Spain, United Kingdom|
|Citalopram||Forest Laboratories’ Celexa, Lundbeck’s Cipramil/Seropram||20 mg||United States, France, Germany, Italy,Spain, United Kingdom|
|Escitalopram||Forest’s Lexapro, Lundbeck’s Cipralex||10mg||United States, France, Germany, Italy,Spain, United Kingdom|
|Mirtazapine||Organon’s Remeron/Remergil/Nc irset/Rexer/Zispin||30mg||United States, France, Germany, Italy,Spain, United Kingdom|
|Trazodone||Sanofi-Aventis’s Molipaxin, Bristol-Myers Squibb’s Desyrel, generics||200 mg||United States, Germany, Italy, Spain, United Kingdom, Japan|
|3mg||United States, France, Germany, Italy,Spain, United Kingdom, Japan|
|Alprazolam||Pfizer’s Xanax/Xanax XR, generics||1.5mg||United States, France, Germany, Italy,Spain, United Kingdom, Japan|
|6mg||United States, France, Germany, Italy, Spain,United Kingdom, Japan|
Bupropion has been launched in the United Kingdom, France, Germany, Italy, and Spain for smoking cessation only.
qd = Once daily;
bid = Twice daily;
tid = Three times daily.
Table Common Trial End Points for Bipolar Disorder Studies lists the end points, and their abbreviations, used in Bipolar disorder clinical trials to measure drug efficacy.
Although the FDA does not officially recognize the term mood stabilizer, the term is widely recognized and used to describe the class of drugs that specifically treat Bipolar disorder. In this section, a mood stabilizer is defined as a drug that treats both the manic and depressive phases of Bipolar disorder and prevents onset of these phases. The only agent that meets this strict definition is lithium (GlaxoSmithKline’s Eskalith, Solvay’s Lithobid/Liskonum/Quilonum, Taisho’s Limas, generics). The anticonvulsants and antipsychotics discussed here fit a broader definition of mood stabilizers: a class of drugs that can treat either the manic or the depressive episodes of Bipolar disorder without exacerbating the frequency or severity of episodes. These agents include valproic acid (Abbott Laboratories’ Depakote/Depakene, Sanofi-Aventis’s Epilim/Ergenyl, Kyowa Hakko’s Depakene, generics), lamotrigine (GlaxoSmithKline’s Lamictal), carbamazepine (Novartis’s Tegretol and Tegretol XR, Shire Pharmaceuticals’ Bipotrol/Carbatrol, generics), and olanzapine (Eli Lilly’s Zyprexa).
Mechanism Of Action
Studies have found similarities between lithium and anticonvulsants with mood-stabilizing properties; both modify voltage-sensitive sodium and calcium channels. The regulation of these ion channels may stabilize neurotransmitter levels of dopamine, serotonin, norepinephrine, and gamma-aminobutyric acid-aminobutyric acid, providing a partial answer why some anticonvulsant agents seem effective for the treatment of Bipolar disorder.
TABLE . Comparisons of Current Therapies for Bipolar Disorder
|Lithium||Effective for acute and prophylactic treatment of Bipolar disorder I.
Protective against depression ( [n = 317]).
|Not effective for more-complicated Bipolar disorder II cases.
Black box warning: Lithium toxicity (can occur at doses close to therapeutic levels). Dosing requires careful monitoring due to risk of toxicity.
|Reduction of excessive mortality associated with Bipolar disorder.||Weight gain similar to valproic acid; [open-label, chart review, n = 214].||Combination therapy with selective serotonin reuptake inhibitors may induce dizziness, confusion, tremor, and diarrhea.|
|Valproic acid||Effective for acute and prophylactic treatment of Bipolar disorder I and II.||Minimal efficacy in depression.
Black box warning: hepatic failure resulting in fatalities. Can produce teratogenic effects and therefore contraindicated in women of childbearing age. Also, life-threatening pancreatitis. Weight gain similar to lithium ([open-label, chart review, n = 214]).
|Olanzapine||Effective for prophylactic treatment of Bipolar disorder I and II and for short-term treatment of acute mixed or manic episodes.(a)||More weight gain than with lithium or valproic acid.|
|Adjunctive therapy in patients who exhibit a poor response to lithium, valproic acid, or carbamazepine monotherapy ( [open-label, n = 23]). Protective against depression ( [randomized, controlled, double-blind, n = 833]).||Label warning of severe hyperglycemia and diabetes.|
|Lamotrigine||Effective prophylactic treatment of Bipolar disorder I.
Protective against depression ( [open-label, continuation, n = 124]). Most beneficial in patients with Bipolar disorder II disorder ([n = 75];2000 [double-blind, placebo-controlled, n = 182]). Does not cause weight gain.
Monitoring of serum levels not required.
|Black box warning: serious rashes requiring hospitalization and discontinuation of treatment. Required titration regimen to prevent treatment-associated rash makes the drug less beneficial as an acute treatment. Less effective than lithium in preventing mania.|
|Carbamazepine||Alternative when patients cannot tolerate daily side effects associated with lithium and valproic acid.||Contraindicated in women of childbearing age.
Black box warning: aplastic anemia and agranulocytosis.
|Oxcarbazepine||Effective as an acute, adjunctive antimanic or antidepressive Bipolar disorder I treatment ( [open-label, prospective, n = 30]).||In controlled clinical trials, hyponatremia occurred in 2.5% of patients treated.|
|Effective in refractory manic patients who have not responded to lithium monotherapy, are not good candidates for valproic acid because of side effects, and have not tolerated or responded well to adjunctive carbamazepine.
Does not cause weight gain (Deutschman DA, 2003 [restrospective, n = 249]).
|Lithium + valproic acid||Effective in lithium-refractory patients with manic, mixed,(a) and rapid-cycling features] [double-blind, controlled, n = 24]).||More likely to cause moderate or severe side effects (such as Gl distress, tremor, cognitive impairment, and alopecia) than lithium alone ( [single-blind, n = 12]).
Combination causes severe weight gain more significant than either monotherapy.
|Valproic acid + olanzapine||Effective for mixed episodes.)||Combination causes severe weight gain more significant than either monotherapy|
|Lithium + olanzapine||Effective for severe mania or mixed episodes.)||Side effects (weight gain, sedation) may be additive .|
|Lithium + carbamazepine||Effective in rapid-cycling patients (Di Costanzo E, 1991 [retrospective, n = 16]).
More effective as prophylactic therapy than either agent alone ( [retrospective, n = 18]; [double-blind, controlled, n = 52]).
|Use of carbamazepine is contraindicated in women of childbearing age.
Black box warning (carbamazepine): aplastic anemia and agranulocytosis.
|Lithium + lamotrigine||Effective in patients refractory to lithium monotherapy who show prominent depressive symptoms and or rapid cycling.||Black box warning (lamotrigine): serious rashes requiring hospitalization and discontinuation of treatment.|
|Patient current maintenance therapy + olanzapine or risperidone + clonazepam||Effective for breakthrough manic or mixed episodes.f)||Risks associated with polypharmacy.|
|Lithium + topiramate||Prevents weight gain because of weight loss associated with topiramate treatment [n = 20]; [open-label, n = 1 09]; [retrospective, n = 76]); [open-label, chart review, n = 214]).||Topiramate can cause ataxia, impaired concentration, dizziness, paresthesias, and somnolence during the titration phase.|
Other similarities have been found between lithium and anticonvulsants; studies have suggested that lithium, carbamazepine, and valproic acid have similar effects on the sensory neuron growth cones by inhibiting the collapse of these cones and increasing growth of the cone area. Inositol, an isomer of glucose and a natural constituent of the normal human diet, however, reverses the effects of these drugs on sensory neuron growth cones, thus implicating inositol depletion in the three drugs’ action. The effect of lithium, carbamazepine, and valproic acid on sensory neuron growth cones is relevant because it suggests that inositol depletion is how all three drugs work in Bipolar disorder. Other scientists have suggested that glycogen synthase kinase may be the relevant target. Valproic acid has also been linked to inositol depletion .
The mood-stabilizing drug lithium (GlaxoSmithKline’s Eskalith/Liskonum/Quilonum, Taisho’s Limas, Sanofi-Aventis’s Teralithe, generics) has been used to treat acute bipolar mania and for maintenance treatment for more than 30 years. The agent is approved for the treatment of manic episodes and maintenance therapy for Bipolar disorder in all of the major markets.
Lithium’s precise mechanism of action in the treatment of Bipolar disorder is unknown. Investigators have suggested its therapeutic effects stem from its effect on the depolarization-provoked and calcium-dependent release of dopamine and norepinephrine from nerve terminals in the central nervous system; neuronal second-messenger signaling pathways; central nervous system cytoprotective proteins; and the distribution of sodium, calcium, and magnesium across the neuronal membranes.
TABLE . Common Trial End Points for Bipolar Disorder Studies
|Affective Disorders Rating Scale||ADRS||A 34-item scale assessing brief and observable behaviors related to affective experiences|
|Brief Psychiatric Rating Scale||BPRS||An 18-item scale assessing positive symptoms, general psychopathology, and affective symptoms|
|Clinical Global Impression Scale||CGIS||A three-item scale assessing treatment response in psychiatric patients|
|Clinical Global||CGI-BP||A scale, which is a modification of the CGIS, assessing global illness severity and change in patients with bipolar disorder|
|Impressions Bipolar Version-Severity of Depression Scale|
|Global Assessment Scale||GAS||A 1 -item scale assessing a patient’s psychopathology and social function on a scale of 0-100|
|Depressive Syndrome Scale||DSS||A scale derived from the Schedule for Affective Disorders and Schizophrenia|
|Hamilton Rating Scale for Anxiety||HAM-A||A 14-item scale assessing treatment response in patients receiving therapy for anxiety disorders|
|Hamilton Rating Scale for Depression||HAM-D||A 17-, 21 -, or 24-item scale assessing treatment response in patients receiving therapy for depressive disorders|
|Mania Rating Scale||MRS||11 -item scale assessing the degree of a patient’s manic symptoms|
|Montgomery-Asberg||MADRS||10-item scale evaluating the efficacy of antidepressant treatment|
|Depression Rating Scale Schedule for Affective||SADS||Semi-structured interview assessing current and lifetime incidences of affective disorders and schizophrenia|
|Disorders and Schizophrenia Young Mania Rating Scale||YMRS||An 11 -item scale assessing the severity of mania in Bipolar disorder patients|
TABLE . Therapies Used for Treatment-Resistant Bipolar Disorder
|Therapy||Brand Names||Mechanism of Action|
|Acetazolamide||Wyeth’s Diamox||Carbonic anhydrase inhibitor|
|Clonidine||Boehringer Ingelheim’s Catapress||Adrenergic blocker|
|Donepezil||Pfizer’s Aricept||Cholinesterase inhibitor|
|Memantine||Forest’s Namenda||NMDA receptor antagonist|
|Mexiletine||Boehringer Ingelheim’s Mexiletine||Antiarrhythmic|
|Nimodipine||Bayer’s Nimotop, generics||Calcium-channel antagonist|
|Pindolol||Novartis’s Visken, generics||Beta-blocker|
|Propranolol||Wyeth’s Inderol||Adrenergic blocker|
|Riluzole||Sanofi-Aventis’s Rilutek||Glutamate release inhibitor|
|Omega 3 fatty acids||Over-the-counter supplements||–|
|Verapamil||Abbott’s Isop-tine/lsoptin/Manidon/ Securon, Eisai’s Vasolan, generics||Calcium-channel antagonist|
|Vagus nerve stimulation (Cyberonics’ VNS Therapy)|
|Repetitire transcranial magnetic stimulation|
Lithium has shown evidence of its antimanic effect in Bipolar disorder patients with classic (euphoric) mania, whereas the drug has had less of an effect in patients with mixed mania (i.e., patients experiencing both mania and depressive symptoms). The results of studies evaluating the effectiveness of lithium in the maintenance treatment of Bipolar disorder have shown lithium to beneficially alter the course of Bipolar disorder; however, patients with very short episodes of high frequency may be less likely to benefit significantly from lithium and instead benefit from the addition of another drug to treat their Bipolar disorder.
Lithium showed evidence of efficacy in the treatment of classic mania in a study comparing lithium, divalproex (Abbott Laboratories’ Depakote, the most often used form of valproic acid), and placebo in a randomized, double-blind, parallel-group study. The study involved hospitalized patients (n = 179) meeting the research diagnostic criteria for manic disorder based on the structured interview and scores on the Mania Rating Scale (MRS) (derived from the Schedule for Affective Disorders and Schizophrenia [SADS]). The primary end point of the study was at least a 50% improvement from baseline in scores on the MRS; secondary measurements were made using the Global Assessment Scale (GAS), individual items of the MRS, and factors on the Affective Disorders Rating Scale (ADRS). At the conclusion of the three-week study, both lithium and divalproex were significantly more effective than placebo in reducing the symptoms of acute mania; however, the superiority of lithium was limited to patients with classic (euphoric) mania, whereas in patients with mixed mania, the difference between lithium and placebo was not significant. Divalproex, however, was superior to placebo in patients with both classic and mixed mania. Moreover, the difference between lithium and placebo was not significant in patients with a history of more than 11 manic episodes or 4 depressive episodes, whereas the superiority of divalproex over placebo remained significant in such patients. Lithium-treated patients had a greater proportion of terminations than did patients in the placebo group, and vomiting was more common in the lithium-treated patients than in the other two groups.
In the only placebo-controlled trial of prophylactic treatment for Bipolar disorder using lithium carried out in the last 25 years, lithium and divalproex were compared with placebo in a randomized trial with Bipolar disorder I patients (n = 372) who had recovered within three months of the onset of a manic episode. The primary end point was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, and average change from baseline in the MRS, DSS, and GAS. At the conclusion of the 52-week trial, the two treatments did not differ significantly on the primary measure of efficacy (time to recurrence of any mood episode during maintenance therapy); however, patients treated with divalproex had better outcomes than did those treated with placebo or lithium on several secondary outcomes, including the rates of recurrence of severe affective episodes. Divalproex was more effective than lithium in controlling depressive symptoms.
Lithium will continue to be the mainstay of treatment for Bipolar disorder (particularly the classical course of Bipolar disorder I) because of its efficacy in the treatment of the acute manic phase of Bipolar disorder and as prophylaxis against recurrent manic and depressive episodes. However, patients with more complicated cases of Bipolar disorder, such as mixed states and rapid cycling or substance abuse comorbidity, often benefit less from lithium therapy, and these patients therefore require adjunctive treatment or monotherapy with a different agent.
In addition to lithium’s limited effectiveness in complicated cases of Bipolar disorder, its severe side-effect profile often causes patients to discontinue treatment early in the therapy phase. Weight gain is a significant side effect associated with lithium use. Also, patients who respond well to lithium risk side effects such as tremor, excessive thirst, and polyuria (excessive urination).
The risks of long-term treatment with lithium include hypothyroidism (5-15% of patients) and renal impairment (10-20% of patients). To compound these problems, combining lithium with other drugs — an approach that is often necessary to increase efficacy in patients with refractory disease — may provoke untoward effects. For example, combining lithium with selective serotonin reuptake inhibitors (Selective serotonin reuptake inhibitors) may induce dizziness, confusion, tremor, and diarrhea, making this treatment option impossible for some patients. Finally, the dosing of lithium requires careful monitoring. Lithium has a narrow therapeutic index; doses that are large enough to be therapeutic may approach toxic levels, so patients and clinicians must be watchful for adverse effects that signal toxicity (early signs include diarrhea, vomiting, drowsiness, muscular weakness, and tremor).
Anticonvulsants figure prominently in the treatment of Bipolar disorder. Physicians rely primarily on the so-called first-generation drugs — most notably, valproic acid and carbamazepine. However, several of the newer, second-generation anticonvulsants — including lamotrigine, oxcarbazepine, topiramate, and gabapentin — are used to treat Bipolar disorder, usually as adjunctive therapy for patients who have failed treatment with lithium, valproic acid, or carbamazepine. Use of these agents will expand as they fill important niches in the therapeutic arsenal for Bipolar disorder. Although the anticonvulsant zonisamide (Elan’s Zonegran) is in Phase II development for the treatment of mania and the anticonvulsant levetiracetam (UCB’s Keppra) has shown in studies that it may be effective in the treatment of Bipolar disorder mania, use of these agents off-label in Bipolar disorder is minimal and therefore not covered in detail here.
Mechanism Of Action
First- and second-generation anticonvulsants exert their effects via one of several principal mechanisms. Two of these mechanisms occur most commonly: inhibition of repetitive, high-frequency neuronal firing via blockade of voltage-dependent Na+ channels and potentiation of postsynaptic inhibition mediated by neurotransmitters such as gamma-aminobutyric acid. Researchers believe that several anticonvulsants function via similar mechanisms, even though they show remarkably different patterns of efficacy across individual patients. Such inconsistencies between scientific theory and clinical practice suggest these agents may act at one or more unknown targets in the central nervous system.
Often referred to as a mood-stabilizing agent, valproic acid (Abbott Laboratories’ Depakote/Depakene, Sanofi-Aventis’s Epilim/Ergenyl, Kyowa Hakko’s Depakene, generics) has become a leading alternative and adjunctive treatment to lithium for both the short- and long-term treatment of Bipolar disorder, although the drug is currently approved for short-term treatment only. A number of valproic acid formulations are in use, all of which circulate in vivo as the valproate ion. Depakene is a liquid formulation of valproic acid alone, whereas Depakote (divalproex sodium or valproate semisodium, the most popular formulation of valproic acid) is a coordination compound comprising equimolar amounts of valproic acid and sodium valproate. Divalproex sodium dissociates into valproic acid in the gastrointestinal tract, and absorption occurs one hour later than it does for traditional valproic acid capsules. This delay allows for uniform and reliable absorption with no significant changes in bioavailability, affording maintenance of steadier blood plasma levels. Abbott also markets an intravenous formulation, valproate sodium (Depacon), for use in patients in whom oral administration is temporarily unfeasible. In this section, the term valproic acid encompasses all formulations.
The most often prescribed formulation of valproic acid, valproate semisodium (Abbott’s Depakote/Depakene), was approved in 2000 in the United States for the treatment of acute mania in Bipolar disorder, and in 2001 the drug was approved in the United Kingdom for the same indication and marketed by Sanofi-Synthelabo. Valproate semisodium is also labeled for the treatment of seizures and migraine prophylaxis.
Like lithium, valproic acid appears to directly modulate Germany-proteins and to slow the generation of second-messenger molecules. More generally, the mechanisms of action of valproic acid, lithium, and the anticonvulsant carbamazepine could dampen the excessive intracellular and intercellular signaling that is suspected to be a basic feature of the pathophysiology of Bipolar disorder.
Valproic acid has been shown to be safe and effective in short-term (three-week) clinical trials as a treatment for acute mania. It has proven effectiveness in maintenance treatment studies evaluating valproic acid and lithium treatment (see the previous subsection on lithium for a description of maintenance trial results).
Two randomized, double-blind, placebo-controlled, three-week trials involving inpatients (n = 36; n = 179) diagnosed with DSM-III-R criteria for Bipolar disorder and hospitalized for acute mania evaluated the efficacy of valproic acid in the treatment of acute mania. The smaller study compared lithium with placebo, and the larger study included lithium as an active comparator. Both studies indicated onset of improvement within the first week of treatment.
In the study with the lithium comparator, the primary measures of efficacy were change from baseline on the MRS. At the end of the study, valproic acid was more effective than lithium among patients with mixed mania. Valproic acid was also more efficacious in patients who had more than eight episodes of illness or more than two depressive episodes in a lifetime.
Common side effects of valproic acid include sedation, tremor, diarrhea, alopecia, and weight gain. Rare but potentially more serious side effects include pancreatitis, hepatotoxicity, leukopenia, and thrombocytopenia. The drug is also contraindicated in women of childbearing age owing to its teratogenic side effects. Women taking valproic acid are also at increased risk for developing polycystic ovarian syndrome.
Valproic acid has some advantages over lithium in the treatment of mania for persons with more severe illness and appears to benefit a broader spectrum of bipolar conditions than does lithium. Moreover, valproic acid in combination with lithium may have benefits over either of the two agents used as monotherapy.
A large-scale international trial called the Bipolar Affective Disorder: Lithium Anticonvulsant Evaluation (BALANCE) study is in progress. The open, randomized trial is comparing valproic acid monotherapy, lithium monotherapy, and combination therapy with valproic acid plus lithium. Recruitment for the trial started in 2001, and more than 1,000 participants are expected. Investigators anticipate the trial will be completed in five years.
In June 2003, the FDA approved lamotrigine (GlaxoSmithKline’ s Lamictal) for the long-term maintenance treatment of adults with Bipolar disorder I. The drug is also approved in the United Kingdom for the treatment of Bipolar disorder. Lamotrigine is approved as well in the United States and Europe for the treatment of epilepsy and is preregistered in Japan for that indication. The compound is undergoing Phase III development as an acute treatment for Bipolar disorder in the United States and the United Kingdom, and a regulatory submission is planned for 2006. Lamotrigine is an antiepileptic drug in the phenyltriazine class. The precise mechanisms by which lamotrigine affects mood are unclear, but researchers assume that the drug’s mood-stabilizing effect results from its inhibition of neuronal hyperactivity in the brain. Acting primarily at sodium channels, lamotrigine stabilizes neuronal membranes and inhibits the release of glutamate — an effect that likely regulates aberrant signaling in neurotransmitter systems involved in the pathophysiology of Bipolar disorder. Some researchers suspect the drug’s antidepressant features may be a result of its interaction with the serotonergic system.
The results of the first large, randomized, double-blind, placebo-controlled study (n = 195) of lamotrigine in Bipolar disorder confirmed the drug’s efficacy in the short-term management of bipolar depression. The trial evaluated lamotrigine monotherapy (50 mg or 200 mg daily for seven weeks) versus placebo. The primary measurement of efficacy was the CGIS. At the end of the seven-week trial, patients in the 200 mg group benefited most from the treatment — 51% improvement versus 41% among patients treated with 50 mg daily and 26% among those treated with placebo. Both treated groups also showed significant improvements on the Hamilton Rating Scale for Depression (HAM-D) scale compared with placebo. Lamotrigine treatment was generally well tolerated.
Lamotrigine has been shown to be effective in the prevention of relapse or recurrence of mood episodes, particularly for prophylaxis of depression, in a study of patients with Bipolar disorder I. After an 8- to 16-week open-label study during which treatment with lamotrigine was initiated and other psychotropic medications discontinued, Bipolar disorder I patients (n = 175) who had recently experienced a manic or hypomanic episode were randomized to 100-400 mg per day of lamotrigine, 0.8-1.1 mEq/L of lithium, or placebo as double-blind maintenance treatment for 18 months. The primary measure of efficacy was the time to intervention (addition of pharmacotherapy or electroconvulsive therapy) for any mood episode. Secondary efficacy measures included time to early discontinuation for any reason; time to intervention for a manic, hypo-manic, or mixed episode; time to intervention for a depressive episode; and mean change from baseline in scores on the MRS, HAM-D, CGIS, and GAS during double-blind treatment. At the end of the study, both lamotrigine and lithium were superior to placebo in prolonging the time to intervention for any mood episode; lithium was superior to placebo in prolonging the time to a manic, hypomanic, or mixed episode; and lamotrigine was superior to placebo in prolonging time to a depressive episode.
Evidence of lamotrigine’s efficacy, as adjunctive therapy or monotherapy, in preventing the onset of bipolar depression was further evaluated in a 52-week, open-label continuation study (n = 124) of flexible doses of 100-500 mg per day of lamotrigine. The primary measures of efficacy were the Montgomery-Asberg Depression Rating Scale (MADRS) and the CGIS. The proportion of patients achieving remission by week 4 of the study was 81.4%, and episodes of mania/hypomania in these patients occurred less frequently than in the previous year. Headache was the most common drug-related adverse event. No cases of serious skin reactions were reported, although the most common adverse event leading to study withdrawal was minor rash.
Lamotrigine is generally well tolerated; adverse events (dizziness, headache, nausea) are usually mild and resolve without drug discontinuation. One potentially persistent side effect of lamotrigine treatment is minor skin reaction and, in very rare but more serious cases, toxic epidermal necrolysis. The likelihood of skin rash can be minimized by slowly titrating the dose over a period of several weeks. In clinical trials of the drug in Bipolar disorder, the incidence of skin reactions is similar among lamotrigine- and placebo-treated patients. According to the drug’s label, severe rash occurs in 1 of every 1,000 patients treated with lamotrigine; less severe rash may occur more frequently.
Lamotrigine is a popular choice in the treatment of lithium-refractory patients. One disadvantage with this agent is the need for extended titration, a requirement that limits its use in acute settings. Its future commercial success will ultimately be limited by its titration schedule, its potential to interact with other medications, lingering concerns over its dermatological side effects, and its impending patent expiry.
Carbamazepine (Novartis’s Tegretol/Tegretol XR, Shire Pharmaceuticals’ Carbatrol, generics) is approved for epilepsy and the symptomatic relief of pain of trigeminal neuralgia. Oxcarbamazepine (Novartis’s Trileptal), a carbamazepine analogue launched after carbamazepine, mimics carbamazepine’s effects as a sodium-channel blocker while exhibiting greater tolerability. This section covers only carbamazepine in detail.
Carbamazepine blocks voltage-sensitive sodium channels and may act on potassium channels to increase potassium conductance. It also affects a number of neurotransmitter systems implicated in the pathophysiology of mood disorders. Specifically, carbamazepine alters neurotransmission mediated by adenosine, dopamine, norepinephrine, serotonin, acetylcholine, gamma-aminobutyric acid, glutamate, substance P, and aspartate.
Studies have shown carbamazepine to be an effective maintenance treatment in Bipolar disorder; however, carbamazepine therapy in combination with lithium may have greater efficacy than carbamazepine alone. Five randomized, controlled trials of carbamazepine maintenance therapy in Bipolar disorder have been conducted. Four of the studies were comparisons with lithium, and one was a comparison with placebo. Three of the lithium comparison studies found no difference in efficacy between carbamazepine and lithium, and one study found lithium to be superior to carbamazepine on the primary outcome measurement, which was time in remission from randomization.
The use of carbamazepine in combination regimens is complicated by the drug’s potential to reduce plasma levels of other medications (e.g., lithium, antipsychotics). Also, side effects are a serious concern with carbamazepine. Overall central nervous system depression, ataxia, vertigo, diplopia (double vision), gastrointestinal upset, and skin rashes are all commonly associated with the drug’s use. On rare occasions, the drug has been associated with serious hematologic side effects such as aplastic anemia, agranulocytosis, and leukopenia. These severe blood disorders have been reported in carbamazepine-treated patients at an incidence five to eight times greater than in the general population. Thus carbamazepine use always requires regular blood monitoring.
Carbamazepine’s short half-life relative to that of other antimanic agents is its greatest drawback. This problem was addressed in the United States and Europe with the arrival of Novartis’ s Tegretol XR, an extended-release formulation that allows for twice-daily dosing. Also in the United States, Shire markets Carbatrol, a similar carbamazepine product that enables twice-daily dosing.
Topiramate (Ortho-McNeil’s Topamax, Janssen’s Epitomax) is used off-label for Bipolar disorder in patients who are refractory to or unable to tolerate the side effects of standard regimens, especially weight gain. Topiramate had been in Phase III trials as monotherapy for Bipolar disorder in the United States, but development was discontinued owing to lack of efficacy. According to a Johnson & Johnson press release, the drug failed to show statistically significant effectiveness compared with placebo. Adjunctive trials have produced more encouraging results, so the company intends to continue to develop topiramate as an adjunctive therapy for mania in Bipolar disorder. The drug is available for the treatment of epilepsy in the United States and Europe and has been licensed to Kyowa Hakko in Japan for development in Phase III trials for epilepsy. Topiramate is approved in the United States for the prevention of migraine in adults and is undergoing clinical trials for the treatment of post-traumatic stress disorder.
Topiramate is a structurally unique anticonvulsant whose mechanism of action remains unclear; however, researchers believe that its mood-stabilizing effects derive from several distinct mechanisms of action. The agent has activity at some types of voltage-activated sodium and calcium channels, gamma-aminobutyric acid receptors, and weak antagonism at kainate receptors, a subclass of glutamate receptors.
Although trials evaluating topiramate’s efficacy as a monotherapy for the treatment of Bipolar disorder have been unsuccessful, the drug has successfully been used as an adjunctive therapy to mood-stabilizing agents such as lithium and valproic acid and lithium and valproic acid combined in patients with Bipolar disorder I and II. Moreover, in clinical trials, patients receiving topiramate have experienced a mean weight loss. The mean reduction in weight reported in trials of Bipolar disorder is 10-30 pounds, with the most dramatic weight loss observed in the most obese patients.
Topiramate may be as effective as bupropion for the treatment of Bipolar disorder depression when used together with another drug to treat Bipolar disorder according to a recent study. The efficacy of topiramate (50-300 mg/day) versus bupropion (100-400 mg/day) for the treatment of Bipolar disorder depression, when added to a drug with mood-stabilizing qualities, was evaluated in a single-blind trial with patients (n = 36) meeting DSM-IV criteria for Bipolar disorder depression. The primary measure of efficacy was a 50% or greater reduction from baseline in mean HAM-D scores. At the end of the eight-week trial, 56% of patients taking topiramate and 59% of patients taking bupropion responded to treatment; however, differences between bupropion and topiramate treatment were not significant. Weight loss was the most significant side effect experienced by patients in this trial.
Topiramate’s side effects are typical of most second-generation anticonvulsants; they include ataxia, impaired concentration, dizziness, paresthesia, and somnolence. These effects occur most frequently during the titration phase of administration and eventually resolve in the majority of patients. Physicians sometimes use a slower titration phase and lower maximum doses to minimize side effects. A small percentage of patients (approximately 1.5%) have developed kidney stones in association with topiramate therapy.
The anticonvulsant gabapentin (Pfizer’s Neurontin) was launched in the United States in 1993 for the treatment of epilepsy. It is approved for epilepsy in Europe as well and is licensed to Fujisawa in Japan, where it is in Phase III trials for epilepsy.
Gabapentin’s precise mechanism of action — as an antiseizure and analgesic — is unknown. The drug is structurally related to the amino acid neurotransmitter gamma-aminobutyric acid and was initially believed to mimic its inhibitory effects on synaptic neurotransmission, an action that would relieve pain by disrupting the transmission of nociceptive signals across neurons. However, it has since been shown that the drug does not interact with gamma-aminobutyric acid receptors and is not converted into gamma-aminobutyric acid or a gamma-aminobutyric acid agonist.
Although two open trials have shown gabapentin to be efficacious in the treatment of Bipolar disorder, a Pfizer-sponsored double-blind trial showed gabapentin to be no more efficacious than placebo. However, gabapentin may have a role as an adjunctive therapy particularly in patients with comorbid anxiety disorder or substance abuse.
An open-label pilot study involving Bipolar disorder I and II patients (n = 22) with depression evaluated the efficacy of adjunctive treatment with gabapentin for the treatment of bipolar depression. The primary outcome measures were the HAM-D, the YMRS, and the CGIS. At the conclusion of the 12-week trial, adjunctive gabapentin was found to be effective in patients with mild-to-moderate bipolar depression. Overall, the HAM-D ratings fell 53%. The most common side effect was sedation.
Common side effects of gabapentin are somnolence, dizziness, and dry mouth. Clinically, the most distinguishing characteristics of gabapentin are its superior safety and tolerability, compared with other anticonvulsants. Gabapentin is a water-soluble compound excreted in its unchanged form by the kidneys. In contrast, most anticonvulsants are metabolized in the liver, where they may be broken down into toxic metabolites that frequently trigger side effects, idiosyncratic adverse events, and drug interactions.
Antipsychotics as a class are divided into two groups: typical antipsychotics and atypical antipsychotics. The newer atypical antipsychotics provide clear advantages over typical antipsychotics with regard to adverse side effects. In particular, the newer agents are associated with far fewer drug-induced movement disorders — extrapyramidal symptoms such as parkinsonism and akathisia — and are less likely to cause the most serious movement disorder, tardive dyskinesia. Antipsychotics used to treat Bipolar disorder include the typical antipsychotics, such as haloperidol (McNeil’s Haldol, Dainippon’s Serenace, generics), thioridazine (Novartis’s Mellaril/Melerin, generics), and chlorpromazine (GlaxoSmithKline’s Thorazine, Sanofi-Aventis’s Largactil, generics). The atypical antipsychotics used to treat acute and long-term symptoms of Bipolar disorder are olanzapine (Lilly’s Zyprexa), risperidone (Janssen’s Risperdal), and quetiap-ine (AstraZeneca’s Seroquel). Clozapine (Novartis’s Clozaril/Leponex, available in the United States and Europe only) is often reserved as a third- or fourth-line therapy in Bipolar disorder because it carries the risk of agranulocytosis in approximately 2% of patients.
In September 2003, the FDA recommended that a warning regarding an increased risk of elevated blood sugar levels and diabetes be added to the labeling of all atypical antipsychotics based on a large cohort study (publicly available in abstract form only) that found an increased risk of diabetes associated with olanzapine, risperidone, and quetiapine.
Among the atypical antipsychotics, olanzapine has the most approvals for Bipolar disorder; it has been approved for acute, adjunctive, and prophylactic treatment of Bipolar disorder. Risperidone and quetiapine are approved for both adjunctive and monother-apeutic acute treatment of Bipolar disorder; quetiapine is also in development for Bipolar disorder depression and maintenance treatment. Aripiprazole is in development for Bipolar disorder mania. The following paragraphs cover in detail the primary agents used off-label and approved or awaiting approval to treat Bipolar disorder.
Mechanism Of Action
Clozapine (Novartis’s Clozaril/Leponex, generics), risperidone (Janssen’s Risperdal), olanzapine (Eli Lilly’s Zyprexa), quetiapine (AstraZeneca’s Seroquel), ziprasidone (Pfizer’s Geodon/Zeldox), zotepine (Fuji-sawa’s Lodopin, Sanofi-Aventis’s Nipolept, Orion’s Zoleptil), and perospirone (Sumitomo’s Lullan) are all serotonin-dopamine antagonists (serotonin-dopamine antagonists) — that is, they act at both dopamine and serotonin receptors. Aripiprazole (Otsuka Pharmaceutical/Bristol-Myers Squibb’ s Abilify) is the first dopamine partial agonist to be launched for the treatment of schizophrenia. Nevertheless, all of these drugs demonstrate different receptor-binding profiles, biochemical profiles, and tolerability by patients, variations that may reflect or cause different modes of action.
One notable characteristic that all atypical antipsychotics share is their reduction or elimination of motor side effects (e.g., extrapyramidal symptoms, tardive dyskinesia) compared with typical antipsychotics. Theoretically, this effect could be caused by the blockade of a combination of 5-HT2A receptors and D2 receptors. This serotonin blockage prevents dopamine from being released in the mesolimbic dopamine pathway; hyperactivity of dopamine in this area is associated with extrapyramidal symptoms.
All antipsychotics used on and off-label for Bipolar disorder are available in an oral form. However, a few agents come in alternative formulations that permit faster dosing during treatment of acute phases of Bipolar disorder, that can be used with uncooperative patients, and that can encourage compliance from patients who do not adhere to their prescribed therapy. Both olanzapine and ziprasidone are available as rapid-acting IM formulations, and an IM formulation of quetiapine is in development. Risperidone is the only marketed antipsychotic with a long-acting depot formulation, although a depot formulation for olanzapine is in Phase II development. Olanzapine and risperidone come in quick-dissolving formulations that do not require water for oral administration, and granule formulations of quetiapine and olanzapine are in development.
Newer atypical antipsychotics such as olanzapine will have an increasing role in long-term Bipolar disorder therapy because of accumulating evidence of their mood-stabilizing properties. Olanzapine (Eli Lilly’s Zyprexa), often referred to as a mood stabilizer, is available in the major markets as a treatment for schizophrenia, and it is approved for the treatment of acute mania in the United States and Europe. In May 2000, the FDA approved olanzapine for the treatment of acute Bipolar disorder mania, the first atypical antipsychotic approved for the treatment of acute Bipolar disorder mania; prevention of recurrence of manic, mixed, or depressive episodes related to Bipolar disorder; and maintenance treatment of Bipolar disorder. In January 2004, the FDA approved olanzapine for the long-term prophylaxis (e.g., maintenance therapy) of Bipolar disorder and the treatment of depressive episodes. Olanzapine is also approved for combination therapy with lithium or valproate for short-term treatment of acute manic episodes associated with Bipolar disorder.
Olanzapine’s pharmacological profile closely resembles that of clozapine; each has an affinity for both the serotonergic 5-HT2A and dopaminergic D2 receptors, but they bind more strongly to the 5-HT2A receptor. The ratio of 5-HT2A to D2 activity is somewhat greater for clozapine than for olanzapine, which is twice as active at 5-HT2A receptors. Additionally, olanzapine does not share clozapine’s affinity for alpha-2 adrenergic receptors.
Olanzapine has successfully proven its efficacy in the treatment of Bipolar disorder mania when prescribed either as monotherapy or as adjunctive therapy. Its additional approval for maintenance treatment of Bipolar disorder, along with the approval of Lilly’s other Bipolar disorder drug, OFC (olanzapine/fluoxetine combination [Symbyax]), for the treatment of Bipolar disorder depression, will significantly boost sales of Lilly’s olanzapine franchise.
The efficacy of olanzapine as a monotherapy for maintenance treatment (after use as an acute treatment) was shown in a randomized trial with patients diagnosed with DSM-IV Bipolar disorder (n = 361) (Lilly package insert). In this trial, patients who achieved remission (361 out of 731) in a 6- to 12-week open-label trial with olanzapine were randomized to receive either placebo or olanzapine. The primary measure of efficacy was time to relapse. At the end of the 52-week trial, median time to relapse of either mania or depression was significantly longer for olanzapine patients than for placebo patients (174 days versus 22 days), and rates of mania and depression relapse were lower in patients treated with olanzapine compared with placebo. Additionally, olanzapine delayed relapse in the subgroup of rapid-cycling patients.
Olanzapine may have advantages over lithium in the maintenance treatment of Bipolar disorder. In September 2002, at the Third European Stanley Foundation Conference on Bipolar Disorder, researchers presented the results of a one-year double-blind comparator study examining symptom remission rates in patients treated with either olanzapine or lithium. In the study, remission was defined as a score of 12 or less on the YMRS and a score of 8 or less on the HAM-D. A total of 431 Bipolar disorder I patients who met remission criteria were randomized to undergo 52 weeks of treatment with olanzapine 5-20mg/day (n = 217) or lithium (0.6-1.2 mEq/L blood level) in a dose range of 300-1,800 mg/day (n = 214). Overall, patients treated with olanzapine experienced significantly lower rates of relapse than did patients treated with lithium (30.0% and 38.8%, respectively). Rates of relapse into a depressive episode were similar between treatment groups (16.1% and 15.4%, respectively). However, lithium-treated patients experienced a mania relapse significantly sooner than did those receiving olanzapine. Furthermore, patients in the olanzapine group had significantly lower rates of hospitalization and experienced lower discontinuation rates as a result of adverse events.
Olanzapine’s propensity to induce weight gain is of particular concern because this side effect is the most likely reason for patients to refuse treatment or to comply poorly with treatment regimens. Approximately 29% of olanzapine-treated patients experience at least a 7% increase in body weight, compared with a 3% weight gain in placebo recipients.
Olanzapine increases glucose levels by approximately 21%, and increased glucose levels together with significant weight gain raise the risk of ketoacidosis and diabetes. According to Lilly, diabetes was reported in 0.6% of patients in olanzapine premarketing trials. In the ten-month period following its 2001 launch in Japan, nine cases of diabetic ketoacidosis, coma, or hypoglycemia were reported, and the Japanese Ministry of Health, Labor, and Welfare (MHLW) ordered Lilly to revise its labeling to contraindicate the use of olanzapine in diabetic patients and those with a history of diabetes.
In September 2003, a warning was added to olanzapine’s label according to previously mentioned FDA recommendations. This warning is based on a study (publicly available in abstract form only) that found olanzapine was associated with a 27% increased risk for developing diabetes compared with typical antipsychotics. In April 2004, a law firm announced the filing of the first U.Spain. nationwide class action lawsuit against Eli Lilly on behalf of U.Spain. patients who have used olanzapine. The suit seeks compensation for patients who have been diagnosed with serious side effects (e.g., diabetes, pancreatitis) after taking olanzapine.
Olanzapine also negatively affects cholesterol, and many physicians now test lipid levels in olanzapine-treated patients. According to its package insert, the risk of increased triglycerides associated with olanzapine occurs infrequently (in approximately 1 per 100 to 1 per 1,000 patients). In clinical trials, olanzapine elevated triglyceride levels by an average of 39%; an increased level of triglycerides is a risk factor for coronary artery disease.
Janssen’s risperidone (Risperdal) is approved in the United States and Europe as a monotherapy or for use in combination with lithium or valproate in the short-term treatment of acute manic or mixed episodes associated with Bipolar disorder. The drug is also under regulatory review for the treatment of autism in children and juveniles in the United States and for the treatment of psychosis in Alzheimer’s disease in Europe. In addition to its original tablet form, risperidone is available in an oral liquid solution, orally disintegrating tablets (Risperdal M-Tab), and a long-acting depot formulation (Risperdal Consta).
Risperidone exhibits potent 5-HT2A receptor- and moderate D2 receptor-blocking capacity. Compared with other atypical antipsychotics, it exerts far less activity at the other subsets of the serotonergic and dopaminergic receptor systems. The D2 receptor affinity of risperidone causes dose-dependent extrapyramidal symptoms in an estimated 20% of patients.
Risperidone has been shown to be safe and effective as an adjunctive therapy in the treatment of Bipolar disorder. In a randomized, double-blind, placebo-controlled trial, investigators evaluated therapy with risperidone, haloperidol, or placebo as an adjunct to lithium or valproic acid in patients (n = 156) hospitalized for acute bipolar mania. The primary measure of efficacy was the YMRS, and secondary measurements were the BPRS and the CGIS. At the end of the three-week trial, risperidone as adjunctive therapy and monotherapy was associated with significantly greater improvement in scores on the YMRS and CGIS compared with placebo and as efficacious as haloperidol adjunctive therapy using the same measures. The most common adverse events reported were headache, extrapyramidal disorder, and tremor; these side effects were more frequent in patients who received haloperidol plus a mood stabilizer. The incidence of extrapyramidal symptoms was significantly higher in those patients receiving haloperidol.
A short-term trial demonstrated risperidone’s efficacy as monotherapy in Bipolar disorder. In a December 2003 press release, Janssen reported that the FDA approval of risperidone for the treatment of Bipolar disorder mania was based on three studies — two that analyzed the medication as monotherapy and one in which risperidone was studied in combination with lithium or valproate. Patients in these studies receiving risperidone were given the drug in doses of Italy-6mg per day. In one of the monotherapy trials, a placebo-controlled trial of patients diagnosed with Bipolar disorder I (n = 246) who were in an acute manic episode with or without psychotic symptoms, the primary measure of efficacy was change from baseline in the YMRS total score. At the end of this three-week trial, 43% of the patients treated with risperidone versus 24% of the patients given placebo had at least a 50% reduction in their YMRS total score. The most common side effects in all three studies were extrapyramidal symptoms, sleepiness, dyspepsia, nausea, abnormal vision, and increased saliva. Many of the other side effects linked to risperidone treatment are similar to those produced by clozapine, including orthostatic hypotension, weight gain, and sedation. As a class, the atypical antipsychotics are free of sustained prolactin elevation, although risperidone still has a relatively high incidence of this side effect, similar to that of typical agents. The potential consequences of persistent prolactin elevation in women include menstrual cycle and reproductive disturbances, galactorrhea, hirsutism, vaginal dryness, loss of libido, obesity, decreased bone density, and increased breast cancer risk over the long term. In men, the most common problems associated with persistent prolactin elevation are erectile dysfunction, impotence, hypospermatogenesis, and loss of libido.
In January 2004, quetiapine (AstraZeneca’s Seroquel) was approved in the United States and the United Kingdom as a monotherapy or in combination with lithium or valproate for the short-term treatment of manic or mixed episodes of Bipolar disorder and for the treatment of Bipolar disorder depression, and Phase III trials are under way with quetiapine for Bipolar disorder maintenance. AstraZeneca is developing a sustained-release formulation of quetiapine and expects to file for U.Spain. and European approval in 2006. AstraZeneca also expects to file for approval of a granule formulation of quetiapine in the United States and Europe after 2006.
Like other atypical agents, quetiapine’s efficacy in Bipolar disorder appears to be mediated through a combination of D2 and 5-HT2 antagonism. Its D2 receptor occupancy is low, like that of clozapine; therefore, its primary mode of action is likely to involve more than D2 occupancy. Quetiapine exhibits relatively high binding affinity for serotonin receptors. Quetiapine is also an antagonist of 5-HT1A, Dl, histamine HI, and alpha-1-adrenergic, and alpha-2-adrenergic receptors.
Quetiapine has shown efficacy in a pooled analysis of two double-blind, placebo-controlled trials comparing the efficacy of up to 800 mg per day of quetiapine with placebo in Bipolar disorder I patients with mania (n = 604).
Measures of efficacy were changes from baseline on the YMRS. At the end of the 12-week trials, a statistically significant improvement in YMRS total scores was observed in patients taking quetiapine versus the placebo group.
Quetiapine’s side-effect profile is similar to that of other atypical antipsychotics. Sedation and dizziness are the most commonly reported side effects. Like olanzapine and risperidone, quetiapine causes weight gain, although the incidence of this effect in trials (2%) is lower than in trials of other atypical agents. Changes in eye lenses have been observed in patients who took quetiapine for extended periods (at least six months), but a causal relationship has not been clinically proved. Nevertheless, a lens examination is recommended (at least in the United States) at the initiation of treatment and again every six months. (Risperidone and olanzapine have been reported to cause similar lens problems.) The drug’s relatively short half-life (approximately seven hours) means that quetiapine must be administered in multiple daily doses of 300-600 mg.
Quetiapine’s main advantage over competitor compounds is its favorable side-effect profile: it is the only first-line antipsychotic with placebo levels of extrapyramidal symptoms across the entire dose range and no prolactin elevation.
Aripiprazole (Bristol-Myers Squibb [BMS]/Otsuka Pharmaceutical’s Abilify) was the first dopamine partial agonist launched for the treatment of schizophrenia. The FDA approved aripiprazole for the treatment of schizophrenia in November 2002, and the drug was launched before year-end. In December 2001, Otsuka and BMS submitted a marketing authorization application (MAA) for aripiprazole to the European Agency for the Evaluation of Medicinal Products (EMEA), and the drug was approved for schizophrenia in June 2004. In Japan, it is in Phase III trials for schizophrenia. In July 2003, BMS and Otsuka filed a supplemental new drug application with the FDA for the treatment of acute mania in patients with Bipolar disorder.
Aripiprazole’s distinguishing characteristic is its mechanism of action, which allows the drug to modulate dopamine levels without completely blocking D2 receptors. This mechanism of action may confer comparable antipsychotic efficacy but greater tolerability than available atypical antipsychotics. Specifically, the drug is a partial agonist at dopamine D2 receptors and can act as a dopaminergic stabilizer, performing as a dopamine antagonist in conditions of dopamine hyperactivity and exhibiting dopamine agonist properties in states of hypoactivity.
Numerous studies have shown aripiprazole to be efficacious and tolerable in the treatment of schizophrenia, and preliminary data suggest the drug has potential in Bipolar disorder. In May 2002, at the annual meeting of the American Psychiatric Association, researchers presented the results of a multicenter, double-blind trial in which patients diagnosed with acute mania (n = 262) were randomized to receive aripiprazole (15-30 mg) or placebo. The primary efficacy end point was change from baseline in the total score on the YMRS. Response was defined as a reduction of greater than or equal to 50% in the YMRS total score. At the end of the three-week trial, aripiprazole produced statistically significant improvements in YMRS total score compared with placebo. The changes were significant by day 4 and increased during the three-week treatment period. Furthermore, 40% of patients treated with aripiprazole were classified as responders versus 19% of patients treated with placebo. Aripiprazole was generally well tolerated. The rate of discontinuation due to adverse events did not differ between the drug-treated and placebo groups, and no significant changes in weight versus placebo were reported. The most commonly reported adverse events associated with aripiprazole were headache, nausea, dyspepsia, somnolence, and agitation. The majority of somnolence and gastrointestinal events reportedly occurred during the first week of treatment, and few events lasted more than seven days.
In September 2003, the FDA recommended that a warning regarding an increased risk of elevated blood sugar levels and diabetes be added to the labeling of all atypical antipsychotics based on a large cohort study (publicly available in abstract form only) that found an increased risk of diabetes associated with olanzapine, risperidone, and quetiapine. In March 2004, this warning was added to aripiprazole’s label, but it is less severe and acknowledges that the studies used as the basis for the warning did not include aripiprazole and that it is unknown if aripiprazole is, in fact, associated with an increased risk of hyperglycemia-related adverse events. BMS and Otsuka are petitioning the FDA to remove the warning altogether.
In October 2003, Pfizer submitted an sNDA for the use of ziprasidone for the short-term treatment of acute mania in patients with Bipolar disorder. Ziprasidone (Pfizer’s Geodon) is available for the treatment of schizophrenia in the United States, Germany, and Spain. In Japan, the oral form of ziprasidone is in Phase II trials for this indication. A short-acting IM formulation of ziprasidone is also available in the United States, Germany, and Spain.
Like other atypical agents, ziprasidone’s efficacy is mediated through a combination of D2 and 5-HT2A antagonism. Chemically similar to risperidone, ziprasidone demonstrates a strong affinity for the D2, D3, 5-HT2A, 5-HT1A, 5-HT1D, and alpha-1-adrenergic receptors. It shows a more moderate affinity for HI histamine receptors. Some researchers suggest that the inhibition of alpha-1-adrenergic receptors may suppress positive symptoms, especially in acute schizophrenia.
A major reason for pursuing ziprasidone as a treatment for bipolar mania was a secondary analysis of mood symptoms in patients with schizoaffective disorder. Results from these trials suggested that ziprasidone has dose-related antimanic and antidepressant effects. Because of these findings, its efficacy and safety were further examined in a large, double-blind, randomized, placebo-controlled trial involving patients with acute bipolar mania. In this three-week study, 195 patients were randomly assigned to receive either flexible-dose oral ziprasidone (80-160 mg; n = 131) or placebo (n = 64). Ziprasidone-treated patients showed significantly greater improvement in manic symptoms by the second day of treatment compared with placebo recipients. Ziprasidone was also superior to placebo in improving global functioning and reducing psychosis and overall psychopathology. The most common side effects associated with ziprasidone were somnolence and dizziness.
Ziprasidone’s association with QTc prolongation was a stumbling block in its regulatory approval in the United States for schizophrenia. Pfizer had initially filed an NDA for the oral (pill) form in March 1997, but the FDA issued a not approvable letter in June 1998. After Pfizer refiled the NDA with supplemental electrocardiographic data, the FDA granted U.Spain. marketing approval in February 2001. The drug’s label states that in clinical trials, the electrocardiograms of 0.06% of all patients who received ziprasidone demonstrated QT intervals exceeding the potentially clinically relevant threshold of 500 milliseconds, a condition that has been associated with torsades de pointes (severe ventricular tachycardia) and sudden death.
The treatment of depression associated with Bipolar disorder has not been studied as extensively as has treatment for unipolar depression or bipolar mania. Consequently, pharmacotherapy for bipolar depression relies on treatment strategies that have proved effective in treating unipolar depression. These strategies are indicated as second-line adjuvant therapy for patients whose depression cannot be controlled with mood-stabilizing drugs. Even Bipolar disorder II patients who suffer predominantly depressive symptoms are treated initially with a mood stabilizer rather than an antidepressant, which may be added to the treatment regimen for refractory patients. The use of antidepressant drugs in Bipolar disorder raises concerns separate from those associated with the treatment of unipolar depression. In Bipolar disorder, initiation of antidepressant therapy may induce mania. Patients most vulnerable to this effect are those with asymptomatic or subtly symptomatic mania or hypomania, notably patients with Bipolar disorder II. Because of this risk, physicians’ choice of antidepressant therapy in Bipolar disorder relies in large part on their confidence in the safety of individual agents for treating Bipolar disorder. Clinicians choose from among the different classes of antidepressants, including Selective serotonin reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors. Because Selective serotonin reuptake inhibitors are currently the antidepressant of choice among clinicians, the majority of antidepressants prescribed for Bipolar disorder are agents from this class, such as fluoxetine and sertraline. Other agents occasionally used in Bipolar disorder treatment include the norepinephrine and dopamine reuptake inhibitor bupropion (GlaxoSmithKline’s Wellbutrin, Wellbutrin SR, generics) and the serotonin-norepinephrine reuptake inhibitor venlafaxine.
In studies of unipolar depression, antidepressant medications have been shown to be essentially equal in efficacy. What differentiates antidepressant drug classes, then, is not their efficacy but their side-effect profiles. The physician’s choice of antidepressant for managing depression in Bipolar disorder is based on a combination of factors, including the patient’s symptoms at presentation, physical health, and nonpsychiatric comorbidities; the drug’s anticipated side effects; the physician’s preference; and factors such as cost, insurance, and regulatory constraints. In addition, particular antidepressant classes appear to be more appropriate for treating certain types of illness. For example, Bipolar disorder patients with agitated depression respond well to a sedating tricyclic drug such as ami triptyline. Bipolar disorder patients who are socially withdrawn or have difficulty accomplishing tasks are better candidates for a stimulating antidepressant such as an Selective serotonin reuptake inhibitor (particularly fluoxetine) or bupropion. The discussion that follows highlights OFC, the only drug approved for the treatment of Bipolar disorder depression, and bupropion, an antidepressant often used for the treatment of Bipolar disorder depression and previously investigated for the treatment of Bipolar disorder depression.
Mechanism Of Action
Selective serotonin reuptake inhibitors act by selectively inhibiting the presynaptic reuptake of serotonin (5-HT) while exerting little effect on norepinephrine (NE) or dopamine uptake. After a serotonergic neuron fires, 5-HT is normally transported back into the presynaptic neuron for repackaging and subsequent re-release. Selective serotonin reuptake inhibitors block the reuptake mechanism and consequently increase the level of 5-HT in the synaptic space surrounding the neuron. The excess 5-HT activates all 5-HT receptors, both pre- and postsynaptically. The activation of the anxiogenic postsynaptic 5-HT2A receptors by Selective serotonin reuptake inhibitors may explain the initial increase in anxiety that Selective serotonin reuptake inhibitors cause in some patients, as well as the sexual side effects associated with this class of drugs. Citalopram and escitalopram show the greatest selectivity for serotonin over norepinephrine, followed by sertraline, paroxetine, fluvoxamine, and fluoxetine, in that order.
Like the Selective serotonin reuptake inhibitors, the serotonin-norepinephrine reuptake inhibitors inhibit the serotonin reuptake transporter, and, like the older tricyclic antidepressants, they inhibit the NE reuptake transporter. However, the serotonin-norepinephrine reuptake inhibitors are considered an improvement on the tricyclic antidepressants because they do not affect the histamine, acetylcholine, and adrenergic receptors and therefore do not cause the severe weight gain, dry mouth, and hypotension associated with tricyclic antidepressants. Because serotonin-norepinephrine reuptake inhibitors act on both serotonergic and noradrenergic systems, they are also called noradrenergic and specific serotonergic antidepressants. Venlafaxine is more potent in inhibiting serotonin than in inhibiting norepinephrine. Conversely, milnacipran is twice as potent in inhibiting norepinephrine reuptake as it is in inhibiting serotonin reuptake; hence, milnacipran is sometimes referred to as a norepinephrine/serotonin reuptake inhibitor.
Tricyclic antidepressants block the synaptic reuptake of serotonin and NE to varying degrees. They have little effect on dopamine and are potent blockers of muscarinic, histaminergic HI, and alpha-1-adrenergic receptors.
Second-generation antidepressants, which were launched in the 1980s, resulted from an effort to improve the pharmacological profiles of the first-generation antidepressants, the tricyclic antidepressants. Tricyclic antidepressants are effective in treating most forms of depression, but their mechanism of action — blockage of histaminergic, muscarinic, and alpha-1-adrenergic receptors — causes a wide array of side effects. Second-generation antidepressants are more receptor-specific — that is, they have less effect at receptors responsible for many of the side effects associated with tricyclic antidepressants. Several different mechanisms of action characterize second-generation antidepressants: some block norepinephrine uptake, some block dopamine uptake, and some block serotonin reuptake.
Lilly’s OFC (Symbyax) received FDA approval for bipolar depression in December 2003. Lilly will probably pursue other psychiatric indications, including major depression, for the drug.
OFC is both a 5-HT reuptake inhibitor and a 5-HT and dopamine receptor antagonist. The combination of olanzapine and fluoxetine may have greater therapeutic efficacy than either drug alone because of the synergistic effect the drugs have on dopamine and norepinephrine. Animal studies have shown that three hours after administration of olanzapine, norepinephrine and dopamine concentrations in the rat prefrontal cortex returned to baseline values; with fluoxetine treatment, norepinephrine and dopamine levels increase to 188% and 143% of baseline values, respectively. However, when both drugs are given, norepinephrine and dopamine levels increase to 269% and 349% of baseline values, respectively.
Olanzapine/fluoxetine combination treatment has proved effective in Bipolar disorder depression. In a double-blind, randomized controlled trial, 833 patients with DSM-IV Bipolar disorder I and a MADRS score of at least 20 were randomly assigned to receive placebo, olanzapine (5-20 mg/day), or olanzapine/fluoxetine combination (6 and 25 mg/day, 6 and 50 mg/day, or 12 and 50 mg/day). The primary measure of efficacy was change in MADRS total scores from baseline to week 8. Secondary measures of efficacy were changes in CGI-BP, YMRS, and HAM-A. Rates of and time to response and remission were also assessed. At the end of the eight-week trial, olanzapine was more effective than placebo, and the olanzapine/fluoxetine combination was more effective than olanzapine and placebo in the treatment of Bipolar disorder I depression. In all three groups, treatment-emergent mania (defined as a YMRS score less than 15 at baseline and 15 or more at any time thereafter) was low, and there were no statistically significant differences in emergent mania among groups. Time to response and remission were significantly shorter for the combined olanzapine/fluoxetine group than for the placebo and olanzapine groups. The adverse-event profile for the combined olanzapine/fluoxetine group was similar to that for olanzapine monotherapy but also included statistically significantly higher rates of nausea and diarrhea. Weight gain was not significantly different between the olanzapine and olanzapine/fluoxetine groups, but in both cases it was significantly greater than the placebo group.
First approved in the United States in 1985, bupropion was withdrawn from the market in 1986 for nearly three years because of concerns about increased seizure risk. When the drug was reintroduced in 1989, prescriptions for bupropion were written by specialists only, but prescribers’ hesitancy about using this drug has waned significantly since its relaunch. Now, both primary care physicians and specialists prescribe bupropion, either alone or together with an Selective serotonin reuptake inhibitor, to treat depression. In 1997, the FDA approved bupropion as a smoking cessation aid. Approval for the smoking cessation indication was granted more recently in the Netherlands, the reference member state for approval throughout the European Union. Bupropion is now available in France, Germany, Italy, Spain, and the United Kingdom for smoking cessation but not for depression.
Bupropion is unique among second-generation agents. Although the drug’s precise effects on neurotransmitters are not well understood, it has been shown to inhibit both dopamine and norepinephrine reuptake and appears to have only marginal effects on serotonin. It exhibits no antagonism of either alpha-1-adrenergic or muscarinic receptors.
In the United States, bupropion competes with Selective serotonin reuptake inhibitors as psychiatrists’ first-choice antidepressant therapy for bipolar depression because of their perception that the drug is less likely than other antidepressants to induce mania and because clinical trials have shown bupropion to be effective in treating depression in Bipolar disorder. Researchers have reported that bupropion may be less likely than tricyclic antidepressants to induce a latent mania.
The major risk associated with bupropion therapy is the potential for seizures at high doses; as a precaution, physicians initially prescribe low doses of the drug. Side effects of bupropion include weight loss and central nervous system symptoms (e.g., agitation, insomnia), which usually resolve after initial treatment.
Benzodiazepines, especially clonazepam (Roche’s Klonopin/Rivatril, generics) and lorazepam (Wyeth’s Ati-van/Tavor/Wypax, generics), are sometimes used to control agitation in acutely manic patients. These agents are usually prescribed as adjuncts to lithium and/or antipsychotic drugs. Recently, several studies established the antipanic efficacy of clonazepam together with its use in the treatment of other disorders, such as Bipolar disorder. Benzodiazepine treatment is indicated following an acute manic episode for a few weeks or months only, after which these agents are discontinued or prescribed in lower doses. Chronic use of Benzodiazepines leads to tolerance of their anxiolytic and anticonvulsant effects. Use of Benzodiazepines is declining in the major markets because of the increased use of maintenance therapies that are reducing the need to prescribe adjunctive Benzodiazepine treatment.
Studies have shown that clonazepam, when added to the treatment regimen of Bipolar disorder patients, can reduce relapse into manic or depressive episodes of Bipolar disorder. Many patients using a combination of anticonvulsants and lithium to treat their Bipolar disorder can be switched to a clonazepam and lithium combination without suffering acute relapse into an episode. A retrospective review of Bipolar disorder patients taking adjunctive clonazepam as part of their maintenance therapy found that in 6 of 17 patients previously receiving combined lithium and anticonvulsant therapy, clonazepam successfully replaced the anticonvulsant. Nevertheless, the potential for abuse and dependency associated with Benzodiazepines discourages their use. Benzodiazepines have been used to treat symptoms of Bipolar disorder since 1960. However, there are few comprehensive studies analyzing and quantifying the efficacy of Benzodiazepines in Bipolar disorder, so this section does not address these drugs in detail.
Mechanism Of Action
Benzodiazepines act at the gamma-aminobutyric acid receptor to facilitate the activity of endogenous gamma-aminobutyric acid. Gamma-aminobutyric acid hypoactivity is thought to be one of the causes of anxiety disorders.