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State of mind

Tried and tested strategies dominate bipolar treatment but new regimens are on the horizon

x-ray view of a brainBipolar disorders are characterised by episodes of pathologically elevated mood or mania, alternating with periods of depression. Symptoms of a manic episode include elevated or irritable mood, increased energy and a decreased need to sleep, distractibility, poor judgement, abuse of drugs and alcohol, and unusual behaviour. Patients may also experience periods of hypomania, a mild or moderate level of manic symptoms.

A depressive episode is most commonly characterised by feelings of sadness, anxiety, guilt, anger, isolation and hopelessness, as well as sleep and appetite disturbances, anhedonia, and generally altered mood. In severe cases, suicidal ideation may be present.

Episodes of mania or depression may include symptoms of psychosis, such as hallucinations or delusions. Occasionally, both manic and depressive symptoms can manifest together, resulting in what is termed as a mixed episode.

Approximately 2.6 per cent of the adult US population has bipolar disorder. Though there are genetic factors involved in the development of bipolar disorders, there are also other unknown contributing factors. Bipolar disorder is classed based on the severity of illness: a diagnosis of bipolar I disorder requires occurrence of at least one manic or mixed episode, with or without a depressive episode; bipolar II disorder is diagnosed by the occurrence of at least one hypomanic episode, as well as at least one major depressive episode.

Several drug classes are being used, or are in development for, bipolar disorders. The gold standard treatment for bipolar disorders is lithium - a mood stabiliser. Though lithium is an effective treatment for mania, it has a narrow therapeutic window and can cause serious side effects.

Current treatments for bipolar disorders include anticonvulsants, such as sodium valproate, carbamazepine and lamotrigine, as well as antipsychotics such as quetia-pine, olanzapine and aripiprazole.

Antidepressants are less widely used in bipolar patients due to their potential to cause or exacerbate mania.

Antipsychotics
Though the main use for antipsychotic drugs is to treat psychotic disorders such as schizophrenia, they have found use in the treatment of bipolar disorders. As well as treating the episodes of mania and depression themselves, they are useful for the treatment of psychotic symptoms that may become apparent during the course of the illness.

Bifeprunox (Solvay Pharmaceuticals; H Lundbeck; Wyeth) is an atypical antipsychotic with partial agonist activity at the dopamine D2 and serotonin 1A receptors, and is currently in phase III development for bipolar disorders in the US and Europe.

This mechanism of action is somewhat unique to bifeprunox, with aripiprazole being the only other atypical antipsychotic displaying partial agonist activity. Though there is no clinical data available for the efficacy of bifeprunox in patients with bipolar disorders, the drug has been shown effective and well tolerated in a phase II trial in patients with schizophrenia.

Asenapine (Schering-Plough) is a dopamine D2 receptor antagonist and serotonin 2A receptor antagonist. A new drug application for the treatment of acute mania and mixed episodes was accepted for review by the US FDA in November 2007.

Results of two phase III studies in the US (ARES 7501004 and ARES 7501005) suggest that asenapine is effective for the treatment of mania in patients with bipolar I disorder. The placebo-controlled ARES 7501005 study recruited a total of 488 patients, with olanzapine treatment as a positive control. The authors of the study concluded that asenapine is effective and safe in the treatment of acute mania associated with bipolar I disorder.

Paliperidone (Invega; Johnson & Johnson) is a dopamine D2 and serotonin2 receptor antagonist, with a controlled-release formulation currently in phase III development. Paliperidone has been launched for the treatment of schizophrenia, but J&J is currently conducting several phase III trials worldwide to assess its efficacy and tolerability in bipolar disorders.

Cariprazine (Gedeon Richter; Forest Laboratories) is an antagonist at the dopamine D3, D2 and serotonin 2B receptors. A randomised, double-blind phase II trial of cariprazine monotherapy is currently recruiting patients in the US, with an intended total of 240 subjects.

 

TREATMENT CLASSES FOR BIPOLAR DISORDER
GENERIC NAME MANUFACTURER INDICATION
Bifeprunox Solvay Pharmaceuticals; H Lundbeck; Wyeth Antipsychotic
Asenapine Schering-Plough Acute mania
Paliperidone Invega; Johnson & Johnson Antipsychotic
Cariprazine Gedeon Ritcher; Forest Laboratories Antipsychotic
Licarbazepine Novartis Anticonvulsant
Eslicarbazepine Sepracor; Bial Bipolar disorder
Zonisamide Eisai; Dainippon Sumitomo Pharma Acute mania
MEM 1003 Bayer Acute mania
Armodafinil Nuvigil; Cephalon Bipolar disorder
RG 2417 Repligen Bipolar disorder


Anticonvulsants

Anticonvulsants, such as lamotrigine and valproic acid, have been found useful as mood stabilisers, preventing the extremes of mania and depression in patients with bipolar disorders. The main advantage of anticonvulsants over lithium is their relatively improved tolerability, which results in better patient compliance.

Licarbazepine (Novartis) is a sodium channel antagonist anticonvulsant and mood stabiliser. Phase II development has been completed and several phase III studies are currently underway or recently completed. Licarbazepine is the hydroxyl derivative of oxcarbazepine, which is itself an analogue of carbamazepine.

Eslicarbazepine (Sepracor; Bial) has reached phase II trials for bipolar disorders. Eslicarbazepine was designed with the intention of an improved toxicity profile in comparison to carbamazepine and oxcarbazepine, and a reduced risk of drug-drug interactions.

Zonisamide (Eisai; Dainippon Sumitomo Pharma) is in phase II trials as a treatment for acute mania. Zonisamide appears capable of blocking voltage-gated sodium channels, as well as T-type calcium channels.

Other treatments
MEM 1003 (Bayer), a calcium channel antagonist, has completed a phase IIa trial in patients with acute mania associated with bipolar disorder, though the trial failed to meet its primary or secondary endpoints.

Armodafinil (Nuvigil, Cephalon) is currently being investigated as a therapy for bipolar disorders. Armodafinil is an alpha 1 adrenergic receptor agonist, and the R-isomer of modafinil, a therapy for narcolepsy and attention-deficit hyperactivity disorder.

A phase II trial is currently underway to assess the efficacy of armodafinil in patients with bipolar depression.

RG 2417 (Repligen) is a mitochondrial function enhancer based on uridine. There is evidence that mitochondrial dysfunction in the brain may play a role in bipolar disorders, and it is hoped that RG 2417 will correct down-regulation of certain genes encoding mitochondrial proteins.

Positive results have been reported from a six-week, 80-patient trial, with a significant improvement on the Montgomery Asberg depression rating scale, and a trend towards improvement on the clinical global impression of change in bipolar disorder scale in RG 2417-treated patients.

Going forward
Though the treatment of bipolar disorders continues to centre on tried and tested regimens, such as the refinement of anti-psychotic and anti-epileptic therapies, new treatment strategies are continually being developed.

ACR 325 (NeuroSearch) is a dopamine receptor modulator and glutamate agonist that commenced phase I trials in October 2006. Though there are no results as yet detailing preliminary efficacy for bipolar disorders, initial pharmacokinetic and tolerability studies in volunteers indicate the treatment is relatively well tolerated.

As advances in treatments continue, the possibility exists that a drug to smooth the extreme ups and downs of bipolar disorder will soon be found.

Pipeline was written by Bernard Kerr of Adis International, using data derived from Adis Clinical Trials Insight and R&D Insight. For further information on Adis services, please contact Camille Scot-Smith on 020 7981 0733

2nd May 2008

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