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3 New Bipolar Medications (2015): Drugs In Clinical Trials

Bipolar disorder is a condition characterized by cyclical mood swings, transitioning from depression to mania (or hypomania).  For a period of time, an individual with bipolar disorder will experience debilitating bouts of depression – and often unexpectedly, their entire neurophysiology will shift to facilitate a state of mania (elevated mood).  Diagnostically, there are multiple types of bipolar disorder, including “type 1” known for manic or mixed episodes spanning over a period of at least one full week.

Those with “type 1” bipolar disorder generally are thought to experience bouts of depression for an approximate average of 2 weeks before their mood shifts back to mania.  In rarer cases, individuals with Bipolar 1 experience “rapid cycling” in which they endure 4+ episodes of depression, mania, hypomania, or mixed episodes within a single calendar year.  On the other hand, those with “type 2” bipolar disorder are thought to experience mostly depressive symptoms, and sporadically transition to a milder form of mania known as “hypomania.”

It is estimated that over 5.7 million adults in the United States have bipolar disorder; accounting for 2.6% of the population.  The economic costs associated with bipolar disorder exceed $40 billion annually – mostly related to missed work days.  Fortunately, there are some highly effective pharmacological treatments that can be pursued to “balance” mood – preventing incessant emotional flux from depressive to manic states.

3 New Bipolar Medications (2015): Drugs in Clinical Trials

There are several new medications for bipolar disorder in late stage clinical trials.  However, one of these pipeline drugs is merely an injectable version of Aripiprazole (brand name Abilify) – a chemical already FDA approved for bipolar disorder.  Perhaps the pipeline medication with the most novelty is Cariprazine – a drug that may treat both manic and depressive symptoms via dopaminergic modulation.

  1. Abilify Maintena

  • Mechanism: D2 partial agonist / 5-HT1A partial agonist
  • Company: Bristol-Myers Squibb / Otsuka Pharmaceuticals
  • Status: Phase III clinical trials

Abilify (Aripiprazole) is a drug that was approved in 2002 for the treatment of schizophrenia, but has since received approval to treat acute manic episodes of bipolar disorder.  A newly engineered version of Abilify called “Abilify Maintena” provides a full month’s worth of Abilify in one intramuscular injection, eliminating the need for popping a daily pill.  As of 2015, Abilify Maintena is in Phase III clinical trials for the treatment of bipolar mania.

Due to the fact that Abilify Maintena contains the same active ingredient (aripiprazole) as standard Abilify, some practitioners are already prescribing Abilify Maintena as an intervention for bipolar mania.  Abilify Maintena appears equally effective as standard Abilify and is thought to maximize patient compliance in that they will not “forget to take” or decide not to take their daily medication.

Abilify Maintena is thought to treat acute mania primarily via effects as a partial agonist at the D2 and 5-HT1A receptors.  Since Abilify is commonly used as an antidepressant augmentation strategy among those with major depression, it may also minimize the likelihood (or intensity) of bipolar depression when used as an adjunct.  It seems as though it’s just a matter of time before Abilify Maintena is approved as a maintenance treatment for bipolar mania.

  • Source: http://www.otsuka.com/en/rd/pharmaceuticals/pipeline/pdf.php?financial=376
  1. Cariprazine

  • Mechanism: D2 & D3 receptor partial agonist
  • Company: Forest Laboratories / Gedeon Richter
  • Status: FDA approval pending

Cariprazine (RGH-188) is an atypical antipsychotic under development by Forest Laboratories and Gedeon Richter.  Like most antipsychotics, it is intended primarily for the treatment of positive symptoms associated with schizophrenia (e.g. hearing voices, delusions, etc.).  The drug has proven safe, tolerable, and effective in clinical trials for the treatment of schizophrenia, as well as mania associated with bipolar disorder.

As a result of meeting clinical trial endpoints, it is currently awaiting FDA approval for both schizophrenia and bipolar mania.  The drug is similar to current-market antipsychotics in that it acts as a partial agonist at the D2 receptor, but differs in that it is also a partial agonist of the D3 receptor.  Cariprazine antagonizes dopamine receptors when they become overstimulated, yet agonizes the receptors when an individual has low dopamine.

This modulating effect of dopamine receptors may prove effective for managing both bipolar mania, mixed-states, and bipolar depression.  Testing is currently underway to determine whether Cariprazine is clinically effective for the treatment of bipolar depression.  Should Cariprazine attain FDA approval to treat manic and depressive phases, it will be the third antipsychotic agent to do so.

  1. Rozerem (Ramelteon Sublingual)

  • Mechanism: MT1 & MT2 receptor agonist
  • Company: Takeda Pharmaceuticals
  • Status: Phase III (Unknown)

Rozerem (Ramelteon or TAK-375SL) is a drug that was designed by Takeda Pharmaceuticals to treat insomnia.  It was approved by the FDA in 2005 for the treatment of insomnia, and regarded as the first sleeping pill to act as a selective agonist of melatonin receptors (MT1 & MT2) within the suprachiasmatic nucleus (SCN) region.  Most traditional sleeping pills (hypnotics) act on GABAA receptors and are thought to be dangerous psychiatric drugs in that they may cause dementia, memory impairment, and rapid tolerance development.

Although approved to treat insomnia, Rozerem was under investigation as a treatment for “type 1” bipolar disorder.  One trial tested the efficacy of Rozerem as an adjunct maintenance therapy for bipolar disorder.  Results from the trial indicated that those receiving Rozerem were 50% less likely to experience symptomatic relapse as those given a placebo.

Rozerem’s efficacy for bipolar maintenance and mania attenuation may stem from its ability to regulate circadian rhythms.  Regulation of circadian rhythms minimizes likelihood of mood stability and prevents cycling to a manic and/or depressive state.  Despite demonstrating preliminary efficacy as an adjunct, it is unclear as to whether its development was abandoned or whether it is still in clinical trials for bipolar disorder.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22963894
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/20861739

5 Newest Bipolar Medications (FDA Approved)

Below is a list of newest medications for the treatment of bipolar disorder.  Keep in mind that certain drugs may only be FDA approved to treat acute mania, while others (e.g. Latuda) are solely approved for the treatment of bipolar depression.  Other drugs like Seroquel XR are FDA approved for the treatment of acute mania and bipolar depression, and can also be used for maintenance therapy.

  1. Latuda (Lurasidone)

  • Mechanism: D2 receptor & 5-HT2A receptor antagonist
  • Company: Sunovion Pharmaceuticals
  • FDA approval: 2013 (Bipolar depression)

Latuda is an atypical antipsychotic that was initially approved for the treatment of schizophrenia, but has since received FDA approval (as of 2013) for the treatment of bipolar depression among those with “type 1” bipolar disorder.  It is considered effective as a standalone agent, but the FDA suggests it can also be administered as an adjunct to a mood stabilizer (e.g. lithium) for reduction of depressive symptoms.

The drug functions primarily as a D2 receptor and 5-HT2A receptor antagonist, modulating dopaminergic and serotonergic activity.  By targeting the D2 receptor, it is thought to effectively reduce positive symptoms of schizophrenia such as hallucinations and delusions.  Since Latuda doesn’t significantly affect histaminergic or muscarinic acetylcholine receptors, it may not cause “brain fog” like many other antipsychotics.

In fact, some reports suggest that Latuda may even enhance certain aspects of cognition among those with cognitive impairment.  It also has a favorable side effect profile compared to other antipsychotics, particularly in terms of weight gain; Latuda is considered weight neutral. Latuda remains one of very few antipsychotics that have been FDA approved for the depressive phases of bipolar disorder.

  1. Saphris (Asenapine)

  • Mechanism: D2 receptor & 5-HT2A receptor antagonist
  • Company: Actavis Pharmaceuticals
  • FDA approval: 2009 (Acute bipolar mania)

Saphris is an atypical antipsychotic that is approved by the FDA for the treatment of schizophrenia and acute mania associated with bipolar disorder.  Perhaps most unique about Saphris is the fact that it is a chemical derivative of Mianserin, a tetracyclic antidepressant (TeCA).  This drug has been FDA approved as a standalone treatment for mania and also as an adjunct to a mood stabilizer (e.g. lithium).

Unlike many other antipsychotics, significant weight gain isn’t associated with Saphris, and overall, the drug is thought to have a favorable side effect profile.  Despite Saphris’ favorable side effect profile, the drug acts similarly to other atypical antipsychotics in that it antagonizes the D2 and 5-HT2A receptors, exerting dopaminergic and serotonergic effects.  It also affects a variety of other receptor sites including: 5-HT1A (as a partial agonist), Alpha-1 (as an antagonist), H1 (as an antagonist), and 5-HT2B / 5-HT2C / 5-HT5A / 5-HT6 / 5-HT7 receptors (as an antagonist).

Due to the fact that Saphris is an antipsychotic designed primarily to treat psychosis, it may be especially effective for managing bipolar disorder with psychotic features.  In terms of efficacy, Saphris appears to be less effective than most other antipsychotics (and lithium) for the treatment of mania and mixed states.  Although it is a newer medication with favorable side effects, it may not work as well to attenuate mania compared to other FDA approved agents.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/21851976
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/21689438
  1. Risperdal Consta (Risperidone LAI)

  • Mechanism: D2 receptor & 5-HT2A receptor antagonist
  • Company: Janssen Pharmaceuticals
  • FDA approval: 2009 (Bipolar maintenance)

Risperdal (Risperidone) is a drug that has been approved since 2003 for the treatment of acute bipolar mania.  It was eventually reengineered into a long-acting injectable formulation called “Risperdal Consta.”  Risperdal Consta differs from standard Risperdal in that it is administered via intramuscular injection (gluteal or deltoid) by a medical professional.

The long-acting injectable form of Risperdal is comprised of microspheres or microcapsules (containing the active ingredient risperidone).  Risperidone acts primarily as an antagonist of the D2 receptor and 5-HT2A receptor – minimizing the likelihood of psychotic symptoms, while simultaneously preventing mania.  As of 2009, the long-acting Risperdal Consta had received FDA approval as a maintenance agent for “type 1” bipolar disorder.

A meta-analysis published in 2011 suggested that Risperdal is among the most effective medications for the treatment of manic phases of bipolar disorder.  Some believe that Risperdal Consta is advantageous over pill-based Risperdal due to the fact that it doesn’t require daily administration – Risperdal Consta is administered bi-weekly (once every 2 weeks).  Patients taking Risperdal Consta need not worry about “forgetting” to take pills and thus may do better with this treatment.

Note: There are various spinoffs of Risperdal Consta in development as new medications for schizophrenia.  Many of these spinoffs will provide longer-lasting efficacy (up to a full month) and incorporate a smoother, more controlled-delivery system and quicker onset of action.  It is speculated that these will likely be used for bipolar maintenance upon approval.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/21851976
  1. Seroquel XR (Quetiapine extended-release)

  • Mechanism: D2 receptor & 5-HT2A antagonist / 5-HT1A partial agonist
  • Company: AstraZeneca Pharmaceuticals
  • FDA approval: 2008 (Acute bipolar mania, bipolar depression, bipolar maintenance)

Seroquel XR is an atypical antipsychotic drug developed by AstraZeneca for the treatment of bipolar disorder and schizophrenia.  It functions as a D2 receptor and 5-HT2A receptor antagonist, as well as a 5-HT1A partial agonist.  Its effect on the D2 and 5-HT2A receptors as an antagonist is thought to attenuate manic symptoms, whereas its effect as a partial agonist on the 5-HT1A receptor is thought to improve depressive symptoms.

The first, standard version of Seroquel was approved in 2004 for the treatment of acute mania and 2006 for bipolar depression.  However, AstraZeneca reengineered Seroquel from a pill requiring multiple daily doses to an “XR” (extended release) version – requiring a single daily dose.  Seroquel XR effectively treats symptoms for 24 hours following ingestion of a single pill – whereas the standard version does not.

As a result of its ability to effectively manage all phases of bipolar disorder (mania, depression, and mixed-states), Seroquel XR is a popular first-line treatment for those with “type 1” bipolar disorder.  It is also commonly used as an adjunct to a mood stabilizer (e.g. lithium) for bipolar maintenance.  Many speculate that a long-acting, injectable version of Seroquel will be developed in the future.

  1. Stavzor (Valproic Acid DR)

  • Mechanism: GABAergic
  • Company: Banner Pharmacaps
  • FDA approval: 2008 (Acute bipolar mania)

Stavzor is a drug that was approved in 2008 for the treatment of acute bipolar mania, seizures, and migraine headaches.  The drug contains a delayed-release (DR) valproic acid that was engineered with EnteriCare enteric soft gelatin capsule delivery system.  The thought is that a delayed-release format of valproic acid will minimize likelihood of side effects (particularly gastrointestinal) associated with other formulations.

Although the mechanism by which Stavzor provides therapeutic benefit is poorly understood, many experts speculate that it enhances activity of the neurotransmitter GABA (gamma-aminobutyric acid).  Enhancement of GABAergic functions results in reduced neuronal excitement and appropriately mitigates neurophysiological activity associated with mania.  Another hypothesized mechanism by which Stavzor may attenuate mania is via inhibition of voltage-dependent sodium channels.

Despite the fact that Stavzor is considered highly effective for the treatment of acute bipolar mania, it isn’t generally effective for the treatment of bipolar depression.  For this reason, an individual with “type 1” bipolar disorder will often require an adjunctive medication to manage bouts of depression.

Synopsis: New Medications for Bipolar Disorder in Development

Of the three new bipolar medications in the development pipeline, perhaps the most promising agent is Cariprazine.  Cariprazine is unique in that it functions primarily as both a D2 and D3 receptor partial agonist.  The drug is able to act as an antagonist at these receptor sites when dopamine levels are high, thereby reducing the likelihood of mania (and psychotic symptoms).

However, when levels of dopamine are abnormally low, Cariprazine elicits effects as an agonist – stimulating the dopamine receptors.  For this reason, many suspect that the drug will eventually get approval for the treatment of both bipolar mania and depression.  In addition, Cariprazine may be preferred over older antipsychotic agents in that extrapyramidal side effects are unlikely.

The approval of Abilify Maintena for the treatment of bipolar mania won’t come as a surprise to anyone due to the fact that it is merely a reformatted version of the already-approved drug Abilify.  Abilify Maintena may be advantageous in that monthly injections result in perfect patient compliance and eliminate the possibility of “forgetting” to take a pill each day.  Think of Abilify Maintena as an improved modality of administration for certain patients.

The drug Rozerem was approved in 2005 for the treatment of insomnia, and as of 2014 was in Phase III clinical trials as an adjunct for Bipolar disorder (type 1).  However, it is unclear as to whether it was discontinued from clinical trials or is still under investigation.  Rozerem demonstrated significant preliminary efficacy as an adjunct, likely due to its ability to regulate circadian rhythms via selective action on the MT1 & MT2 receptors.

How could medications for bipolar disorder be improved? (Future Possibilities)

Medications for the treatment of bipolar disorder are far from perfect.  Users of these medications often experience unwanted side effects and adverse reactions including: weight changes, drowsiness, weakness, fatigue, thyroid dysfunction, excessive thirst, concentration difficulties, and memory impairment.  Medications in the future should attempt to minimize many of the aforementioned side effects while still delivering therapeutic benefit.

In addition, new medications should aim to minimize likelihood of deleterious long-term effects such as toxicity.  For example, those taking lithium at standard doses for a long-term may experience: neurotoxicity, skin rashes, kidney problems, thyroid abnormalities, and metabolic alterations.  Attempting to minimize the adverse long-term effects associated with mood stabilizers and antipsychotics is necessary.

Perhaps the easiest way to improve existing medications is to develop long-acting injectable formats of all bipolar medications.  Long-acting injectable formats prevent non-compliance from patients and provide extended symptomatic relief (between 2 to 4 weeks) without needing to take a daily pill.  It is possible that pharmaceutical companies can improve upon injectable drugs and test novel modalities of administration such as intranasal sprays, direct brain injections, and/or make use of nanotechnology to enhance delivery.

Finally, pharmaceutical developers may want to consider the fact that there are few FDA-approved medications for the treatment of both bipolar mania and bipolar depression.  Currently the only agents approved to treat both mania and depression include: Seroquel (Quetiapine) and Zyprexa (Olanzapine).  Engineering polypharmacological agents that are able to simultaneously prevent manic highs and depressive lows would be beneficial for patients – as many dislike taking multiple agents.

Devising new polypharmacological medications for bipolar disorder

Due to the fact that there are only a few bipolar medications in the pipeline, (and really only one “novel” drug with promise), there is an increasing need for new, more targeted treatments.  These days, most psychiatric drug developers have resorted to concentrating efforts on antipsychotic development, hoping that the mechanisms of their latest antipsychotic will have carryover for treating bipolar disorder.  Although many antipsychotics successfully treat bipolar disorder, they cannot be considered targeted treatments.

Devising a targeted treatment that effectively prevents mania and depression – with non-antipsychotic properties is more challenging, but warrants consideration.  It should be speculated that as neuroimaging techniques continue to improve and genetic underpinnings of bipolar disorder are elucidated – more targeted, non-antipsychotic treatments can be developed.  Until these discoveries are made, we can expect more slightly tweaked and possibly improved versions of older antipsychotics and mood stabilizers.

Which new medications for bipolar disorder are you most excited about?

Assuming you have bipolar disorder or know someone with bipolar disorder, mention which new medications you are most excited about in the comments section below.  Share whether you think any of the medications in development will offer any distinct advantages over currently available options.  Also discuss whether you’d prefer an intramuscular injection of a medication (with an effect spanning between 2 to 4 weeks) or take a daily pill.

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