Cariprazine in the Treatment of Bipolar Disorder: Within and Beyond Clinical Trials

Do, A., Keramatian, K., Schaffer, A., & Yatham, L. (2021). Cariprazine in the Treatment of Bipolar Disorder: Within and Beyond Clinical Trials. Frontiers in psychiatry, 12, 769897. https://doi.org/10.3389/fpsyt.2021.769897

Hello everyone, and welcome back to another (slightly overdue!) journal club. It has definitely been longer than a month since the last one, so my apologies. Life happens, but we’re back on track now.

Today I’m talking about an article called “Cariprazine in the treatment of bipolar disorder within and beyond clinical trials”, published in 2021 in the journal Frontiers in Psychiatry. This journal often features newer, more experimental research and is generally well regarded in the psychiatric community.

The authors are psychiatrists from across Canada, from Vancouver to Toronto – a very beautiful part of the world. Before we dive into the content, it’s important to note some potential conflicts of interest. One author has a fellowship funded by Janssen (a pharmaceutical company). Another has been on speaker and advisory boards and received research grants from several drug companies, and a third has similar links. That doesn’t automatically make the paper “bad”, but it does mean we should keep in mind that the article may lean a little in favour of medication-based (biological) treatments and their effectiveness.

For me, that means when I read this review, I assume it is going to focus heavily on medications rather than on psychological, social, or lifestyle approaches—which are also very important in bipolar disorder.

The article starts by describing bipolar disorder as a chronic (long-term) and recurrent (coming in episodes) mental illness that can cause major difficulties in work, relationships, and daily life. The authors say that the “mainstay” of treatment is medication. I partly disagree here. In my view, medications are often necessary, but behavioural strategies, psychological therapies, lifestyle changes (sleep, routines, substances, stress), and environmental supports are just as important for long-term recovery and quality of life.

The authors also say that even though medications have improved, many people—especially those with bipolar depression—do not reach full remission (meaning symptoms don’t fully settle). I think that’s a bit too pessimistic. I see many people who do achieve significant remission and live rich, meaningful lives. At the same time, I agree that bipolar depression can be particularly tricky to treat, and not everyone responds to the first or even second medication. The article also reminds us that many medications, especially second-generation antipsychotics, can cause side effects that limit their usefulness.

The main goal of this paper is to review how cariprazine works in the body, how effective it is, and how well people tolerate it (in other words, what the side effects are like).

To understand cariprazine, we first need to talk about dopamine. Dopamine is a fascinating brain chemical. It was discovered in 1910, but its role as a neurotransmitter (a chemical messenger between brain cells) was only understood in 1958—work that won a Nobel Prize. Dopamine is made from an amino acid called tyrosine, which we get from protein foods such as fish, poultry, eggs, and bacon. In the body, tyrosine is converted into L-dopa, and then into dopamine by specific enzymes. Dopamine is then broken down into other chemicals by more enzymes. The point here isn’t to memorise the chemistry, but to know that dopamine is a key messenger that can be increased or decreased by different medications.

There are at least five known dopamine receptors in the brain—D1, D2, D3, D4, and D5. Think of these as slightly different “locks” that dopamine can fit into. In simple terms, D1 and D5 receptors tend to increase the activity of certain brain cells, while D2, D3, and D4 tend to decrease it, although in real life it’s a bit more complex.

Dopamine also travels along several important pathways in the brain:

• The mesocortical pathway goes to the frontal lobes, important for motivation, planning, and emotional regulation.

• The mesolimbic pathway is involved in reward, pleasure, and reinforcement.

• The nigrostriatal pathway is involved in movement, and this is where some antipsychotic medications can cause movement-related side effects.

• The tuberoinfundibular pathway links to the pituitary gland, and changes here can affect hormones such as prolactin (sometimes causing menstrual changes, breast changes, or sexual side effects).

Cariprazine is part of a chemical family called piperazines. Piperazine itself is just a chemical structure, but it’s been used in a range of medications, including some antibiotics, sildenafil (used for erectile dysfunction), and several psychiatric medications. Another antipsychotic medication, ziprasidone, is also a piperazine derivative.

Cariprazine acts as a partial agonist at the D2 and D3 dopamine receptors. That means it doesn’t fully switch these receptors “on” or “off” but rather fine-tunes them—sometimes turning down overactivity and sometimes boosting underactivity, depending on what the brain is doing. Cariprazine has a stronger preference for the D3 receptor than many other medications, and researchers think this may be part of why it could be helpful for mood and possibly cognitive (thinking) symptoms.

Cariprazine has already been shown to work in schizophrenia, and in some countries it is approved by the FDA for bipolar disorder, including bipolar depression. The 2018 Canadian guidelines list cariprazine as a second-line option for bipolar I depression, meaning it is not usually the first thing we try, but it is considered a reasonable choice after more established options. At the time of this article, there was less evidence to support its use as a long-term maintenance treatment in bipolar I (i.e. staying on it to prevent future episodes over many years).

The article then goes into how cariprazine behaves in the body—how it’s absorbed, how long it lasts, and how it is broken down (this overlaps with what doctors call pharmacokinetics and pharmacodynamics). They suggest that cariprazine may cause fewer movement-related side effects than some older antipsychotic medications, because of how strongly (or weakly) it acts in certain dopamine pathways.

The authors also suggest that cariprazine might have some cognitive-enhancing effects, particularly in people with schizophrenia, because of its action on D3 receptors in brain areas involved in thinking and memory. I think this is an interesting idea, but at this stage it feels a bit optimistic. The evidence is still developing.

In fact, I found the technical section of the paper slightly unsatisfying. It is too simplified to be truly rigorous scientifically, but still too technical for most lay readers. Some of the claims—such as the idea that cariprazine might have “anti-abuse” potential in substance use disorders—seem to be based mostly on early animal studies and theoretical models, not solid evidence from real-world patients. As we know, addictions involve complex psychological, social, and environmental factors—not just a single chemical imbalance.

Cariprazine also affects some serotonin receptors, though we still don’t fully understand what this means in practice. It has a relatively weak effect on histamine receptors, which is interesting because strong histamine effects can be linked to sedation and weight gain in other antipsychotics.

One practical point that really matters for patients is the half-life of the medication. Cariprazine has a half-life of about 2–4 days, and its active breakdown products can stay in the system for one to three weeks. In plain English, this means that the medication and its metabolites build up slowly in the body. Even if we don’t change the daily dose, the total effect can continue to rise over several weeks. As a result, it can take quite some time before people feel the full benefit—or before side effects fully settle into a steady pattern. That can be frustrating, but it can also be reassuring to know that delayed improvements are possible.

The authors reviewed clinical trials and “post-hoc” analyses (studies done after the initial trials, often using existing data in new ways). They identified three randomised controlled trials (RCTs) looking at cariprazine for mania in bipolar disorder, and four RCTs looking at its use in bipolar depression. RCTs are considered one of the strongest types of study because people are randomly assigned to either the medication or a placebo (an inactive “dummy” pill).

In terms of safety and tolerability, the authors conclude that cariprazine is generally safe and reasonably well tolerated. However, they use slightly soft language when they describe “treatment-emergent adverse events”—which is essentially a more technical way of saying “side effects that appeared during treatment”. I do wonder if that wording makes things sound gentler than patients actually experience them.

They describe most side effects as “mild to moderate”. That may be true from a research perspective, but it is important to remember that even a so-called “mild” side effect can be very distressing in day-to-day life. For example, akathisia—a sense of inner restlessness and an inability to sit still—is a common side effect with cariprazine. Even a “mild” level of akathisia can be incredibly uncomfortable and can significantly affect someone’s quality of life.

The paper acknowledges that people on cariprazine were more likely to stop the medication than those on placebo, and that akathisia was the most common reason. On the positive side, they report that cariprazine did not seem to cause significant weight gain or major changes in metabolic markers (such as blood sugar and cholesterol), which is an advantage compared with some other antipsychotic medications.

Interestingly, in the depression studies, the rate of side effects was more similar between the placebo and medication groups than in the mania studies, although akathisia still appeared as an issue. The authors mention that beta-blockers (a type of heart and blood pressure medication) can be used to help manage akathisia. What they do not mention is that beta-blockers themselves can sometimes worsen low mood in vulnerable people, which is a relevant concern if we’re treating bipolar depression.

The article also touches on more specific areas such as mixed episodes (where manic and depressive symptoms occur together), cognition and functioning, and how cariprazine might perform in these situations. They report a number needed to treat (NNT) of about 5–7. This means that for every 5 to 7 people given cariprazine, one additional person will reach remission compared with placebo. This NNT is similar for both mania and depression in bipolar disorder and is fairly typical for psychiatric medications—helpful for some, not a miracle cure.

The authors repeatedly state that cariprazine is “well tolerated”, but in my view they do not fully emphasise the impact of akathisia on everyday life, nor do they fully explore how often this leads to people stopping the medication.

They also note that, at the time of writing, there were no head-to-head trials directly comparing cariprazine with other antipsychotics in bipolar disorder. Despite this, they still suggest that cariprazine may have better tolerability than other medications. Without direct comparison trials, this is more of an educated guess than a hard fact.

Another interesting point is that the article leans on existing treatment guidelines as part of its argument, even though guidelines themselves are based on the same studies the article is discussing. It becomes a bit of a “chicken and egg” situation: studies inform guidelines, and then guidelines are used to support the importance of the studies.

In their conclusion, the authors say that cariprazine has good efficacy and safety for bipolar disorder, and they highlight possible “pro-cognitive” benefits. I would take a more balanced view. While the medication does appear effective for many people, the akathisia and other side effects are clinically significant and, in my opinion, deserve equal weight in the conclusion. For some patients, the side effects may overshadow any cognitive benefits.

Overall, I see this article as a scientifically grounded and useful review, but not a neutral one. The authors’ ties to pharmaceutical companies and the language choices throughout suggest a subtle positive bias towards cariprazine. As psychiatrists—and as patients and families—it’s important that we read such papers with a critical eye, ask what’s not being emphasised, and remember that no medication exists in a vacuum.

Finally, it’s worth noting what the article doesn’t cover: there is virtually no discussion of non-pharmacological interventions for bipolar disorder—things like psychotherapy, family support, sleep and routine stabilisation, substance use treatment, exercise, and social and vocational support. In real life, these are essential parts of care. A truly holistic approach to bipolar disorder combines medication (when needed) with psychological, social, and lifestyle strategies tailored to the person. Cariprazine may become one useful option in the toolbox, but it is not—and should not be seen as—the whole toolbox.