Bipolar disorder (BD) is challenging to diagnose due to its episodic and highly variable nature. People with BD often have a poor experience with commonly prescribed antidepressants and require different therapies. Pharmacogenetic testing can help establish the correct diagnosis and guide patients to more effective and better-tolerated treatments.

The initial BD symptoms can vary among individuals and may develop gradually. It often begins with depressive episodes characterized by persistent feelings of sadness, hopelessness, fatigue, insomnia, loss of interest, and difficulty concentrating. While individuals seek medical help when they feel unwell, during the hypomanic phase, they may experience feelings of elation, increased energy, a reduced need for sleep, racing thoughts and speech, impulsive behaviour, and sometimes poor judgment.

Three bipolar subtypes:

Bipolar I – manic episodes last one week or longer, alternating with depression.

Bipolar II – hypomania, a less elevated mood state than mania, which alternates with depression.

Cyclothymic – a milder form of BD with mood swings that lack extreme mania or depression.

Why is it hard to diagnose bipolar disorder?

Depressive and manic episodes often alternate, but their frequency and duration can vary significantly. As a result, doctors primarily see patients during depressive episodes rather than during hypomania. Since bipolar symptoms can change gradually, most primary care physicians do not monitor mood changes over time. An individual presenting with depression may not be asked about any history of mania or hypomania, potentially leading to treatment focused solely on depression. Consequently, the diagnosis often lags behind symptom onset by about 7 to 10 years.

Individuals experiencing irritable depression, repetitive negative thinking (anxious rumination), or those with personality disorders marked by mood instability may be misdiagnosed with bipolar disorder. Bipolar patients often report negative experiences with antidepressants, prompting them to seek alternative treatments for burdensome symptoms such as insomnia, anxiety, and depression. However, these symptomatic medications fail to be effective without a proper diagnosis and an appropriate treatment strategy.

Furthermore, BP screening tools, such as the Mood Disorder Questionnaire (MDQ), are frequently used by primary care physicians. This self-administered questionnaire inquires about manic and hypomanic symptoms, as well as the family history of bipolar disorder or “manic-depressive illness.” The Rapid Mood Screener may also help assess whether patients with depressive symptoms require further evaluation for BD. However, the guidelines from the Canadian Network for Mood and Anxiety Treatments (CANMAT) and the International Society for Bipolar Disorders (ISBD) note that BD screening tools, including the MDQ, “have poor sensitivity and specificity but, nevertheless, can help flag those individuals for whom a more detailed assessment is needed.” Even the latest AI model shows only 10-16% sensitivity in identifying suspected bipolar cases in electronic medical records.

Bipolar medication list: Which medications are the most effective?

As described above, people presenting with symptoms of depression are most likely to be prescribed an antidepressant. However, SSRIs affect the serotonin pathway, and bipolar patients often experience bad side effects even after taking just one or two pills. In fact, CANMAT guidelines recommend against using SSRIs for patients with a history of antidepressant‐induced mania or hypomania, current or predominant mixed features, or recent rapid cycling. There are many SSRIs, and they are equally ineffective when taken alone.

Bipolar disorder therapy may require a combination of different drug types:

Mood stabilizers – Lithium is often considered the gold standard for bipolar disorder, has been used for decades and is particularly effective for preventing manic episodes and reducing suicide risk.

Anticonvulsants – Originally developed to treat seizures, several are effective for bipolar disorder:

• Valproate (Depakote)
• Lamotrigine (Lamictal) – Particularly effective for bipolar depression
• Carbamazepine (Tegretol)
• Oxcarbazepine (Trileptal)

Atypical antipsychotics – These medications can act as mood stabilizers:

• Quetiapine (Seroquel)
• Olanzapine (Zyprexa)
• Risperidone (Risperdal)
• Aripiprazole (Abilify)
• Lurasidone (Latuda) approved specifically for bipolar depression

Lithium is the oldest mood-stabilizing drug used to treat bipolar disorder. It is the best tolerated, but the stigma associated with lithium as an “old” and “psychiatric” medication puts some people off.

Lamotrigine is also recommended as first-line therapy. The most common complaints from patients regarding lamotrigine are cognitive side effects such as sedation and dulling.

Atypical antipsychotics, such as cariprazine, lumateperone, lurasidone, olanzapine-fluoxetine combination, and quetiapine, have been approved for the treatment of acute bipolar disorder. Risperidone, olanzapine and aripiprazole can be effective for managing acute mania in children and adolescents. However, some antipsychotics, like aripiprazole and mifepristone, are not recommended as the first line of therapy due to poor tolerability in individuals with altered drug metabolism.

How does genetic testing for medication response help select bipolar treatment?

The tolerability and risk of adverse events can be assessed through DNA testing. Liver enzymes are essential for the metabolism and removal of toxins and medications. Genetic variations in these enzymes can influence the blood levels of certain medications, along with their tolerability and effectiveness. Depending on your inherited drug metabolism profile, you may tolerate some medications while experiencing significant side effects from others.

Severe skin toxicity, known as Stevens–Johnson syndrome (SJS), is a rare but potentially fatal complication that occurs in some individuals taking anticonvulsants, including lamotrigine and valproic acid. Nearly all SJS cases present within the first two to eight weeks of starting the medication. The risk of SJS and other skin toxicities is associated with specific Human Leukocyte Antigen (HLA) types that are crucial for the immune system’s ability to distinguish “self” from “non-self.” Some of the high-risk HLA-B alleles are more prevalent in the Asian population. HLA testing is recommended before starting anticonvulsants to lower the risk of severe, potentially fatal toxicity.

Bipolar medication list and drug metabolism

Why should a pharmacist review my medications and pharmacogenetic test results?

DNA testing for drug response, known as pharmacogenetic testing, can provide valuable insights. However, various factors such as medications, foods, smoking, and more can further influence your drug metabolism. For example, oral contraceptives, pregnancy, and hormone replacement therapy may significantly lower lamotrigine levels in the bloodstream, necessitating dosage adjustments throughout different stages of a woman’s life. Smoking, exposure to air pollutants, caffeine, and barbecued foods affect the activity of the CYP1A2 gene, requiring dosage adjustments for olanzapine, duloxetine, and other medications metabolized by this enzyme. To provide correct therapy recommendations, it is critical to interpret the PGx test results in the context of other drugs, smoking and diet to account for pertinent drug-gene-food interactions.

The Pillcheck pharmacogenetic testing service combines DNA testing with a medication review by a clinical pharmacist. Clinical pharmacists will evaluate your medication history, vitamins and supplements in the context of your inherited drug metabolic profile. For patients with an established diagnosis, a combination of an anticonvulsant along with SNRI or other drugs might be recommended based on symptoms and presentation. For people with suspected bipolar disorder, the pharmacist may suggest a diagnosis reassessment by an expert psychiatrist.

Non-drug Treatments

Many psychotherapies, including cognitive behavioural therapy, interpersonal therapy, and family-focused therapy, help support people with bipolar disorder. Personalizing psychotherapy for the patient’s condition and underlying social and demographic factors is essential to developing a comprehensive treatment plan.

Summary

• Many patients with bipolar conditions are undiagnosed and experience poor tolerability of commonly prescribed antidepressants.
• Primary care doctors struggle to establish correct diagnoses due to this condition’s episodic nature and the screening questionnaires’ low sensitivity.
• Lithium, anticonvulsants and atypical antipsychotics are most effective for treating bipolar disorder. However, stigma and significant side effects can affect a patient’s adherence to treatment.
• DNA testing for medication response can help to clarify whether poor antidepressant tolerability is related to altered drug metabolism or an alternative diagnosis.
• Pillcheck pharmacogenetic testing and medication review by expert pharmacists help physicians and patients select optimal therapy options.

Selected references

Kessing LV et al., Comparative responses to 17 different antidepressants in major depressive disorder: Results from a 2-year long-term nation-wide population-based study emulating a randomized trial Acta Psychiatr Scand. 2024 Feb 20. doi: 10.1111/acps.13673.

Yatham LN et al., Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder Bipolar Disord. 2018 Mar 14;20(2):97–170.

Vita G et al., Systematic Review and Network Meta-Analysis: Efficacy and Safety of Antipsychotics vs Antiepileptics or Lithium for Acute Mania in Children and Adolescents Journal of the American Academy of Child & Adolescent Psychiatry, Volume 64, Issue 2, 143 – 157.