I often see patients who have trialed and failed multiple SSRIs and SNRIs, with the complaint these medications worked at first but lost efficacy over time. I will hear things such as they noticed significant improvement in their mood in the first few months, later resulting in increased anxiety and worsening depressive symptoms. Through careful interviewing and the utilization of screening instruments such as the Mood Disorder Questionnaire, I frequently learn the patient is not suffering from major depressive disorder, but bipolar disorder. The unfortunate reality is sometimes patients can be stuck in this cycle for years, before receiving a bipolar diagnosis and a treatment plan that adequately addresses their complaints.
A diagnosis of bipolar disorder can be difficult to make, especially in a setting of concurrent substance use (including alcohol and marijuana), underlying personality disorders such as borderline personality disorder, or a neurodevelopmental disorder such as attention-deficit hyperactivity disorder. It is the job of a clinician to carefully evaluate the patient to discern the clinical picture so an accurate diagnosis is made because the treatment is different. In fact, if bipolar disorder is treated like major depressive disorder, it can worsen symptoms of depression and anxiety. SSRIs like Zoloft or Lexapro inhibit the reuptake of serotonin to relieve depressive symptoms. The risk of increasing serotonin levels in an individual suffering from bipolar disorder is that doing so can disrupt the neurochemical balance, potentially triggering rapid mood cycling by destabilizing emotional regulation.
This is why the patient will come in and describe “really high highs” and “really low lows.” The SSRI will initially help to relieve depressive symptoms, but if followed over time, I find the medication has helped to relieve a depressive episode, only to have pushed the mood too far in the other direction (hypomania or mania), resulting in worsening depressive episodes. I like to explain this as, “what goes up, must come down” and it becomes like a yo-yo of the patient’s mood.
When I determine a patient is suffering from bipolar depression as opposed to unipolar depression, I start by initiating a mood stabilizer such as Lamictal. Mood stabilizers are imperative in treating bipolar disorder but often require slow dose titration, meaning it can be several weeks before a therapeutic dose can be achieved. Furthermore, while Lamictal has FDA approval for bipolar depression maintenance, it does not carry the approval for acute bipolar depression.
In such cases, I will turn to Latuda (lurasidone). Latuda is FDA approved for acute bipolar depression, making it first line for this purpose.
Latuda is a second-generation antipsychotic that acts as a serotonin 5HT2A and 5HT7 receptor antagonist and a partial agonist at 5HT1A. The medication can treat depression in a bipolar patient without destabilizing emotional regulation and causing rapid cycling.
Below are some interesting points to consider:
Latuda is an antagonist at D2 and 5HT2A at moderately high amounts, which gives it antipsychotic actions. This is what is responsible for treating symptoms such as agitation, disorganized thinking, hallucinations, delusions, paranoia and in some cases, mania.
Latuda has a high affinity for the D4 and 5HT7 receptors, which are linked to cognition and memory, particularly 5HT7 (a receptor linked to Alzheimer’s). When I think of a medication that is a strong antagonist at 5HT7, I think of Trintellix (vortioxetine). Trintellix is a medication used to treat depression and specifically advertised for its ability to improve cognition in depression. This is why Latuda is implicated as an agent that can improve cognition in depression.
I cannot tell you how many times a patient has presented, convinced they have undiagnosed ADHD, citing cognitive symptoms such as frequent forgetfulness or inability to concentrate, when they are severely depressed. I always explain I treat mood before cognition because of the diagnostic overlap between bipolar disorder and ADHD. While it is entirely possible for a patient to have both bipolar disorder and ADHD, most of the time, cognitive symptoms will abate with proper treatment of mood symptoms.
Latuda’s partial agonist activity at 5HT1A is responsible for its anxiolytic properties. This action is similar to what is seen in medications such as Abilify (aripiprazole) and Buspar (buspirone). Anxiety is highly comorbid with depression, with patients reporting feeling on edge or “keyed up” and an inability to relax. I will explain to the patient that Latuda can help to alleviate these symptoms due to this mechanism.
To this point we understand Latuda is a viable option to treat depression in bipolar disorder, but what about side effects? I, like most psychopharmacologists, am a nerd when it comes to pharmacodynamics and pharmacokinetics, but patients (understandably) do not care. They want to know, what side effects is this drug going to cause me?
Side effects and what the drug looks like in “real life” is always my top priority because it is the top priority of the patient. If a medication causes bothersome side effects, the patient is not going to continue taking it and everyone is wasting their time. Every drug has side effects and a clear risk versus benefit analysis must take place with every encounter.
Points to consider with regard to side effects:
I have found and the research has affirmed, Latuda is one of the best tolerated medications of its class. It has a favorable metabolic profile, with less risk of weight gain. Weight gain is one side effect patients are extremely concerned about and rightly so. Not only does weight gain cause issues with a patient’s self-esteem and body image, it poses significant health risks. I always tell patients I cannot ignore physical health to treat mental health. We must take a holistic approach, ensuring we consider all parts of the human body.
Lack of weight gain is one of the biggest positives to Latuda. Even when compared to another second generation antipsychotic such as Abilify, which is also known to have a favorable metabolic profile, the risk from Latuda is minimal.
Latuda has minimal risk of inducing cardiac arrhythmias through QT prolongation (the time it takes for the ventricles of the heart to depolarize and repolarize). QT prolongation risk is common amongst many medications, especially in psychiatry. While it is rare for a medication to induce a life-threatening arrhythmia (torsades de pointes/polymorphic ventricular tachycardia) it should always be a consideration.
While the FDA has done away with their pregnancy risk categories, Latuda is one of two second-generation antipsychotics that is class B in pregnancy (the other being clozapine). Class B drugs in pregnancy have shown no evidence of risk in animal studies but lack well-controlled studies in pregnant women, or animal studies showed risk not confirmed in humans. While the patient may not be pregnant when they are seen, it is something that should always be considered in a woman of child bearing age.
With Latuda, akathisia (a feeling of needing to move or restlessness, or as I like to think of it, “ants in your pants”) is less common than other antipsychotics when dosed once a day at night.
Latuda is effective and has a favorable side effect profile, what else should be considered? Some other points:
Latuda is known to cause sedation (due to antagonism at 5HT2A and alpha-1 adrenergic receptors), so it should be dosed in the evening. However, it has minimal activity at histamine H1 receptors, making it less sedating than many antipsychotics.
Latuda should be taken with food, so I instruct patients to take with an evening meal or dinner. A minimum of 350 calories is needed for Latuda to absorb due to its low solubility and high lipophilicity (it dissolves better and is more effectively absorbed in the presence of fat and food). Some clinicians use the nickname “Lafooda.”
Latuda is metabolized by CYP3A4. This means a CYP3A4 inducer, such as Tegretol (carbamazepine), can lower Latuda levels to subtherapeutic. Think of inducers as agents that push down on the gas peddle, causing rapid metabolism at the enzyme. On the other hand, CYP3A4 inhibitors, such as Ketoconazole or macrolide antibiotics, like erythromycin and clarithromycin, may increase Latuda levels. Think of inhibitors as agents that push down on the brake, stopping metabolism at the enzyme.
Latuda is dosed from 20 mg per day to 80 mg per day for bipolar depression. The maximum dose is 160 mg per day for schizophrenia but rarely used. Evidence is lacking in the treatment of depression at higher doses. I usually start at 20 mg per day and go slow to cut down on nausea (most drugs can cause nausea, especially in the beginning and if taken on an empty stomach).
Latuda has impressive data for depression with mixed features (or “soft” manic features). When I talk about mixed features in depression, I am thinking about the four As, including agitation, anger, anxiety, and attention problems. As of this writing, Latuda does not carry an FDA indication for MDD with mixed features but it could gain it in the future, especially since it is now generic.
Latuda lacks evidence for the treatment of acute mania and for bipolar maintenance. Again, I prefer a mood stabilizer for bipolar maintenance. Consider Latuda a “weak” second-generation antipsychotic for schizophrenia and may not work at all in bipolar mania or for maintenance. There are better options for these conditions, which I will discuss in a future post.
All and all, Latuda is a medication I use a lot in practice for the treatment of bipolar depression. If you are a prescriber, I hope you found this information helpful. If you are concerned you may have bipolar depression, reach out to your provider to discuss treatment options.
This post was written by Richard Gray, PMHNP-BC. The above information is for educational/entertainment purposes and is not intended to be treated as medical advice. If you have questions about a medication you are taking, discuss these questions with your medical provider.