Treatment Selection for Bipolar Disorder


Nidal Moukaddam, MD, PhD, provides insight on the evolving treatment landscape for bipolar disorder and optimizing therapies for disease management.

Nidal Moukaddam, MD, PhD: In the United States, medications would be approved by the FDA [Food and Drug Administration]. If you were in Europe, they’d be approved by the EMA [European Medicines Agency]. That’s the equivalent of the FDA here. The medications can be approved for the initial stage of bipolar disorder, which is mania. That would be acute treatment, but a medication could also have an approval for maintenance treatment. Obviously, one would want to initially go with treatments that have FDA approval. That being said, when a patient is very sick, sometimes you end up with some off-label prescribing, but that should not be your first step. The field has evolved a lot. As I’ve said, we have a lot of options now. You have your mood stabilizers: lithium, Depakote, carbamazepine, and lamotrigine. You also have your atypical antipsychotics and second-generation antipsychotics. Second-generation antipsychotics are a fascinating drug class because they take what the previous class of antipsychotics have done, which is dopamine agonism, and work on dopamine but not in the same way, not to the same extent, and not on the same receptors. Now, as a clinician I have a lot of choices. I can start with a mood stabilizer: lithium, as in the case of this young man. Or I could start with an atypical antipsychotic. Usually, what you’ll see is that patients don’t know. Thus, it is up to us, but we develop algorithms depending on where we’ve trained and how we’ve trained and the populations that we treat: very sick or not very sick.

Where do we go from here? Based on the metabolic profile of the patient, their family history, their medical history, and what I’m seeing right now, I would have to pick an agent that hopefully catches the symptomatology and controls it. First, we want it to be monotherapy. It’s always better to do monotherapy instead of 2 or 3 agents. People don’t like it when you give them 3 or 4 prescriptions because they feel that they’re broken; they feel that they’re really sick. Sometimes we need that, but ideally, monotherapy is what your patient will stay with. We’re thinking a little about dopamine, glutamate, and serotonin here, and it’s beyond the scope of this talk to talk about all the receptors. But with dopamine agonism, the older agents used to focus on the detour receptors. The newer agents would lean toward D3 receptor agonism, and instead of having full agonism or full antagonism, now we have partial agonism and partial receptor agonism, which is extremely precious because it gives you more nuanced effects. Some of the newer atypical ones will have partial agonism, and that’s helpful. Also, in this type of treatment, we really value the effect on serotonin receptors, and when the atypical and the second-generation antipsychotics first came out, it was a really big deal that they worked on 5HD2 and conversely on 5HD2C. 2A and 2C are the 2 serotonin receptors that are opposing in action, but activation of 5HD2C as in the case of olanzapine could trigger some of the weight gain.

Why do we care about serotonin? We care about serotonin because it modulates dopamine release. Dopamine is a big agent in bipolar disorder. It’s a neurotransmitter that causes a lot of these symptoms, and modulating dopamine is one of our goals. We do it via serotonin and glutamate, but because there are so many other receptor subtypes involved when we pick an agent, we want that agent to cover a wide variety of profiles. We want that profile to cover some dopamine, some serotonin. We would like to have some histaminergic agent to help with sleep but not too much, and we definitely don’t want a muscarinic agent because this is when you get your anticholinergic adverse effects.

One of the considerations we have not talked about, but it would change how you approach things, is age. You want to make sure the person knows that this is potentially a lifelong treatment and that if they are female and of childbearing age, this will change. They would have to use contraception, and if they get pregnant, then it could affect them. The treatment could affect the pregnancy, and bipolar I disorder could also affect the pregnancy, and the pregnancy in turn could affect the bipolar I symptomatology. Thus, with women, you want to caution them that the postpartum period would be a very high-risk period for depression, etc.

My approach to the treatment of patients who have failed multiple therapies is to make sure that I’m maximizing the use of psychosocial treatments, especially psychotherapy, and then to deviate from monotherapy to maybe adding other agents.

My first step would be to add psychotherapy. I would want to make sure that the patient really understands what’s going on and is maximizing the use of their own psychological resources. Then, I would go beyond monotherapy, and I would consider adding a second or perhaps a third agent. In the case of this young man, we have lamotrigine and quetiapine. I would consider 2 agents and then maybe consider an adjunct. Maybe this person needs a little bit of help for anxiety or for sleep, so I would like to combine psychosocial treatment with psychotherapy and then change agents. I would also talk to the patient about how realistic it is when we talk about mood control and adverse effects, and this is where the tough conversation of benefit outweighs risk comes in. If they have a 5-lb weight gain, could that be acceptable? If they tell me a 20-lb weight gain I would say, “No, that’s really too much.” But if it’s a small weight gain or if it’s an adverse effect that’s mild, could we then accept it if the medication gives us benefit? That conversation has to be very customized and very tailored to the patient’s presentation and it relies on your rapport with the patient. If you have a good rapport with the patient, usually you end up with a much better outcome when treating those conditions. There are other things we have not talked about; ECT, which is electroconvulsive therapy for mania, is there when somebody is really ill. There is hospitalization, but we’re assuming for the purposes of this case that this is outpatient.

Transcript Edited for Clarity

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