Selection of treatment for bipolar disorder

Nidal Moukaddam, MD, PhD: In the United States, the drugs would be approved by the FDA [Food and Drug Administration]. If you were in Europe they would be EMA approved [European Medicines Agency]. It’s the equivalent of the FDA here. Medications may be approved for the initial stage of bipolar disorder, which is mania. It would be an acute treatment, but a drug could also be approved for maintenance treatment. Obviously, one would first want to go with treatments that have FDA approval. That being said, when a patient is very sick, you sometimes end up with off-label prescriptions, but that shouldn’t be your first step. The field has evolved a lot. Like I 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 class of drugs because they take what the previous class of antipsychotics did, which is dopamine agonism, and act on dopamine but not in the same way, not in the same measure and not on the same receivers. 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 the patients don’t know it. So it’s up to us, but we develop algorithms based on where we trained and how we trained and the populations we treat: very sick or not very sick.

Where do we go from here? Based on the patient’s metabolic profile, family history, medical history, and what I’m seeing right now, I should choose an agent that hopefully catches the symptom and controls it. First, we want it to be monotherapy. It is always better to do monotherapy instead of 2 or 3 agents. People don’t like being given 3 or 4 prescriptions because they feel like they’re broken; they feel they are really sick. Sometimes we need it, but ideally monotherapy is what your patient will stay with. We’re thinking a bit about dopamine, glutamate, and serotonin here, and talking about all of the receptors is beyond the scope of this talk. But with dopamine agonism, older agents focused on deflection receptors. The new agents would lean towards D3 receptor agonism, and instead of having full agonism or full antagonism, we now have partial agonism and partial receptor agonism, which is extremely valuable because it gives you effects more nuanced. Some of the newer atypicals will have partial agonism, and that’s helpful. Also, in this type of treatment, we really value the effect on the serotonin receptors, and when the atypical and second generation antipsychotics came out, it was really huge that they act on 5HD2 and vice versa on 5HD2C . 2A and 2C are the 2 serotonin receptors that oppose each other in action, but the 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 major agent in bipolar disorder. It’s a neurotransmitter that causes a lot of these symptoms, and dopamine modulation is one of our goals. We do this via serotonin and glutamate, but since there are so many other receptor subtypes involved when we choose an agent, we want that agent to cover a wide variety of profiles. We want this profile to cover a little dopamine, a little serotonin. We would love to have a histaminergic agent to help with sleep, but not too much, and we certainly don’t want a muscarinic agent, because that’s when you get your anticholinergic side effects.

One of the considerations that we haven’t talked about, but that would change the way you approach things, is age. You want to make sure the person knows this is potentially a lifelong treatment and if she is a woman of childbearing age that will change. They should use contraception, and if they get pregnant, it could affect them. Treatment could affect pregnancy, and bipolar I disorder could also affect pregnancy, and pregnancy in turn could affect bipolar I symptomatology. So with women, you want to warn them that the postpartum period would be a period at very high risk of depression, etc.

My approach to treating patients who have failed multiple therapies is to ensure that I maximize the use of psychosocial treatments, particularly psychotherapy, and then move away from monotherapy to perhaps add other agents.

My first step would be to add psychotherapy. I would like to make sure that the patient really understands what is going on and maximizes the use of their own psychological resources. Then I would go beyond monotherapy and consider adding a second or maybe a third agent. In this young man’s case, we have lamotrigine and quetiapine. I would consider 2 agents and then maybe consider an assistant. Maybe this person needs a little help with anxiety or with sleep, so I would like to combine psychosocial treatment with psychotherapy and then change agents. I would also like to tell the patient how realistic it is when we talk about mood control and adverse effects, and this is where the difficult conversation about benefits outweighing risks comes in. If they have a 5 pound weight gain, could that be acceptable? If they told me a 20 pound weight gain, I would say, “No, that’s really too much.” But if it is a small weight gain or a mild side effect, can we then accept it if the drug brings us a benefit? This conversation should be very personalized and very tailored to the presentation of the patient and it is based on your relationship with the patient. If you have a good rapport with the patient, you generally get much better results when treating these conditions. There are other things we haven’t talked about; ECT, which is electroconvulsive therapy for mania, is there when someone is really sick. There is hospitalization, but we assume for the purposes of this case that it is an outpatient visit.

Transcript edited for clarity

Martin E. Berry