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A psychiatric nurse practitioner shares gaps in care in bipolar 1 disorder treatment.

Unmet Needs in Bipolar Disorder Management

A psychiatric mental health nurse practitioner shares her approach to treating bipolar 1 disorder and considers the role of comorbidities in shaping treatment selection for patients.

Pharmacological Treatment Considerations for Bipolar Disorder

Bethanie Simmons-Becil, DNP, MSN, APRN, PMHNP-BC, APHN-BC, highlights the importance of patient communication and education when treating bipolar 1 disorder.

Role of Patient Education for Bipolar 1 Disorder Treatment

Bethanie Simmons-Becil, DNP, MSN, APRN, PMHNP-BC, APHN-BC, presents the case of a 75-year-old female with bipolar 1 disorder and discusses challenges in bipolar disorder treatment.

Patient Case: 75-Year-Old Female With Bipolar 1 Disorder

frequently receive polypharmacy, with up to 20% of patients getting 4 or more bipolar medications.

 Problematic drug-drug interactions occur often, impacting effectiveness or safety. They can be pharmacokinetic or pharmacodynamic. Yet these interactions receive little attention in the various practice guidelines and algorithms for the psychopharmacologic management of bipolar disorder. Some of these will be summarized here and in a subsequent article.

—especially olanzapine, quetiapine, and clozapine—can cause even more weight gain when added to valproate.

Lithium is well known to interfere with the synthesis and release of 

 hormones and, in the brain’s effort to compensate for this, thyroid-stimulating hormone will increase. Periodic monitoring is required. What is not so well known is that carbamazepine (CBZ) decreases T4, possibly by induction of the UGT metabolizing enzyme, which exacerbates or hastens the onset of hypothyroidism.

 Thus, the combination of lithium and CBZ may present additive risks. Quetiapine also has some evidence of causing thyroid dysfunction.1

Lithium and anticonvulsants—especially valproate and CBZ—produce a metabolic-type or action tremor (ie, it is worse when doing an action like extending the arms—similar to benign familial essential tremors and tremors associated with hyperthyroidism, electrolyte abnormalities, and alcohol intoxication and withdrawal). When these medicines are used in combination, the severity or likelihood of tremor increases.

Antipsychotics—especially the older neuroleptics and risperidone/paliperidone—produce 

 (resting tremors—slower than metabolic tremors, rhythmic, typically 4 to 6 beats per second).

 Lithium seems to increase antipsychotic-induced Parkinsonian tremors by a not-well-understood mechanism.

Antipsychotics that raise prolactin (eg, risperidone, paliperidone, and most first-generation antipsychotics) increase osteoporosis risk through a pharmacodynamic effect. For this reason and others, guidelines now recommend routine monitoring of 

 Selective serotonin reuptake inhibitors (SSRIs), which are usually not recommended in bipolar patients but often used, also increase osteopenia by a different mechanism involving serotonin. With use of both agents, one can expect an additive harmful effect on bone metabolism.

CBZ also causes osteoporosis through its effect to induce the metabolism of vitamin D. Thus, the combination of CBZ with the prolactin-inducing antipsychotics or with SSRIs, or all three in combination, may produce additive bone harms over the long term.

 But here’s some good news: Lithium may protect from osteoporosis. The use of lithium in combination with antipsychotics and/or SSRIs could reduce the risk associated with the other agents. Better still: Use lithium alone for your patients with bipolar disorder if you can.

Watch out for drug-drug interactions with combinations involving ziprasidone, haloperidol, citalopram, escitalopram, quetiapine, risperidone, and lithium.

is associate professor of psychiatry at Harvard Medical School and codirector, US Department of Veterans Affairs, National Bipolar Disorder Telehealth Program, in Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

Possible pharmacodynamic and pharmacokinetic drug-drug interactions that are likely to be clinically relevant and/or frequent in bipolar disorder.

2. Osser DN. Neuroleptic induced pseudoparkinsonism. In: Joseph AB, Young RR, eds. 

Movement Disorders in Neurology and Neuropsychiatry, 2nd Edition

Prolactin monitoring in first-episode psychotic patients.

4. Hindley G, Gall N. QT interval prolongation. In: Taylor DM, Gaughran F, Pillinger T, eds. 

The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Up to 20% of patients with bipolar disorder have 4 or more medications, so it is important to be aware of these common drug-drug interactions.

Drug-Drug Interactions in Patients with Bipolar Disorder

 I really enjoyed the roundtable discussion. I really enjoyed how thorough everybody was. There were a lot of questions about “Well, how did you make the diagnosis of bipolar I? Give me more details about the mania. Flesh out the case for me.” I would not want to give someone a diagnosis of bipolar I, which is a lifelong disorder, without knowing exactly what they've been through, and I thought that was nice. People talked about dilution of care and how quick encounters where patients are not given the time that they need is not a good thing, and I agree. People also talked about how important it is to educate patients and work with them and establish that nice rapport that makes you know your doctor is on your side. Your doctor is really trying to get you to be functional and happy. I also thought it was interesting that you have people who are willing to start with atypical second-generation antipsychotics and people who are willing to start with lithium, and I'd say the room was evenly split. That probably indicates that the trends in treatment of bipolar disorder are changing throughout our country.

Dr Moukaddam discusses key takeaways for the management of bipolar disorder.

Takeaways for Bipolar Disorder Management

 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.

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

Treatment Selection for Bipolar Disorder

 The art of psychiatry is making sure to look at the patient holistically and having a comprehensive history that then links to treatment, because you don’t want to ignore important things such as their medical history, metabolic profile, constraints on their job, and family history. Let me go into some of these. If you think that the treatment that they would benefit from is a pill that’s given 3 times a day, but their work does not allow them to do that, then you would not want to proceed because the patient would not be adherent. Similarly, financial considerations are very important. If I think a particular pill would be fantastic for the patient, but they cannot afford it for more than a month, then it would not be sustainable.

These would be your first considerations: Can they afford it, will it mesh with their schedule, and does it fit well with their medical profile? We have not talked about this patient’s medical history but somebody who has obesity, diabetes, or other conditions could not potentially take an agent that causes weight gain. Because even though the agent could be beneficial for psychiatric symptoms, the weight gain would be unacceptable and make the other conditions worse. Those are huge considerations: the metabolic profile and medical history. As mentioned in the case, this patient developed hyperthyroidism, so that’s one of the things we consider with lithium, especially long-term treatment.

The one other thing you discuss with the patient, which is really important, is that bipolar disorder doesn’t typically go away. You will have to be on medications for an extended period of time, perhaps for the rest of your life, so we really want to find a medication regimen that is comfortable for you. When I say treatment, treatment is not only medications. We have to consider whether there’s any therapy that could work. Psychotherapeutic modalities are extremely effective for certain things, especially for rhythm therapy and making sure people know how to manage their sleep and energy and how to catch symptoms before they start. Psychoeducation is your first step. You can do that in office, but therapy is often missed or underused, and I think that would be important for anybody making a treatment plan.

Dr Moukaddam shares factors to consider when approaching the treatment of bipolar disorder.

Approaching the Treatment of Bipolar Disorder

 Today, we’re going to talk about a new case. A 30-year-old man has taken short-term disability leave from work due to the progression of a depressive episode. He received a diagnosis of bipolar I disorder about 10 years ago. He had his first episode of mania at the age of 20 and 2 subsequent episodes of mania between the ages of 21 and 29. He was treated with lithium, which was highly effective, but he experienced excessive thirst and developed hyperthyroidism. His lithium level at the time was in the therapeutic range of 0.8 mEq/L. He was switched to valproate; however, valproate lacked the efficacy of lithium and caused adverse effects of sedation and weight gain. During his third manic episode, he started on olanzapine but experienced excessive weight gain. He was then cross-titrated to quetiapine, which improved his manic symptoms. However, weight gain again became an adverse effect, and he also complained of sedation. The patient reported sleeplessness and made unnecessary online purchases when unable to sleep, but the quetiapine sleepiness was unacceptable. Despite these adverse effects, he continued taking] quetiapine until he decompensated into his third depressive episode. The quetiapine was then augmented with lamotrigine, which was titrated up to 300 mg per day but demonstrated no efficacy. At the time of presentation, the patient was adhering to the medications. He did not have a substance use disorder, which was confirmed by a negative toxicology screen. His TSH [thyroid-stimulating hormone] level was in the middle of the normal range, and he had no suicidal ideations or psychotic symptoms.

I think the most important thing to do when somebody comes to you, even if they tell you they have a diagnosis, is to confirm the diagnosis. You want to start by making up your own mind, and sometimes the patient is not a good source of information. But in the case of bipolar disorder without psychosis, you expect the patient to be able to give you a solid history. Typically, the part of the history that’s hardest to nail down is mania. When people experience mania, they have excessive energy and excessive activation that creates the need for sleep, and sometimes they like it. They feel that this is the way it should be, so they don’t point it out as pathological. Now, the 

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

] criteria tell us that mania that leads to hospitalization or some negative consequence like incarceration is problematic no matter what the duration is. Assuming the patient did not end up in the hospital or in prison, we want to verify the story of mania. In the current case presentation, I can see many of my colleagues saying, “Hey, you’re not giving us enough symptoms of mania. He’s a bit sleepless. He makes frivolous purchases. That’s bipolar disorder but not bipolar I; maybe it’s bipolar II.”

Thus, my first step would be to explain that this patient had at least a week without sleep. During that week, he was spacing, had pressured speech, and was talking fast to the point that others around him commented about it. He became more impulsive, and buying things was the tip of the iceberg. He also became more sexual to the point where it got him in trouble in his relationships, he spent more money than he had planned, etc. These examples of impulsivity often nail down the diagnosis of bipolar disorder. Of course, these symptoms change with the time that we live in. For example, before unlimited plans on cell phones, you would have been taught to ask: “Do you get a very high bill on your phone when you’re manic?” Because patients with mania talk a lot, and the bills would be higher when they call across state lines or internationally. First, I would recommend verifying the diagnosis. My impression of the patient is that this is somebody with a set diagnosis of bipolar I. Three manic episodes is a lot. He has impairment because of it, and it’s affected his job. Thus, my first step is confirming the diagnosis. My second would be a lot of psychoeducation; make sure that the patient understands what he’s up against and why he needs treatment.

Nidal Moukaddam, MD, PhD, presents the case of a 30-year-old male diagnosed with bipolar 1 disorder and shares her initial impressions on diagnosis.

Patient Case: 30-Year-Old Male With Bipolar Disorder

Patients need to be educated frequently about what can increase or decrease their lithium levels, leading to either toxicity or loss of effectiveness. Prescribers need to be reminded as well.

The following are some common circumstances that can increase lithium levels (instruct patients to inform you of any symptoms and get extra levels in these situations):

Dehydration (eg, from vomiting or diarrhea, as may occur in acute gastroenteritis)

Reduced renal filtration rate (eg, in glomerulonephritis and diabetic nephropathy; also age related)

Thiazide diuretics (eg, hydrochlorothiazide) can produce increases from 25% to 400% (very unpredictable).

Nonsteroidal anti-inflammatory drugs (NSAIDs; eg, ibuprofen, naproxen, meloxicam) and probably COX-2 inhibitors (eg, celecoxib, diclofenac) can increase levels 10% to 400% over the course of days to months.

Angiotensin-converting enzyme (ACE) inhibitors (eg, lisinopril, enalapril) can induce up to a 400% increase over several weeks.

Angiotensin II inhibitors (eg, losartan, valsartan) probably prompt similar effects to ACE inhibitors.

The following can decrease lithium levels:

Mania may cause levels to go down 50% despite confirmed adherence.

 The mechanism is unclear, but it might be that lithium goes into the intracellular compartment during mania. If you increase dose to improve the plasma level, toxicity symptoms can appear—or they may appear after the mania remits and the lithium returns to the extracellular space.

Caffeine may promote renal excretion of lithium.

The following have little effect on lithium levels

Amiloride is a potassium-sparing diuretic and sometimes does raise levels (need to monitor).

Sulindac is an NSAID that may or may not raise levels (need to monitor).

 we discussed the importance of keeping maintenance lithium levels in the range of 0.6 to 0.8 mEq/L as well as avoiding even brief occurrences of levels more than 1.0 to minimize the risk of long-term kidney impairment.

During meetings with patients, it is important to give frequent reminders of the aforementioned factors that affect levels so that patients will be more likely to call and inform prescribers and to have lithium levels drawn when necessary. Temporary adjustment of doses while waiting for levels (or if it is impossible to get levels) may be advised in some cases.

is associate professor of psychiatry at Harvard Medical School and codirector, US Department of Veterans Affairs, National Bipolar Disorder Telehealth Program, in Brockton, Massachusetts. He is also an Editorial Board member for 

. The author reports no conflicts of interest concerning the subject matter of this article.

The Maudsley Prescribing Guidelines in Psychiatry, 14th Edition

Mood-dependent changes of serum lithium concentration in a rapid cycling patient maintained on stable doses of lithium carbonate

3. Mester R, Toren P, Mizrachi I, et al. 

Caffeine withdrawal increases lithium blood levels

4. Ciraulo DA, Shader RI, Greenblatt DJ, Creelman W. 

. Lippincott Williams & Wilkins; 2006:272-275.

Tips for lithium dosing for optimal renal safety

Here are a few reminders to help avoid both toxicity and loss of effectiveness.

Bipolar I Disorder