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Patient FileThe Case: The woman who was either manic or fat

The Question: Will patients be compliant with effective mood stabilizers that cause major weight gain?

The Dilemma: Can you find a mood stabilizer that does not cause weight gain or a medication that blocks the weight gain of the mood stabilizer?

Pretest Self Assessment Question(answer at the end of the case) Which of the following most accurately describes asenapine?

A. Has a high risk of metabolic side effects

B. Is available as a sublingual formulation

C. Works primarily as a very potent dopamine D3 receptor agonist

Patient Intake 32-year-old woman diagnosed with bipolar 1 disorder

Current chief complaint– Patient’s mania has been relatively stable for four months but she experienced 50 pounds of weight gain on olanzapine (Zyprexa) just before getting pregnant and is now 60 pounds overweight 2 months into her pregnancy– Uncertain about whether the weight gain is unsafe or if stopping her olanzapine would be unsafe

Psychiatric History She was diagnosed with bipolar disorder almost seven years ago

Since then has had fairly resistant and chronic mania with intermittent mixed or depressive states less commonly

No medication other than olanzapine seems effective for her mania, including many other antipsychotics, anticonvulsant mood stabilizers, and lithium

Unfortunately, she has incredible weight gain (at least 40 pounds) associated with massive hunger every time she takes olanzapine to attain remission of mania, and then discontinues it because of the weight gain and relapses

This is the third time she has tried olanzapine, failing each time to find an effective alternate medication, with olanzapine being highly effective as a mood stabilizer every time she has taken it

She takes olanzapine about 10 mg/day for mania as higher doses seem to induce depression (above 12.5 mg/day)

Without olanzapine she becomes “catatonic,” crying, numb, and apathetic, a state of irritable mixed mania and depression, mostly irritable mania with lesser depression

She also became angry and bitter against psychiatry due to the toll her bipolar illness and its treatment have taken on her and the inability of others to help her get back to work, have no symptoms, and also normal weight

She is also bitter around home and is having domestic conflict with her husband and wants to divorce him after she delivers her baby

Treatment History Previous medication trials– Lithium: discontinued when it became toxic at 900 mg/day (level 1.7) and ineffective– Ziprasidone (Geodon): not effective for mania and mood cycling at doses as high as 240 mg/day; it may also have uncovered allergies leading to vomiting and sneezing– Oxcarbazepine (Trileptal): made patient feel “catatonic” at 150 mg twice per day– Aripiprazole (Abilify): not effective for mania at 15–30 mg/day and caused akathisia– Risperidone: not as effective as olanzapine at 2 mg twice per day and also caused weight gain– Divalproex (Depakote): not effective and caused “moon face” due to weight gain in the face as well as liver problems

Patient also had 27 electroconvulsive therapy (ECT) treatments two years ago that were effective for her depression but left her with significant cognitive impairment

She has tried numerous antidepressants in the past, including sertraline, paroxetine, venlafaxine XR, and bupropion XL without robust results and with possible worsening of mixed states

She has not tried asenapine, carbamazepine, clozapine, iloperidone, paliperidone, quetiapine, or lurasidone

Social and Personal History Married 4 years, pregnant with first child

Non smoker

No drug or alcohol abuse

College educated

Teacher, but had to resign due to disability from her mania several years ago

Medical History BP normal

Normal fasting glucose

Triglycerides elevated when overweight and when taking olanzapine

Normalize when she stops olanzapine (but becomes manic)

Family History Mother: with depression

Maternal uncle: alcohol abuse

Maternal grandmother: “manic depressive”

Current Medications Fluoxetine 40 mg/day

Olanzapine 10 mg/day

Lamotrigine 400 mg/day

Considering her history and current pregnancy, would you make any of the following adjustments to her medication regimen?

Discontinue/switch olanzapine

Discontinue/switch fluoxetine

Discontinue/switch lamotrigine

Attending Physician’s Mental Notes, Initial Psychiatric Evaluation Manic symptoms may worsen during pregnancy, necessitating some form of treatment

The risk of treatment during pregnancy must be weighed against the risk of no treatment

Atypical antipsychotics may be preferable to anticonvulsant mood stabilizers during pregnancy

Olanzapine is a risk category C drug (some animal studies show risk, no controlled studies in humans)– Early findings suggest no adverse consequences to infants exposed in utero

Fluoxetine is a risk category C drug (some animal studies show risk, no controlled studies in humans)– May not be recommended for use during pregnancy, especially in the first trimester– Longitudinal studies suggest that continuous treatment during pregnancy is not harmful to the fetus or developing child– There may be increased bleeding in the mother at delivery and of sedation in the newborn

Lamotrigine is a risk category C drug (some animal studies show risk, no controlled studies in humans)– Has been associated with increased incidence of cleft palate/lip deformity if exposure occurs during first trimester– If lamotrigine is used during pregnancy it may be necessary to check plasma levels as they can be reduced during pregnancy, possibly requiring increased doses with dose reduction following delivery

Patient is currently asymptomatic in terms of mood

Distressed over weight gain on olanzapine

Considering the patient’s history of fairly chronic mania, especially whenever she stops olanzapine, and the risks versus the benefits to the fetus, including the implications to the fetus and newborn in terms of a mother with mania versus a mother in remission, the decision is made to maintain her medications

Case Outcome: First Interim Followup, Month 6 The patient returns at eight months pregnant reporting that her mood is stable but that she has gained a substantial amount of weight during her pregnancy (>100 pounds)

Wants to know if she can stop her medications as soon as she delivers so she can get the weight off

Current medications– Fluoxetine 40 mg/day– Olanzapine 10 mg/day– Lamotrigine 400 mg/day

Which of the following would you most likely choose for this patient?

Maintain her current medication regimen post-partum

Switch olanzapine to an agent with less propensity to cause weight gain postpartum

Augment with an agent that may mitigate weight gain

If you were to switch, which of the following antimanic medications (i.e., those she has not yet tried) would you most likely choose for this patient?

Asenapine

Carbamazepine

Clozapine

Iloperidone

Lurasidone

Paliperidone

Quetiapine

If you were to augment, which of the following would you most likely choose for this patient?

Metformin

Pramlintide

Topiramate

Zonisamide

Naltrexone

Bupropion

Phentermine

Attending Physician’s Mental Notes: First Interim Followup, Month 6 Because her symptoms are stable, it would not be prudent to switch from olanzapine during the high risk period for mania recurrence postpartum (i.e., until at least 3–6 months postpartum)

After the patient is past the vulnerable postpartum period, could consider giving an agent that could possibly reduce weight along with olanzapine– An anticonvulsant such as topiramate or zonisamide, which have been associated with weight loss– The antidepressant bupropion has been associated with weight loss– The opiate antagonist naltrexone has been associated with weight loss– Experimental treatment with antidiabetic agents have been reported to cause weight loss caused by antipsychotics– Metformin– Pramlintide

A number of weight loss agents combining known weight loss agents are in testing, as are some novel compounds– Lorcaserin, a 5HT2C agonist– Combination of the weight loss agent phentermine plus topiramate in sustained release formulations aimed at lowering the dose, reducing the side effects and increasing weight loss– Combination of bupropion SR with naltrexone SR– Combination of zonisaminde with bupropion SR

For now, these are not practical considerations until more research is completed on these agents, but she could try several agents after she delivers including metformin, bupropion, naltrexone, or zonisamide

Probably best to avoid phentermine, a stimulant, so as not to activate her mania and destabilize her

Advised her to continue psychotropic medications for at least six months following delivery of her baby and to consider one of the weight loss medications as augmentation after she delivers

Case Outcome: Second Interim Followup, Month 22 Patient delivered a healthy baby boy, and her mood stayed stable throughout pregnancy and delivery

She did not want to add another medication to address the weight gain post partum

Plus she wanted to breast feed and she was advised not to do so while taking the recommended psychotropic medications and weight loss medications

Instead, she insisted on stopping olanzapine for the fourth time, starting three months after the birth of her son

A few months later, relapses, developing depression and mixed/rapid cycling states off all medications

However, she lost over 60 pounds of the 100 pounds she had gained during pregnancy

She refused re-treatment with olanzapine

To treat her relapse, was given– Lithium 750 mg/day– Quetiapine extended release 600 mg/day– Lamotrigine 400 mg/day– Fluoxetine 10 mg/day– Temazepam 60 mg/day for insomnia

She experiences hypomanic/manic and mixed dysphoric states (no pure major depressive episodes)– She reports that she feels manic most days and that the mania worsens diurnally as the day proceeds, characterized by “my pupils being huge,” agitation and anger towards her husband, racing thoughts, and impulsivity

This continuous state of instability persists over the course of a year despite many medication adjustments– Increased quetiapine dose (seemed to exacerbate mania)– Added olanzapine 15 mg/day while decreasing quetiapine dose (to 500 mg/day)– Discontinued lithium (did not think it was helping)– Discontinued fluoxetine (possibility it might exacerbate mania)– Added carbamazepine 200 mg/day in divided doses (worked well for helping the patient sleep but she discontinued after 10 days when she researched the drug and “freaked out” about potential side effects)– Added oxcarbazepine because of inadequate prior trial and titrated to 1200 mg in split doses (was well tolerated and patient liked it – “mood enhancer … makes me feel good, my attitude is better”)

Patient abruptly stopped quetiapine during oxcarbazepine titration– Oxcarbazepine exacerbated her migraines and despite apparent therapeutic effects it had to be stopped– Due to continuing weight problems, another attempt was made with ziprasidone 60 mg twice per day, but it destabilized her and was discontinued– Added topiramate 25 mg/day but she felt “wacko” and cut her wrists so topiramate was discontinued– During this time, she lost all of the 100 pounds she had gained on olanzapine

Reluctantly, restarts olanzapine– Olanzapine 15 mg/day– Lamotrigine 400 mg/day– Temazepam 60 mg/day for insomnia– Propranolol 10 mg twice per day for akathisia– Has already gained 30 pounds in 2 months and still only an incomplete recovery although a clear therapeutic effect since starting olanzapine

Of the following options (i.e., those she has not yet tried or had an adequate trial), which would you most likely choose for this patient?

Add/switch to asenapine

Add/switch to carbamazepine

Add/switch to clozapine

Add/switch to iloperidone

Add/switch to lurasidone

Add/switch to paliperidone

Add/switch to zonisamide

Add/switch to a conventional antipsychotic

Attending Physician’s Mental Notes: Second Interim Followup, Month 22 Asenapine may be beneficial as it has a pharmacological profile that is similar to olanzapine’s but seems to carry less risk of weight gain

Carbamazepine may also be useful as it was effective previously for sleep (but without an adequate trial); in addition, oxcarbazepine, which is the 10-keto analog of carbamazepine, was previously effective for her mood symptoms

Although clozapine is generally the most effective of the antipsychotics, it carries as much if not more weight gain risk as olanzapine

Iloperidone may be beneficial as it seems to carry less risk of weight gain than olanzapine

Paliperidone is the active metabolite of risperidone, which was previously ineffective and caused weight gain

Lurasidone (Latuda) not available at the time of this appointment, is now available and associated with a low risk of weight gain

Zonisamide may be useful as augmentation for weight issues, but is not well studied in bipolar disorder

A conventional antipsychotic may be helpful, but as she already has akathisia it may be preferable to avoid agents with higher risk of movement disorder

Case Outcome: Third Interim Followup, Month 26 Asenapine 5 mg twice per day is added

After a few weeks she reports improvement in mania and also a surprising and welcome reduction in appetite

Her insomnia continues and the dose of temazepam is increased to 60 mg in split doses

Her current regimen includes– Olanzapine 5 mg three times per day– Asenapine 5 mg twice per day– Lamotrigine 400 mg/day– Temazepam 15 mg four times per day– Propranolol 10 mg three times per day

She appears to have an irritable edge of a hypomanic state but no overt depression or mania and is relatively stable

She starts losing weight as soon as asenapine is started despite continuing olanzapine

Asenapine increased to 10 mg twice a day and other medications unchanged

Lost all weight she had gained on olanzapine

Has become stable

What would you do now?

Taper olanzapine

Increase asenapine above the recommended dose range of 10 mg twice a day

Leave well enough alone for now

Other

Case Debrief This patient with bipolar disorder has chronic treatment-resistant mania and mixed, rapid cyclic states

These seem to be inadequately controlled when not taking olanzapine; however, olanzapine causes unacceptable weight gain

Addition of asenapine seems to have ameliorated the metabolic side effects associated with olanzapine, though it is not clear why

She is relatively stable on a complicated regimen of medications including at the moment antipsychotic polypharmacy which is not only expensive but poorly studied

Because she is taking large doses of medications, it remains a possibility that she does not absorb them well and it may be beneficial to take plasma levels

Further options for this patient include:– Increasing doses of both asenapine and olanzapine while monitoring blood plasma levels

Adding carbamazepine (previously beneficial but not tried for adequate trial)

Switching asenapine and olanzapine to lurasidone

For now, left well enough alone

The case continues ….

Posttest Self Assessment Question: answer Which of the following most accurately describes the recently approved drug asenapine?

A. Has a high risk of metabolic side effects

– Experience so far does not suggest a high risk of metabolic side effects, but some patients do gain weight

B. Is available as a sublingual formulation

– This is true

C. Works primarily as a very potent dopamine D3 receptor agonist

– Thought to work primarily as a D2 and 5HT2A antagonist

Answer: B