Pretest self-assessment question (answer at the end of the case)
Which of the following approaches likely has the most evidence to support its use as a weight-loss strategy in patients suffering from antipsychotic-associated weight gain (AAWG)?
A. Orlistat (Xenical)
B. Sibutramine (Meridi 4)
C. Fenfluramine (Pondi Min)
D. Topiramate/phentermine combination (Q-Symia)
E. Metformin (Glucophage)
F. Naltrexone/bupropion combination (Contrave)
G. Lorcaserin (Belviq)
H. Bariatric surgery
Patient evaluation on intake
32-year-old woman with a chief complaint of unremitting depression for several years, who was transferred from another provider who had just retired
Psychiatric history
The patient had onset of MDD in her 20s, which was likely predated by comorbid GAD
Presents moderately depressed but is partially responding to medication now
Depressive symptoms have fluctuated from mild to severe but have never remitted
Sober from prior AUD for three years
Despite these symptoms, has been gainfully employed at times and has been able to return to school for college credits on a part-time basis
Exhibits classic symptoms of MDD but the depression is also vegetative in that she is not predominantly sad, but more anhedonic with blunted affect, and poor energy and concentration
Admits to passive suicidal thoughts but has never acted on them
Required no psychiatric hospitalizations in her lifetime
– A review of psychiatric systems revealed no other formal anxiety disorder, psychosis, mania, eating disorder
– Has undergone eclectic, supportive psychotherapy in the past but her mental state at this presentation made reciprocal talk therapy almost impossible given her psychomotor slowing and lethargy
– There is no evidence of marked personality disorder
– Inherited from a previous psychiatrist, the patient currently takes an SNRI (duloxetine [Cymbalta]) and a stimulant (methylphenidate [Concerta])
– The stimulant is for depression augmentation and she only experiences dry mouth as a side effect
– States she is about 30% better on this regimen
– Previously, the patient failed to respond to
Two or three SSRIs prescribed in the primary care setting prior to being seen in psychiatry. She is unaware of the dose strength utilized but states she spent several months on each
Adequately dosed NaSSA, mirtazapine (Remeron) 45 mg/d
Patient had previous trials of a TCA but these appear to be low doses used for treating insomnia and pain only
– Continues to be seen weekly by a supportive psychotherapist with whom she has a good rapport
Social and personal history
Divorced and has two children
Is high school educated, working part-time and taking courses part-time
Has supportive parents and siblings who help her with childcare
Does not drink alcohol, smoke cigarettes, or take illegal drugs
Medical history
Iron deficiency anemia treated with iron supplements
Successful bariatric surgery, lost 70 lbs., and weighs 130 lbs.
Is normotensive
History of lower back pain
Family history
SUD in parents and many relatives, largely AUD
MDD in mother
No history of schizophrenia or bipolar disorder in the family
Current psychiatric medications
Question
Based on this patient’s history and the available evidence base, do you consider augmentation with stimulants to be a reasonable approach?
Yes
No
What makes, or would make you comfortable using a stimulant augmentation?
Stimulants are not approved but are covered in many psychopharmacology texts as legitimate augmentations, and in many peer-reviewed journal review articles, and there are a few trials available in the literature supporting the practice
Larger controlled trials seem to indicate that, if not a full antidepressant, stimulants have anti-fatigue and procognitive effects useful in treating MDD
Stimulants often offset side effects induced by SSRI and SNRI, such as sedation, fatigue, executive dysfunction, and weight gain
Stimulants often treat residual depressive symptoms not managed by SSRI, such as fatigue and poor concentration
What makes, or would make you uncomfortable with stimulant augmentation?
A history of addiction
A history of cardiac or hypertensive issues
A history of tic or movement disorders
A history of anxiety
Attending physician’s mental notes: initial evaluation
This patient seems to be typical of many patients referred for inadequate response to antidepressants in that she is in her 30s, moderately depressed, and has failed mostly SSRI treatment in primary care settings
The previous psychiatrist changed classes of medications from the SSRI to an SNRI and achieved a partial response
– This approach follows most MDD guidelines where, if there is a failure on initial SSRI montherapy, then a switch to a novel pharmacological class antidepressant is the next step
A stimulant augmentation was added to promote more clinical symptom response and also likely to avoid side-effect weight gain in this case
Unfortunately, she is not in remission, which requires further action and prescribing
Common practice suggests looking at the current medication regimen, and if safe, reasonable, and rational, doses can be increased within approved limits to see if remission can occur before adding yet another medication
She has minimal side effects and likes her current regimen, hence compliance looks to be favorable
Further investigation
Is there anything else you would especially like to know about this patient?
What medical details concerning this patient are you concerned about?
– She has a history of AUD but has been sober for three years. She is taking duloxetine (Cymbalta) now, which has warnings about its use in acute alcoholism due to liver damage issues
Her liver function tests are normal
– She has a history of being overweight but underwent successful bariatric surgery
– Does she have any history of BN?
No, psychiatric interview at present shows no eating disorder and psychological evaluation prior to bariatric surgery also showed no contraindication
– She has chronic depression; therefore, is there a medical cause such as hypothyroidism or anemia?
Thyroid panel is normal. Cell count is normal and she is on iron replacement
Question
Based on what you know about this patient’s history, current symptoms, and treatment responses, do you think that maximal doses of her antidepressant are warranted at this time?
Yes, clinical experience dictates that increased doses work better in some patients
Yes, psychopharmacology textbooks suggest that increased doses may work better in certain patients
No, her doses are clinically adequate
No, her dose is average and the FDA suggests no benefit from higher doses
Attending physician’s mental notes: initial evaluation (continued)
The patient is clearly depressed
Her medications are well tolerated and have room to be maximized with regard to dose
The patient has a good supportive psychotherapist and should continue with that, but perhaps consider augmenting this psychotherapy with group CBT
She seems to be a typical treatment-resistant patient, but has good prognostic factors
Case outcome: interim follow-ups through three months
The patient’s duloxetine (Cymbalta) SNRI is maximized to 120 mg/d without clear benefit or improved partial response
Methylphenidate-ER (Concerta) is next increased to 54 mg/d without clear benefit. There are no additional side effects
– Blood pressure, heart rate, and weight are monitored
Lamotrigine (Lamictal) is gaining popularity as a bipolar maintenance treatment and as an antidepressant augmentation as it has minimal day-to-day side effects
– Less stringent unipolar depression augmentation trials have suggested effectiveness, whereas more stringent monotherapy trials suggest little benefit over placebo
– Lamotrigine also has a purported mechanism of action that is novel (glutamate dampening by inhibiting the release of glutamate into the synapse) compared to the patient’s current regimen, which uses a rational polypharmacy approach where each psychotropic contributes a novel mechanism of action to the regimen
– Lamotrigine is known for minimal to no weight-gain effects, but does have serious, but rare rash adverse effects to consider. Given this, it must be titrated very slowly, which makes it an inopportune acute antidepressant treatment as it takes six to eight weeks to reach 200 mg/d
Patient is mildly depressed now given the partial response noted earlier. Therefore, a slow titration is acceptable clinically. The lack of weight-based side effects is comforting in this case
Fortunately, she gains no weight, has no side effects, but she has no mood stabilizer benefit despite dosing of lamotrigine up to 300 mg/d
Question
Considering her current medication failures (SSRI, SNRI, stimulant, and antiepileptic), what would you consider next?
Discontinue current ineffective medications and
– Start a new SNRI and consider combining with an NDRI such as bupropion-XL (Wellbutrin-XL), which all together continue to facilitate synaptic DA, NE, and serotonin (5-HT), albeit with a different combination of medications
– Remove lamotrigine (Lamictal), maintain the SNRI, and add mirtazapine (Remeron), a NaSSA, instead seeking a “California rocket fuel” combination to maximize synaptic NE and 5-HT
– Remove all agents, washout, start an MAOI
– Refer for ECT, VNS, TMS treatments
– Refer for a course of group CBT
Attending physician’s mental notes: four months
The patient has been compliant with visits and medications
She now has several failed full medication trials where the drugs inhibit monoamine reuptake pumps
Weight-gain potential medications like mirtazapine (Remeron), the TCAs, and the atypical antipsychotics will not be appreciated by the patient
The newer MAOI transdermal patch selegiline (Emsam) has data suggesting minimal weight gain and utilizes a novel mechanism of action elevating all three monoamines in one monotherapy, and may be a rational choice
Case outcome: interim follow-ups through six months
The patient accepts education and the risks of drug and diet interactions and starts this MAOI after appropriate washout of her previous antidepressants
– An appropriate washout in this case was a gradual taper off of each medication to avoid withdrawal, followed by five half-life duration waiting periods specific to each agent prior to MAOI initiation
Selegiline (Emsam) patch is escalated eventually to the full 12 mg/d maximal dose but without any clinical response
This drug is discontinued and appropriate washout implemented
– Two weeks must lapse prior to a contraindicated medication being started
– This allows for adequate replenishment of MAO enzymes to be synthesized and return of drug metabolism to normal capability
She elects, despite some weight-gain potential, to take a TCA and is titrated to therapeutic doses and levels of nortriptyline (Pamelor), but also without clinical response
Metformin (Glucophage) is a diabetes medicine known to cause weight loss and is initiated and titrated to 2000 mg/d, and weight gain is halted but not reversed
– There is a reasonable evidence base to support the use of metformin prophylactically or after the fact to lower or inhibit AAWG
She has gained 15 lbs
Laboratory blood samples are drawn and renal function is normal and there is no acidosis with metformin use. Blood glucose is normal
The wakefulness-promoting agent modafinil (Provigil) is added now to her current TCA as a depression augmentation, and titrated eventually to 400 mg/d
Her chief symptoms continue to be anhedonia, blunted affect, and low energy
There was only a minimal response and weight starts to increase on this combination again
Orlistat (Xenical) is an approved weight-loss medication, which patient agrees to start (360 mg/d). It is a fat-blocking (intraluminal lipase inhibitor) drug with two-year regulatory effectiveness in overweight patients but has a minimum of evidence for its use in iatrogenic weight gain from psychotropic administration
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