CME
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: May 07, 2020
Expiration: May 06, 2021
As we reviewed some of the more common AEs recorded in the clinical trials of the second-generation antipsychotics, it is important to realize that those studies do not always capture every AE we will see in clinical practice; it depends on how they defined AEs when designing those trials.
The clinical reality includes a broader list of potential AEs with second-generation antipsychotics, including every AE listed on this slide. From agitation to constipation and everything in the middle, each of these can occur with every one of the agents currently approved by the FDA for treatment augmentation of patients with MDD.20 So being aware of these is important no matter which treatment you use. This slide illustrates how dramatically each of these AEs can threaten adherence.
Although every clinician wants their patients to have zero AEs, that is not achievable for every patient. Our best strategy is 2-pronged. First, match each patient with the ideal treatment option. Second, offer patients psychoeducation about potential AEs and reassurance that we can help if we work together as a team.
I counsel my patients to contact me if issues arise and to avoid stopping their medication without connecting with me. This combination strategy can help us overcome a great conundrum of both acute and chronic threats to medication adherence.
All of the second-generation antipsychotics we have discussed are associated with some risk for weight gain. However, some have a lower risk than others, as shown on this slide. These data should be interpreted with some caution, as these are from short‑term studies.
Moreover, weight gain here is defined at a very high level, 7% or more of baseline. So, a patient with a 6% weight gain is not captured, although that patient might be very unhappy about gaining that much weight.
With these caveats, I think it is still an important dataset to be familiar with. It appears that choice of medication matters a great deal if our goal is to minimize weight gain, as does duration of treatment.
Weight gain is not the only metabolic issue to consider when administering second generation antipsychotics; they can also cause unwanted changes in blood glucose, cholesterol, and triglycerides.21 The risks differ for each agent and each metabolic indicator, but I think it is wise to be aware that every agent could potentially cause a worsening metabolic status.
We should carefully monitor the metabolic health of every patient and offer psychoeducation to help minimize their risk, as evidence suggests that both nonpharmacologic and pharmacologic interventions can mitigate some of this risk.22
For more information on metabolic risk in depression, see the module on comorbidities.
Among the pharmacologic interventions that can help prevent weight gain in patients receiving second-generation antipsychotics are metformin, D‑fenfluramine, sibutramine, topiramate, and reboxetine. In this meta‑analysis of 32 randomized, controlled trials of 15 different medications used to mitigate weight gain, these 5 agents demonstrated a significant difference vs placebo.23
The best way to counteract the AEs is to prevent them before they happen (ie, primary prevention). Upon treatment initiation, clinicians should select the lowest-risk antipsychotic, if possible.24 We should also offer our patients healthy lifestyle counseling and interventions, including recommending they join support groups, walking groups, and so on. In my opinion, it is inappropriate to start any of these medications without considering this primary prevention.
Regarding secondary prevention, when an AE is present (in this case, metabolic dysfunction), we should continue with healthy lifestyle counseling and intervention, perhaps modifying as appropriate.24 In addition, if the patient is receiving a higher‑risk antipsychotic medication, we should consider changing to a lower‑risk antipsychotic. If we are concerned, we should consider a weight loss intervention, be it pharmacologic or nonpharmacologic; we should not wait for significant weight gain before incorporating that that kind of intervention.
When we reach tertiary prevention, our patient likely has considerable challenges.24 Here again, we should continue with healthy lifestyle counseling and intervention and should also consider switching to a lower-risk antipsychotic, if applicable. We should also add targeted treatment for the AE, for example, pharmacologic treatment to help lower blood glucose levels (perhaps through collaboration with their primary care provider). Patients with a specific issue should be referred to a specialist. Our patients deserve all the tools we have at our disposal.
As mentioned previously, all of the approved second-generation antipsychotics have the potential to cause any of the AEs we have covered.
Akathisia tends to be a significant challenge, particularly at the beginning of treatment, but I have found that it can occur at almost any treatment phase. Although the risk with each agent differs, in my experience all have some risk.
As an example of primary prevention, let’s look at the results of the Interactive Treatment Decision Support Tool to see what the 5 experts, including myself, chose for a patient with akathisia concerns.
In this example of a patient with akathisia concerns, most experts recommended augmentation with brexpiprazole, likely because in placebo-controlled studies, brexpiprazole revealed low rates of akathisia.19 As akathisia is a known risk for diminishing adherence, based on my experience and keeping the risk–benefit profile in mind, I would select this medication as my first option.
How should we manage this AE beyond primary prevention? If akathisia is noted in a patient receiving antipsychotic therapy, we have the following immediate options: We can reduce the dose, we can change the antipsychotic to one that has lower risk, or we can add a specific antiakathisia agent.25
Let’s explore each of these options further. Reducing the dose of the antipsychotic medication should be temporary, with the goal of rechallenging the patient with the appropriate therapeutic dose once the akathisia has resolved and some time has passed.
Switching to a lower‑potency antipsychotic medication can be helpful, and we are fortunate to have several good options among the second-generation antipsychotics that are approved for adjunct treatment of MDD.
Finally, adding an antiakathisia agent is something I often do in practice. My first‑line agents are propranolol, mirtazapine, or anticholinergics, the latter of which is preferred for patients experiencing a combination of akathisia and parkinsonian symptoms. Second-line antiakathisia agents include amantadine, clonidine, benzodiazepines, and cyproheptadine, which is a 5-HT2A antagonist.
I would urge clinicians to take akathisia very seriously. It can cause significant impairment for patients and can lead to high rates of discontinuation if not addressed appropriately.
Second-generation antipsychotics can also lead to a host of sexual AEs.26 Too often, the potential for these AEs is not discussed by clinicians, even though they can cause patients to stop the medication.
Although sexual AEs were not specifically documented in the registration trials of treatment augmentation in MDD, I want to highlight the potential for these to occur and threaten adherence. In my practice, I have seen patients struggle with all of these issues to varying degrees, including issues with libido, arousal, and orgasm, on top of the metabolic challenges that can occur.
They are not very common, but it is important to be aware of the potential for sexual AEs and to be watchful should a patient have adherence challenges.
How should we manage treatment-emergent sexual dysfunction if it occurs? First, we can consider a switch to another approved second-generation antipsychotic.27 If that is not a desirable option for the clinician or the patient, we can use a watch-and-wait approach. In my experience, many patients are willing to try this approach, especially if they are experiencing other benefits from their medication. Some will develop tolerance to the sexual AE(s).
Alternatively, we can reduce the dose of the medication.27 Some recommendations have even suggested drug holidays, but personally I discourage that approach owing to the risk for re-emergent depression, which would be a significant challenge.
Finally, we can consider nonpharmacologic treatment options to address the sexual AEs and/or referral to a therapist who specializes in sexual dysfunction; these options are more ideal for higher‑functioning patients.27 For example, adding a medication for erectile dysfunction can be quite helpful in men and to some degree in women. I have had a number of patients report that this not only resolves the problem but diminishes the risk of them stopping their medication or being partially adherent to it.
The take-home message is that sexual dysfunction, although not very common and with varying risks with specific agents, can occur in patients receiving antipsychotics. Based on my clinical practice, asking patients about it can help to detect and address this occult AE and help patients remain adherent to their treatment plan.
Hyperprolactinemia is another challenge that can occur in patients taking second-generation antipsychotics. As shown on this slide, it can lead to several clinical manifestations, ranging from mental health issues to physical issues.28
Patients with hyperprolactinemia are also at an increased risk of cardiovascular disorders and potentially breast cancer, although the evidence on the latter is not conclusive.
Clearly, hyperprolactinemia is something we should take seriously.
The risk for hyperprolactinemia differs among antipsychotic agents, as shown in this meta-analysis of patients receiving antipsychotics for schizophrenia.29
If we focus on the second-generation antipsychotics that are approved for treatment augmentation of patients with MDD, we can see that aripiprazole has the lowest risk, followed by quetiapine and olanzapine. Brexpiprazole, which is not shown, does not generally increase prolactin levels.30
Current practice guidelines offer recommendations for monitoring AEs in patients with MDD receiving second-generation antipsychotics for treatment augmentation.6
The American Psychiatric Association advises that we should consider the potential advantages and disadvantages of each medication we are considering for an individual patient.31
Dosing of antipsychotics is generally lower for patients with MDD vs bipolar disorder and psychotic disorders; we need to be aware of the correct dosing and use the lowest possible dose to minimize the risk of AEs.
In addition, we should monitor for AEs, including those we have previously discussed, as well as objective markers of weight, body mass index, and metabolic indices that can only be obtained through serum analysis. We should conduct this monitoring at baseline and at regular intervals. This should not be considered optional; it is part of good clinical practice and we should be exercising it.
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