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EXPERT Q&A
Raising the Bar in Schizophrenia Treatment
Brian Miller, MD, PhD, MPH
Professor of Psychiatry at the Medical College of Georgia, Augusta, and President of the Georgia Psychiatric Physicians Association.
Dr. Miller receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.
TCPR: Antipsychotics are the standard of care in schizophrenia, but what can we do beyond that?
Dr. Miller: Several things come to mind. Therapeutic alliance, addressing the full symptom picture, and greater use of clozapine in treatment-resistant cases.
TCPR: Let’s start with therapeutic alliance.
Dr. Miller: Nonadherence with medications is the rule in this population, so it’s very important to develop rapport. I use any means possible to find out about what interests them, whether it’s movies, music, video games, sports, or art. Ask, “What are your interests? What do you like to do?” or “How do you spend your time?” If they draw a blank, ask, “Are there things you used to do in the past that you haven’t been doing so much lately?” I look for interests that get them physically active and out of the house and try to encourage those. It’s important to assess psychopathology, but we can build a stronger alliance by finding out what’s going well for them.
TCPR: What types of symptoms do you address in addition to psychosis?
Dr. Miller: Depression, insomnia, and physical health are common ones. For depression, I’ll often start an antidepressant or psychotherapy. Patients with schizophrenia do respond to cognitive behavioral therapy. In terms of antidepressants, I tend to use SSRIs, SNRIs, and bupropion. There is a theoretical concern that the dopaminergic effects of bupropion could exacerbate psychosis, but that risk didn’t pan out in controlled studies, including smoking cessation studies in schizophrenia. Smoking cessation is a good reason to prefer bupropion in this population, as is bupropion’s low risk of sexual side effects, which are often a problem with antipsychotics.
TCPR: Any tips on distinguishing depression from negative symptoms?
Dr. Miller: Depression will usually cause distress for the patient, but negative symptoms are more likely to cause distress for the family. Patients with negative symptoms may have apathy, amotivation, and anhedonia, but they are unlikely to complain of sadness or depressed mood. On the mental status examination, you’ll see restrictions in emotional expression, like a blunted affect that doesn’t change even when talking about positive things. They use short sentences and give one- or two-word answers—alogia, a poverty of speech.
TCPR: Can antipsychotics cause negative symptoms?
Dr. Miller: They can, particularly first-generation antipsychotics, but some of them may also improve negative symptoms to a limited extent. One thing that’s important to rule out is negative symptoms that are caused by psychosis, such as threatening voices telling the patient not to move or speak.
TCPR: Some antipsychotics also help depression. Does that have any relevance here?
Dr. Miller: It may, but I’m not aware of any evidence that the antipsychotics approved for use in bipolar or unipolar depression improve mood in schizophrenia.
TCPR: A lot of medications have a little bit of evidence for negative symptoms, from antidepressants to lithium to antibiotics. Do you use any of those?
Dr. Miller: Sometimes I use anti-inflammatory treatments. Inflammation can contribute to negative symptoms. Obesity, poor diet, sedentary lifestyle, smoking, and chronic health problems are all risk factors for inflammation, and you can screen for inflammation with a high-sensitivity C-reactive protein (cutoff > 3 mg/L). Anti-inflammatories that may help negative symptoms include minocycline (200 mg QHS), the NSAID celecoxib (200 mg BID), and possibly high-dose aspirin (1000 mg Qday) (Correll CU et al, JAMA Psychiatry 2017;74(7):675–684).
TCPR: How do you treat insomnia in schizophrenia?
Dr. Miller: I try to maximize sleep hygiene before adding a hypnotic. Caffeine use and evening blue light from TVs or smartphone screens are good places to intervene. In terms of hypnotics, I use a lot of trazodone (50–200 mg QHS) and hydroxyzine (20–100 mg QHS). There are also some data showing that melatonin (3–5 mg QHS) has metabolic benefits and reduces oxidative stress (Porfirio MC et al, Neuropsychiatr Dis Treat 2017;13:2167–2174). I take a good substance use history before prescribing benzodiazepines or the z-drugs such as zolpidem.
TCPR: What do you look for in patients’ physical health?
Dr. Miller: Metabolic and cardiovascular health are particularly important. These patients develop cardiovascular disease 20 years earlier than the average population. I’ll check in on nutrition and physical activity, and screen for blood pressure, lipids, and glucose. If I find abnormalities, I’m comfortable starting a first-line medication and referring to primary care from there.
TCPR: Which medications do you start with?
Dr. Miller: For hypertension, White patients are more likely to respond to ACE inhibitors and beta-blockers, so I tend to start with a low-dose ACE inhibitor like lisinopril 10 mg Qday. Black patients are more likely to respond to calcium channel blockers or diuretics, so hydrochlorothiazide 12.5–25 mg Qday or amlodipine 5 mg Qday. For hyperlipidemia, any of the statins are fine—I tend to start with simvastatin 10 mg qday.
TCPR: How do you educate patients about schizophrenia?
Dr. Miller: Patients differ in their cognitive abilities and their level of recovery, so we need to tailor their education appropriately. Start by asking, “What questions do you have for me? They can be about this illness, your medications, or other treatments.” In general, I’ll want them to know that schizophrenia is a treatable illness, that they can lower their risk of relapse by about 80% if they stay on their medication, and that I’m open to adjust the dose if it’s difficult to take. But I also inform them that physical activity, a healthy diet, and good social connections are part of their recovery. It’s also important to educate families and caregivers, and the National Alliance on Mental Illness is a great resource for them.
TCPR: Sounds like you try to instill hope. That’s not easy to do in this illness, where full recovery is not the norm.
Dr. Miller: That is true, and you need to be realistic. One avenue where I do see hope is clozapine. Many patients are able to go back to school or return to work after starting clozapine.
TCPR: Are we using enough clozapine?
Dr. Miller: We’re not. The guidelines are consistent on the evidence for clozapine. Patients should be offered a clozapine trial if they have a partial or non-response to two antipsychotic trials, assuming those antipsychotic trials are an adequate dose and duration (four to eight weeks). About 25%–30% of patients with schizophrenia have crossed that threshold, but only 5% are taking clozapine in the US.
TCPR: Which antipsychotics do you try before clozapine?
Dr. Miller: The best antipsychotic is the one that they will take. If adherence is the issue, I will move to a long-acting injectable. After that, I look for what worked in the past. Antipsychotics that kept people well for a long time are often stopped because the patient moved, got hospitalized, or just stopped taking them. I also ask if any family members had psychosis and did well on particular medications, because genetic variations in CYP enzymes can influence antipsychotic serum levels. If the patient has a metabolic problem, which many do, I’m more likely to select an antipsychotic with a favorable metabolic profile such as aripiprazole or ziprasidone on the generic side, and brexpiprazole (Rexulti), lumateperone (Caplyta), or lurasidone (Latuda), which are more costly branded alternatives.
TCPR: All things being equal, what do you typically start with?
Dr. Miller: Risperidone. Stefan Leucht did a network meta-analysis that found slight superior efficacy for risperidone and olanzapine compared with other non-clozapine antipsychotics (Leucht S et al, Lancet 2013;382(9896):951–962). Olanzapine is also worth trying before clozapine, but I use it second line because of its metabolic risks. So a typical course is to start with risperidone, then olanzapine, and then clozapine. However, if the patient has metabolic problems, I might start with aripiprazole or lurasidone instead of risperidone.
TCPR: How high do you go on the dose for an adequate trial?
Dr. Miller: It depends. In general, patients who are in their first episode or early in the illness tend to respond to approximately half the usual maintenance dose of an antipsychotic. Quetiapine is one exception—it tends to require the same dosing early in the illness as it does in chronic schizophrenia. For risperidone, I usually start at 4 mg/day and go up to 6 mg/day for chronic illness, or start at 1–2 mg/day and go up to 3 mg/day in the early course. I usually divide it twice a day to reduce side effects, but it can be dosed all at night if patients have trouble remembering to take it.
TCPR: And what do you do if clozapine doesn’t work?
Dr. Miller: First I’d want to make sure we’ve maximized the dose, and for that we rely on blood levels. Patients on clozapine are most likely to exhibit a therapeutic effect when total concentrations of clozapine + norclozapine are > 450 ng/mL. Eight weeks at a therapeutic dose is an adequate trial. After that, we don’t have randomized controlled trials to guide us, so what I’m going to say is gathered from experience and uncontrolled studies. If they are tolerating clozapine and deriving at least a little benefit from it, I will keep it going and add something in, starting with a second antipsychotic—this is one of the rare situations where I would combine antipsychotics. Aripiprazole and risperidone have some evidence to augment clozapine (Lähteenvuo M and Tiihonen J, Drugs 2021;81(11):1273–1284). ECT should also be considered at this stage. It mainly treats positive psychotic symptoms, but it can also help mood, suicidality, and even substance use comorbidities (Wang G et al, J Psychiatr Res 2018;105:23–32).
TCPR: Any other options?
Dr. Miller: We have a few medications that may help the overall psychopathology, including positive and negative symptoms. Lamotrigine, for example, has some beneficial effects when added to clozapine, according to a small meta-analysis (dose 50–200 mg Qday after titration) (Tiihonen J et al, Schizophr Res 2009;109(1–3):10–14). Another meta-analysis found benefits for adjunctive topiramate—both for positive and negative symptoms and for metabolic parameters (start 25 mg Qday, titrate to max of 200 mg BID) (Correll CU et al, J Clin Psychiatry 2016;77(6):e746–e756).
TCPR: Thank you for your time, Dr. Miller.
General Psychiatry Expert Q&ADr. Miller: Several things come to mind. Therapeutic alliance, addressing the full symptom picture, and greater use of clozapine in treatment-resistant cases.
TCPR: Let’s start with therapeutic alliance.
Dr. Miller: Nonadherence with medications is the rule in this population, so it’s very important to develop rapport. I use any means possible to find out about what interests them, whether it’s movies, music, video games, sports, or art. Ask, “What are your interests? What do you like to do?” or “How do you spend your time?” If they draw a blank, ask, “Are there things you used to do in the past that you haven’t been doing so much lately?” I look for interests that get them physically active and out of the house and try to encourage those. It’s important to assess psychopathology, but we can build a stronger alliance by finding out what’s going well for them.
TCPR: What types of symptoms do you address in addition to psychosis?
Dr. Miller: Depression, insomnia, and physical health are common ones. For depression, I’ll often start an antidepressant or psychotherapy. Patients with schizophrenia do respond to cognitive behavioral therapy. In terms of antidepressants, I tend to use SSRIs, SNRIs, and bupropion. There is a theoretical concern that the dopaminergic effects of bupropion could exacerbate psychosis, but that risk didn’t pan out in controlled studies, including smoking cessation studies in schizophrenia. Smoking cessation is a good reason to prefer bupropion in this population, as is bupropion’s low risk of sexual side effects, which are often a problem with antipsychotics.
TCPR: Any tips on distinguishing depression from negative symptoms?
Dr. Miller: Depression will usually cause distress for the patient, but negative symptoms are more likely to cause distress for the family. Patients with negative symptoms may have apathy, amotivation, and anhedonia, but they are unlikely to complain of sadness or depressed mood. On the mental status examination, you’ll see restrictions in emotional expression, like a blunted affect that doesn’t change even when talking about positive things. They use short sentences and give one- or two-word answers—alogia, a poverty of speech.
TCPR: Can antipsychotics cause negative symptoms?
Dr. Miller: They can, particularly first-generation antipsychotics, but some of them may also improve negative symptoms to a limited extent. One thing that’s important to rule out is negative symptoms that are caused by psychosis, such as threatening voices telling the patient not to move or speak.
TCPR: Some antipsychotics also help depression. Does that have any relevance here?
Dr. Miller: It may, but I’m not aware of any evidence that the antipsychotics approved for use in bipolar or unipolar depression improve mood in schizophrenia.
TCPR: A lot of medications have a little bit of evidence for negative symptoms, from antidepressants to lithium to antibiotics. Do you use any of those?
Dr. Miller: Sometimes I use anti-inflammatory treatments. Inflammation can contribute to negative symptoms. Obesity, poor diet, sedentary lifestyle, smoking, and chronic health problems are all risk factors for inflammation, and you can screen for inflammation with a high-sensitivity C-reactive protein (cutoff > 3 mg/L). Anti-inflammatories that may help negative symptoms include minocycline (200 mg QHS), the NSAID celecoxib (200 mg BID), and possibly high-dose aspirin (1000 mg Qday) (Correll CU et al, JAMA Psychiatry 2017;74(7):675–684).
TCPR: How do you treat insomnia in schizophrenia?
Dr. Miller: I try to maximize sleep hygiene before adding a hypnotic. Caffeine use and evening blue light from TVs or smartphone screens are good places to intervene. In terms of hypnotics, I use a lot of trazodone (50–200 mg QHS) and hydroxyzine (20–100 mg QHS). There are also some data showing that melatonin (3–5 mg QHS) has metabolic benefits and reduces oxidative stress (Porfirio MC et al, Neuropsychiatr Dis Treat 2017;13:2167–2174). I take a good substance use history before prescribing benzodiazepines or the z-drugs such as zolpidem.
TCPR: What do you look for in patients’ physical health?
Dr. Miller: Metabolic and cardiovascular health are particularly important. These patients develop cardiovascular disease 20 years earlier than the average population. I’ll check in on nutrition and physical activity, and screen for blood pressure, lipids, and glucose. If I find abnormalities, I’m comfortable starting a first-line medication and referring to primary care from there.
TCPR: Which medications do you start with?
Dr. Miller: For hypertension, White patients are more likely to respond to ACE inhibitors and beta-blockers, so I tend to start with a low-dose ACE inhibitor like lisinopril 10 mg Qday. Black patients are more likely to respond to calcium channel blockers or diuretics, so hydrochlorothiazide 12.5–25 mg Qday or amlodipine 5 mg Qday. For hyperlipidemia, any of the statins are fine—I tend to start with simvastatin 10 mg qday.
TCPR: How do you educate patients about schizophrenia?
Dr. Miller: Patients differ in their cognitive abilities and their level of recovery, so we need to tailor their education appropriately. Start by asking, “What questions do you have for me? They can be about this illness, your medications, or other treatments.” In general, I’ll want them to know that schizophrenia is a treatable illness, that they can lower their risk of relapse by about 80% if they stay on their medication, and that I’m open to adjust the dose if it’s difficult to take. But I also inform them that physical activity, a healthy diet, and good social connections are part of their recovery. It’s also important to educate families and caregivers, and the National Alliance on Mental Illness is a great resource for them.
TCPR: Sounds like you try to instill hope. That’s not easy to do in this illness, where full recovery is not the norm.
Dr. Miller: That is true, and you need to be realistic. One avenue where I do see hope is clozapine. Many patients are able to go back to school or return to work after starting clozapine.
TCPR: Are we using enough clozapine?
Dr. Miller: We’re not. The guidelines are consistent on the evidence for clozapine. Patients should be offered a clozapine trial if they have a partial or non-response to two antipsychotic trials, assuming those antipsychotic trials are an adequate dose and duration (four to eight weeks). About 25%–30% of patients with schizophrenia have crossed that threshold, but only 5% are taking clozapine in the US.
TCPR: Which antipsychotics do you try before clozapine?
Dr. Miller: The best antipsychotic is the one that they will take. If adherence is the issue, I will move to a long-acting injectable. After that, I look for what worked in the past. Antipsychotics that kept people well for a long time are often stopped because the patient moved, got hospitalized, or just stopped taking them. I also ask if any family members had psychosis and did well on particular medications, because genetic variations in CYP enzymes can influence antipsychotic serum levels. If the patient has a metabolic problem, which many do, I’m more likely to select an antipsychotic with a favorable metabolic profile such as aripiprazole or ziprasidone on the generic side, and brexpiprazole (Rexulti), lumateperone (Caplyta), or lurasidone (Latuda), which are more costly branded alternatives.
TCPR: All things being equal, what do you typically start with?
Dr. Miller: Risperidone. Stefan Leucht did a network meta-analysis that found slight superior efficacy for risperidone and olanzapine compared with other non-clozapine antipsychotics (Leucht S et al, Lancet 2013;382(9896):951–962). Olanzapine is also worth trying before clozapine, but I use it second line because of its metabolic risks. So a typical course is to start with risperidone, then olanzapine, and then clozapine. However, if the patient has metabolic problems, I might start with aripiprazole or lurasidone instead of risperidone.
TCPR: How high do you go on the dose for an adequate trial?
Dr. Miller: It depends. In general, patients who are in their first episode or early in the illness tend to respond to approximately half the usual maintenance dose of an antipsychotic. Quetiapine is one exception—it tends to require the same dosing early in the illness as it does in chronic schizophrenia. For risperidone, I usually start at 4 mg/day and go up to 6 mg/day for chronic illness, or start at 1–2 mg/day and go up to 3 mg/day in the early course. I usually divide it twice a day to reduce side effects, but it can be dosed all at night if patients have trouble remembering to take it.
TCPR: And what do you do if clozapine doesn’t work?
Dr. Miller: First I’d want to make sure we’ve maximized the dose, and for that we rely on blood levels. Patients on clozapine are most likely to exhibit a therapeutic effect when total concentrations of clozapine + norclozapine are > 450 ng/mL. Eight weeks at a therapeutic dose is an adequate trial. After that, we don’t have randomized controlled trials to guide us, so what I’m going to say is gathered from experience and uncontrolled studies. If they are tolerating clozapine and deriving at least a little benefit from it, I will keep it going and add something in, starting with a second antipsychotic—this is one of the rare situations where I would combine antipsychotics. Aripiprazole and risperidone have some evidence to augment clozapine (Lähteenvuo M and Tiihonen J, Drugs 2021;81(11):1273–1284). ECT should also be considered at this stage. It mainly treats positive psychotic symptoms, but it can also help mood, suicidality, and even substance use comorbidities (Wang G et al, J Psychiatr Res 2018;105:23–32).
TCPR: Any other options?
Dr. Miller: We have a few medications that may help the overall psychopathology, including positive and negative symptoms. Lamotrigine, for example, has some beneficial effects when added to clozapine, according to a small meta-analysis (dose 50–200 mg Qday after titration) (Tiihonen J et al, Schizophr Res 2009;109(1–3):10–14). Another meta-analysis found benefits for adjunctive topiramate—both for positive and negative symptoms and for metabolic parameters (start 25 mg Qday, titrate to max of 200 mg BID) (Correll CU et al, J Clin Psychiatry 2016;77(6):e746–e756).
TCPR: Thank you for your time, Dr. Miller.
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