Liraglutide (rDNA origin) injection, approved by the FDA in 2010 for managing type 2 diabetes mellitus (T2DM), has a new formulation and indication for treating obesity in adults as an adjunct to a reduced-calorie diet and increased physical activity (Table 1).¹

How it works
Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. GLP-1, which regulates appetite and calorie intake, is found in several regions of the brain that are involved in regulating appetite. Patients taking liraglutide lose weight because of decreased calorie intake, not increased energy expenditure.

Liraglutide is endogenously metabolized without a specific organ as a major route of elimination.¹

Dosage and administration
Liraglutide is administered using a prefilled, multi-dose pen that can be injected in the abdomen, thigh, or upper arm. Recommended dosage is 3 mg/d, administered any time of day. Initiate dosage at 0.6 mg/d the first week, then titrate by 0.6 mg a week—to reduce the likelihood of adverse gastrointestinal symptoms—until 3 mg/d is reached.

Discontinue liraglutide if a patient has not lost at least 4% of body weight after 16 weeks of treatment, because it is unlikely the patient will achieve and sustain weight loss.

Efficacy
Liraglutide was studied in 3 clinical trials of obese and overweight participants who had a weight-related condition. Patients who had a history of major depressive disorder or suicide attempt were excluded from the studies. All participants in Studies 1 and 2 received instruction about following a reduced-calorie diet and increasing physical activity. In Study 3, patients were randomized to treatment after losing >5% of their body weight through reduced calorie intake and exercise; those who did not meet the required weight loss were excluded from the study. In these 56-week clinical studies:
   • of 3,731 participants without diabetes or a weight-related comorbidity, such as high blood pressure or high cholesterol, 62% of patients (n = 2,313) who took liraglutide lost ≥5% of their body weight from baseline, compared with 34% of participants who received placebo
   • of 635 participants with T2DM, 49% of patients (n = 311) treated with liraglutide lost ≥5% of their body weight compared with 16% placebo patients
   • of 422 participants with a weight-related comorbidity, 42% of patients (n = 177) lost ≥5% of their body weight compared with 21.7% of placebo patients.

Improvements in some cardiovascular disease risk factors were observed. Long-term follow up was not studied.

Contraindictations
Liraglutide is contraindicated in patients who have a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. In a 104-week study, malignant thyroid C-cell carcinomas were detected in rats and mice given liraglutide, 1 and 3 mg/kg/d; however, it was not detected in groups given 0.03 and 0.2 mg/kg/d. It isn’t known whether liraglutide can cause thyroid C-cell tumors in humans.

Patients should not take liraglutide if they have hypersensitivity to liraglutide or any product components, are using insulin, are taking any other GLP-1 receptor agonist, or are pregnant.

Adverse effects
The most common reported adverse effects are nausea (39.3%), hypoglycemia in patients with T2DM (23%), diarrhea (20.9%), constipation (19.4%), and vomiting (15.7%) (Table 2). In clinical trials, 9.8% of patients discontinued treatment because of adverse effects, compared with 4.3% of those receiving placebo.

Liraglutide has low potential for pharmacokinetic drug-drug interactions related to cytochrome P450 and plasma protein binding. For a full list of drug-drug interactions, see the full prescribing information.¹

Liraglutide (rDNA origin) injection, approved by the FDA in 2010 for managing type 2 diabetes mellitus (T2DM), has a new formulation and indication for treating obesity in adults as an adjunct to a reduced-calorie diet and increased physical activity (Table 1).¹

How it works
Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. GLP-1, which regulates appetite and calorie intake, is found in several regions of the brain that are involved in regulating appetite. Patients taking liraglutide lose weight because of decreased calorie intake, not increased energy expenditure.

Liraglutide is endogenously metabolized without a specific organ as a major route of elimination.¹

Dosage and administration
Liraglutide is administered using a prefilled, multi-dose pen that can be injected in the abdomen, thigh, or upper arm. Recommended dosage is 3 mg/d, administered any time of day. Initiate dosage at 0.6 mg/d the first week, then titrate by 0.6 mg a week—to reduce the likelihood of adverse gastrointestinal symptoms—until 3 mg/d is reached.

Discontinue liraglutide if a patient has not lost at least 4% of body weight after 16 weeks of treatment, because it is unlikely the patient will achieve and sustain weight loss.

Efficacy
Liraglutide was studied in 3 clinical trials of obese and overweight participants who had a weight-related condition. Patients who had a history of major depressive disorder or suicide attempt were excluded from the studies. All participants in Studies 1 and 2 received instruction about following a reduced-calorie diet and increasing physical activity. In Study 3, patients were randomized to treatment after losing >5% of their body weight through reduced calorie intake and exercise; those who did not meet the required weight loss were excluded from the study. In these 56-week clinical studies:
   • of 3,731 participants without diabetes or a weight-related comorbidity, such as high blood pressure or high cholesterol, 62% of patients (n = 2,313) who took liraglutide lost ≥5% of their body weight from baseline, compared with 34% of participants who received placebo
   • of 635 participants with T2DM, 49% of patients (n = 311) treated with liraglutide lost ≥5% of their body weight compared with 16% placebo patients
   • of 422 participants with a weight-related comorbidity, 42% of patients (n = 177) lost ≥5% of their body weight compared with 21.7% of placebo patients.

Improvements in some cardiovascular disease risk factors were observed. Long-term follow up was not studied.

Contraindictations
Liraglutide is contraindicated in patients who have a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. In a 104-week study, malignant thyroid C-cell carcinomas were detected in rats and mice given liraglutide, 1 and 3 mg/kg/d; however, it was not detected in groups given 0.03 and 0.2 mg/kg/d. It isn’t known whether liraglutide can cause thyroid C-cell tumors in humans.

Patients should not take liraglutide if they have hypersensitivity to liraglutide or any product components, are using insulin, are taking any other GLP-1 receptor agonist, or are pregnant.

Adverse effects
The most common reported adverse effects are nausea (39.3%), hypoglycemia in patients with T2DM (23%), diarrhea (20.9%), constipation (19.4%), and vomiting (15.7%) (Table 2). In clinical trials, 9.8% of patients discontinued treatment because of adverse effects, compared with 4.3% of those receiving placebo.

Liraglutide has low potential for pharmacokinetic drug-drug interactions related to cytochrome P450 and plasma protein binding. For a full list of drug-drug interactions, see the full prescribing information.¹

Liraglutide (rDNA origin) injection, approved by the FDA in 2010 for managing type 2 diabetes mellitus (T2DM), has a new formulation and indication for treating obesity in adults as an adjunct to a reduced-calorie diet and increased physical activity (Table 1).¹

How it works
Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. GLP-1, which regulates appetite and calorie intake, is found in several regions of the brain that are involved in regulating appetite. Patients taking liraglutide lose weight because of decreased calorie intake, not increased energy expenditure.

Liraglutide is endogenously metabolized without a specific organ as a major route of elimination.¹

Dosage and administration
Liraglutide is administered using a prefilled, multi-dose pen that can be injected in the abdomen, thigh, or upper arm. Recommended dosage is 3 mg/d, administered any time of day. Initiate dosage at 0.6 mg/d the first week, then titrate by 0.6 mg a week—to reduce the likelihood of adverse gastrointestinal symptoms—until 3 mg/d is reached.

Discontinue liraglutide if a patient has not lost at least 4% of body weight after 16 weeks of treatment, because it is unlikely the patient will achieve and sustain weight loss.

Efficacy
Liraglutide was studied in 3 clinical trials of obese and overweight participants who had a weight-related condition. Patients who had a history of major depressive disorder or suicide attempt were excluded from the studies. All participants in Studies 1 and 2 received instruction about following a reduced-calorie diet and increasing physical activity. In Study 3, patients were randomized to treatment after losing >5% of their body weight through reduced calorie intake and exercise; those who did not meet the required weight loss were excluded from the study. In these 56-week clinical studies:
   • of 3,731 participants without diabetes or a weight-related comorbidity, such as high blood pressure or high cholesterol, 62% of patients (n = 2,313) who took liraglutide lost ≥5% of their body weight from baseline, compared with 34% of participants who received placebo
   • of 635 participants with T2DM, 49% of patients (n = 311) treated with liraglutide lost ≥5% of their body weight compared with 16% placebo patients
   • of 422 participants with a weight-related comorbidity, 42% of patients (n = 177) lost ≥5% of their body weight compared with 21.7% of placebo patients.

Improvements in some cardiovascular disease risk factors were observed. Long-term follow up was not studied.

Contraindictations
Liraglutide is contraindicated in patients who have a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. In a 104-week study, malignant thyroid C-cell carcinomas were detected in rats and mice given liraglutide, 1 and 3 mg/kg/d; however, it was not detected in groups given 0.03 and 0.2 mg/kg/d. It isn’t known whether liraglutide can cause thyroid C-cell tumors in humans.

Patients should not take liraglutide if they have hypersensitivity to liraglutide or any product components, are using insulin, are taking any other GLP-1 receptor agonist, or are pregnant.

Adverse effects
The most common reported adverse effects are nausea (39.3%), hypoglycemia in patients with T2DM (23%), diarrhea (20.9%), constipation (19.4%), and vomiting (15.7%) (Table 2). In clinical trials, 9.8% of patients discontinued treatment because of adverse effects, compared with 4.3% of those receiving placebo.

Liraglutide has low potential for pharmacokinetic drug-drug interactions related to cytochrome P450 and plasma protein binding. For a full list of drug-drug interactions, see the full prescribing information.¹

The less time that passes between the onset of psychosis and initiation of appropriate treatment, the greater the patient’s odds of recovery.¹ However, relapse prevention is a major clinical challenge because >80% of patients will relapse within 5 years, and, on average, 40% to 50% of patients with a first-episode schizophrenia will relapse within 2 years depending on the definition used and patient characteristics.² Although there are several explanations and contributing factors to relapses, non­adherence—partial or complete discontinuation of antipsychotics—is a primary risk factor, contributing to a 5-fold increase in relapse risk.³

As such, optimal antipsychotic selection, dosing, and monitoring play an important role in managing this illness. Patients with first-episode psychosis (FEP) are unusual in some ways, compared with patients with multiple episodes of psychosis and represent a different stage of schizophrenia.

In this 2-part series, we will discuss pharmacotherapy for FEP. This article focuses on antipsychotic selection, dosage, and duration of treat­ment among these patients. The second article, in the July 2015 issue, reviews the rationale and evidence for non-standard, first-line thera­pies, including long-acting injectable antipsychotics and clozapine.

Defining FEP
FEP refers to a patient who has presented, been evaluated, and received treatment for the first psychotic episode associated with a schizophre­nia spectrum diagnosis.⁴ FEP is part of a trajectory marked by tran­ sitional periods. The patient transitions from being “healthy” to a prodromal state characterized by: (1) nonpsychotic behav­ioral disturbances such as depression or obsessive-compulsive disorder, (2) attenu­ated psychotic symptoms not requiring treatment, then converting to (3) psychotic symptoms prompting initial presentation for antipsychotic pharmacotherapy, lead­ing to (4) a formal diagnosis of schizo­phreniform disorder and, subsequently, schizophrenia, requiring treatment to sta­bilize symptoms.

There are 2 critical periods along this continuum: prodromal stage and the dura­tion of untreated psychosis (DUP). The prodromal period is a retrospectively iden­tified time where the patient shows initial nonpsychotic disturbances (eg, cognitive and behavioral symptoms) before exhibit­ing clinical diagnostic criteria for a schizo­phrenia spectrum disorder. Approximately one-third of patients exhibiting these symptoms convert to psychosis within 1 year, and early treatment engagement at this stage has been shown to improve out­comes.⁵ The DUP is the time from when a patient has noticeable psychotic symptoms to initiation of drug treatment. The DUP is a consistent predictor of clinical out­come in schizophrenia, including negative symptoms, quality of life, and functional capacity.¹

Antipsychotic selection
Treatment goals for FEP patients include:
   • minimizing the DUP
   • rapidly stabilizing psychosis
   • achieving full symptomatic remission
   • preventing relapse.

Several treatment guidelines for manag­ing schizophrenia offer variable recommen­dations for initial antipsychotic treatment in patients with first-episode schizophre­nia (Table 1).^6-15 Most recom­mend second-generation antipsychotics (SGAs) over first-generation antipsy­chotics (FGAs)^6,8,9,13,15 with specific recom­mendations on minimizing neurologic and metabolic adverse effects—to which FEP patients are susceptible—by avoid­ing high-potency and neurotoxic FGAs (eg, haloperidol and fluphenazine),⁷ clo­zapine,^11,14 olanzapine,¹¹ or ziprasidone.¹⁴ Two guidelines—the National Institute for Health and Care Excellence and the Scottish Intercollegiate Guidelines Network—do not state a preference for antipsychotic selection.^10,12

Study design and demographics. Research studies of FEP share some simi­larities in study design; however, there is enough variability to make it difficult to compare studies and generalize find­ings (Table 2).¹⁶ The variability of DUP is a limitation when comparing studies because it is a significant predic­tor of clinical outcome. Patients who abuse substances—and often are more challeng­ing to treat¹⁷—typically are excluded from these trials, which could explain the high response rate documented in studies of first-episode schizophrenia.

In addition, some FEP patients included in clinical trials might not be truly antipsy­chotic naïve; an estimated 25% to 75% of patients in these studies are antipsychotic naïve. This is an important consideration when comparing data on adverse effects that occur early in treatment. Additionally, acknowledging the advantages and disad­vantages of how to handle missing data is critical because of the high dropout rate observed in these studies.¹⁸

Efficacy. There is a high response rate to antipsychotic therapy—ranging from 46% to 96%, depending on the study—in patients with first-episode schizophrenia.³ The response mainly is seen in reduction of positive symptoms because typically negative and cognitive symptoms do not respond to antipsychotics. One study reported only 29% of patients achieved both positive and negative symptom remis­sion.¹⁹ It is likely that secondary negative symptoms caused by social withdrawal, reduced speech, and avoidance improve when positive symptoms subside, but pri­mary negative symptoms endure.In general, there is a lack of evidence suggesting that 1 antipsychotic class or agent is more effective than another. Studies mainly assess effectiveness using the primary outcome measure of all-cause discontinuation, such as the Clinical Antipsychotic Trials of Intervention Effectiveness study.²⁰ This outcome mea­sure is a mixture of patient preference, tol­erability, and efficacy that provides a more generalizable gauge on how well the treat­ment works in the clinic rather than tightly regulated settings such as clinical trials. A recent meta-analysis supports no differ­ences in efficacy among antipsychotics in early-episode psychosis.²¹

Tolerability. Because there are no significant differences among antipsychotic classes or agents in terms of efficacy in first-episode schizophrenia, drug selection is guided mainly by (1) the adverse effect profile and (2) what should be avoided depending on patient-specific variables. Evidence sug­gests first-episode patients are more sen­sitive to adverse effects of antipsychotics, particularly neurologic side effects (see this article at CurrentPsychiatry.com for a table comparing adverse effects of antipsychot­ics in first-episode psychosis).^18,22-29 Overall adverse effect profiles remain similar across FEP or multi-episode patients, but tend to be more exaggerated in drug-naïve patients with FEP.

Regarding FGA side effects, McEvoy et al¹⁸ demonstrated the neuroleptic threshold occurs at 50% lower haloperi­dol dosages in patients with first-episode schizophrenia (2.1 mg/d) compared with multi-episode schizophrenia (4.3 mg/d). Other trials suggest SGAs are associated with a lower risk of extrapyramidal side effects (EPS) or use of adjunctive therapies such as anticholinergic drugs or benzo­diazepines.^23-27 An exception to this state­ment is that higher risperidone dosages (≥4 to 6 mg/d) have been found to have higher rates of EPS and use of adjunctive medica­tions to treat these symptoms in FEP.²⁶ This is important because studies report higher discontinuation rates with more severe adverse effects of antipsychotics.

Cardiometabolic effects are of particular concern in first-episode patients because most weight gain happens in the first 3 to 4 months of treatment and remains throughout the first year.^18,24,29,30 Studies have shown that olanzapine, quetiap­ine, and risperidone are associated with more clinically significant weight gain compared with haloperidol and ziprasi­done.^23-25 Olanzapine-associated weight gain has been reported to be twice that of quetiapine and risperidone.¹⁸ Regardless, the EUFEST trial did not find a difference in clinically significant weight gain after 12 months among the antipsychotics studied, including haloperidol and ziprasidone.²⁵

Weight gain associated with these anti­psychotics is accompanied by changes in fasting triglycerides, glucose, total choles­terol,²³ and high-density lipoprotein cho­lesterol as well as an increase in body mass index (BMI) categorization²⁹ (eg, shift from normal to overweight).^18,25 Patients with lower baseline BMI and in racial minor­ity groups might experience more rapid weight gain regardless of antipsychotic selection.^29,30

Hyperprolactinemia could be under-recognized and could contribute to early treatment discontinuation.³¹ Evidence in patients with first-episode schizophrenia suggests similar outcomes as those seen in multi-episode patients, in whom ris­peridone is associated with higher pro­lactin elevations and clinically significant hyperprolactinemia (eg, galactorrhea and gynecomastia) compared with olanzapine, quetiapine, and low-dose haloperidol.^18,23,24 However, there is a lack of studies that assess whether long-term therapy with strong D2 receptor antagonists increases the risk of bone demineralization or path­ological fractures when started before patients’ bones reach maximum density in their mid-20s.³¹

Antipsychotic dosing
Given the high rate of treatment response in FEP and patients’ higher sensitivity to antipsychotic adverse effects, particularly EPS, guidelines recommend antipsychotic dosages lower than those used for multi-episode schizophrenia,¹¹ especially FGAs. Based on trial data, commonly used dos­ages include:
   • haloperidol, ≤5 mg/d^23-25,29
   • olanzapine, 10 mg/d^18,23,25,29
   • risperidone, ≤4 to 6 mg/d.^18,24,29,32

In general, haloperidol and risperidone, 2 to 3 mg/d, were well tolerated and effec­tive in trials. Higher quetiapine dosages of 500 to 600 mg/d could be required.^11,18,25

According to a survey on prescribing practices of antipsychotic selection and dosing in first-episode schizophrenia,4 clinical prescribing practices tend to use unnecessarily high initial antipsychotic dosing compared with trial data. There also is variability in the usual target anti­psychotic dosage ranging from 50% lower dosages to normal dosages in chronic schizophrenia to above FDA-approved maximum dosages for olanzapine (which may be necessary to counteract tobacco-induced cytochrome P450 1A2 enzyme induction).

In addition, these clinicians reported prescribing aripiprazole, an antipsychotic with weaker evidence (eg, case reports, case series, open-label studies) support­ing its efficacy and tolerability in FEP. These prescribing practices could reflect attempts to reduce the DUP and achieve symptom remission, so long as tolerability is not a concern.

Essentially, prescribed dosages should be based on symptom improvement and tolerability. This ideal dosage will vary as illustrated by Kapur et al,³³ who reported that FEP patients (N = 20) given haloper­idol, 1 mg or 2.5 mg/d, had D2 receptor occupancy rates of 38% to 87%, which was significantly dose-related (1 mg/d mean = 59%, 2.5 mg/d mean = 75%). Clinical response and EPS significantly increased as D2 receptor occupancy exceeded 65% and 78%, respectively.

Antipsychotic response
When should you expect to see symp­tom improvement in patients with first-episode schizophrenia?
Emsley et al³⁴ reported a 77.6% response rate among first-episode patients (N = 522) treated with low dosages of risperidone (mean modal dosage [MMD] = 3.3 mg/d) and haloperidol (MMD = 2.9 mg/d). They found variable response times that were evenly dispersed over a 10-week period. Nearly one-quarter (22.5%) did not respond until after week 4 and 11.2% did not respond until after week 8. In a study of FEP patients (N = 112) treated with olanzapine (MMD = 11.8 mg/d) or risperi­done (MMD = 3.9 mg/d), Gallego et al³⁵ reported a cumulative response of 39.6% at week 8 and 65.1% at week 16.

Although there is evidence that, among multi-episode patients, early nonresponse to antipsychotic therapy could predict subsequent nonresponse,³⁶ the evidence is mixed for first-episode schizophrenia. Studies by Emsley et al³⁴ and Gallego et al³⁵ did not find that early nonresponse at weeks 1 or 2 predicted subsequent nonre­sponse at week 4 or later. However, other studies support the idea that early nonre­sponse predicts subsequent nonresponse and early antipsychotic response predicts future response in first-episode patients, with good specificity and sensitivity.^37,38

Overall, treatment response in first-episode schizophrenia is variable. An adequate antipsychotic trial may be lon­ger, 8 to 16 weeks, compared with 4 to 8 weeks in multi-episode patients. Because research suggests that failure to respond to treatment may lead to medication non­adherence,³⁹ it is reasonable to consider switching antipsychotics when a patient experiences minimal or no response to antipsychotic therapy at week 2; however, this should be a patient-specific decision.

How long should you continue therapy after symptom remission?
There is a lack of consensus on the dura­tion of therapy for a patient treated for first-episode schizophrenia because a small percentage (10% to 20%) do not relapse after the first psychotic episode.³ In general, treatment guidelines and expert consensus statements recommend at least 1 to 2 years of treatment before considering a discon­tinuation trial.^7,10-11 Discuss the benefits and risks of maintenance treatment with your patient and obtain informed consent. With patients with minimal insight, obtaining proper consent is not possible and the phy­sician must exercise judgment unilaterally, if necessary, after educating the family.

After at least 12 months of treatment, antipsychotic therapy could continue indefinitely, depending on patient-specific factors. There are no predictors for identi­fying patients who do not require mainte­nance therapy beyond the first psychotic episode. The absence of negative and cog­nitive deficits could provide clues that a patient might be a candidate for antipsy­chotic tapering.

Predicting the treatment course
Research investigating clinical predic­tors or biomarkers that forecast whether a patient will respond to treatment is pre­liminary. Many characteristics have been identified (Table 3^{1,3,4,23,25,40}) and include shorter DUP,¹ poorer premorbid function,³ antipsychotic discontinuation,³ a trusting patient-doctor relationship,⁴¹ and antipsychotic-related adverse effects,^23,25 which are predictive of response, nonre­sponse, relapse, adherence, and nonadher­ence, respectively.
 

Bottom Line
The goals of pharmacological treatment of first-episode schizophrenia are to minimize the duration of untreated psychosis and target full remission of positive symptoms using the lowest possible antipsychotic dosages. Pharmacotherapy should continued for 1 to 2 years, with longer duration considered if it is discussed with the patient and with vigilant monitoring for adverse effects and suboptimal medication nonadherence to prevent relapse.
 

Editor’s note: The second article in this series in the July 2015 issue reviews the rationale and evidence for non-standard, first-line therapies, including long-acting injectable antipsychotics and clozapine.

Related Resources
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.
• Martens L, Baker S. Promoting recovery from first epi­sode psychosis: a guide for families. Centre for Addiction and Mental Health. http://www.camh.ca/en/hospital/ Documents/www.camh.net/AboutCAMH/Guideto CAMH/MentalHealthPrograms/SchizophreniaProgram/ 3936PromotingRecoveryFirstEpisodePsychosisfinal.pdf.

Drug Brand Names
Aripiprazole • Abilify                Lurasidone • Latuda
Asenapine • Saphris                Olanzapine • Zyprexa
Clozapine • Clozaril                 Paliperidone • Invega
Fluphenazine • Prolixin            Quetiapine • Seroquel
Iloperidone • Fanapt               Risperidone • Risperdal
Haloperidol • Haldol                Ziprasidone • Geodon

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.
Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

The less time that passes between the onset of psychosis and initiation of appropriate treatment, the greater the patient’s odds of recovery.¹ However, relapse prevention is a major clinical challenge because >80% of patients will relapse within 5 years, and, on average, 40% to 50% of patients with a first-episode schizophrenia will relapse within 2 years depending on the definition used and patient characteristics.² Although there are several explanations and contributing factors to relapses, non­adherence—partial or complete discontinuation of antipsychotics—is a primary risk factor, contributing to a 5-fold increase in relapse risk.³

As such, optimal antipsychotic selection, dosing, and monitoring play an important role in managing this illness. Patients with first-episode psychosis (FEP) are unusual in some ways, compared with patients with multiple episodes of psychosis and represent a different stage of schizophrenia.

In this 2-part series, we will discuss pharmacotherapy for FEP. This article focuses on antipsychotic selection, dosage, and duration of treat­ment among these patients. The second article, in the July 2015 issue, reviews the rationale and evidence for non-standard, first-line thera­pies, including long-acting injectable antipsychotics and clozapine.

Defining FEP
FEP refers to a patient who has presented, been evaluated, and received treatment for the first psychotic episode associated with a schizophre­nia spectrum diagnosis.⁴ FEP is part of a trajectory marked by tran­ sitional periods. The patient transitions from being “healthy” to a prodromal state characterized by: (1) nonpsychotic behav­ioral disturbances such as depression or obsessive-compulsive disorder, (2) attenu­ated psychotic symptoms not requiring treatment, then converting to (3) psychotic symptoms prompting initial presentation for antipsychotic pharmacotherapy, lead­ing to (4) a formal diagnosis of schizo­phreniform disorder and, subsequently, schizophrenia, requiring treatment to sta­bilize symptoms.

There are 2 critical periods along this continuum: prodromal stage and the dura­tion of untreated psychosis (DUP). The prodromal period is a retrospectively iden­tified time where the patient shows initial nonpsychotic disturbances (eg, cognitive and behavioral symptoms) before exhibit­ing clinical diagnostic criteria for a schizo­phrenia spectrum disorder. Approximately one-third of patients exhibiting these symptoms convert to psychosis within 1 year, and early treatment engagement at this stage has been shown to improve out­comes.⁵ The DUP is the time from when a patient has noticeable psychotic symptoms to initiation of drug treatment. The DUP is a consistent predictor of clinical out­come in schizophrenia, including negative symptoms, quality of life, and functional capacity.¹

Antipsychotic selection
Treatment goals for FEP patients include:
   • minimizing the DUP
   • rapidly stabilizing psychosis
   • achieving full symptomatic remission
   • preventing relapse.

Several treatment guidelines for manag­ing schizophrenia offer variable recommen­dations for initial antipsychotic treatment in patients with first-episode schizophre­nia (Table 1).^6-15 Most recom­mend second-generation antipsychotics (SGAs) over first-generation antipsy­chotics (FGAs)^6,8,9,13,15 with specific recom­mendations on minimizing neurologic and metabolic adverse effects—to which FEP patients are susceptible—by avoid­ing high-potency and neurotoxic FGAs (eg, haloperidol and fluphenazine),⁷ clo­zapine,^11,14 olanzapine,¹¹ or ziprasidone.¹⁴ Two guidelines—the National Institute for Health and Care Excellence and the Scottish Intercollegiate Guidelines Network—do not state a preference for antipsychotic selection.^10,12

Study design and demographics. Research studies of FEP share some simi­larities in study design; however, there is enough variability to make it difficult to compare studies and generalize find­ings (Table 2).¹⁶ The variability of DUP is a limitation when comparing studies because it is a significant predic­tor of clinical outcome. Patients who abuse substances—and often are more challeng­ing to treat¹⁷—typically are excluded from these trials, which could explain the high response rate documented in studies of first-episode schizophrenia.

In addition, some FEP patients included in clinical trials might not be truly antipsy­chotic naïve; an estimated 25% to 75% of patients in these studies are antipsychotic naïve. This is an important consideration when comparing data on adverse effects that occur early in treatment. Additionally, acknowledging the advantages and disad­vantages of how to handle missing data is critical because of the high dropout rate observed in these studies.¹⁸

Efficacy. There is a high response rate to antipsychotic therapy—ranging from 46% to 96%, depending on the study—in patients with first-episode schizophrenia.³ The response mainly is seen in reduction of positive symptoms because typically negative and cognitive symptoms do not respond to antipsychotics. One study reported only 29% of patients achieved both positive and negative symptom remis­sion.¹⁹ It is likely that secondary negative symptoms caused by social withdrawal, reduced speech, and avoidance improve when positive symptoms subside, but pri­mary negative symptoms endure.In general, there is a lack of evidence suggesting that 1 antipsychotic class or agent is more effective than another. Studies mainly assess effectiveness using the primary outcome measure of all-cause discontinuation, such as the Clinical Antipsychotic Trials of Intervention Effectiveness study.²⁰ This outcome mea­sure is a mixture of patient preference, tol­erability, and efficacy that provides a more generalizable gauge on how well the treat­ment works in the clinic rather than tightly regulated settings such as clinical trials. A recent meta-analysis supports no differ­ences in efficacy among antipsychotics in early-episode psychosis.²¹

Tolerability. Because there are no significant differences among antipsychotic classes or agents in terms of efficacy in first-episode schizophrenia, drug selection is guided mainly by (1) the adverse effect profile and (2) what should be avoided depending on patient-specific variables. Evidence sug­gests first-episode patients are more sen­sitive to adverse effects of antipsychotics, particularly neurologic side effects (see this article at CurrentPsychiatry.com for a table comparing adverse effects of antipsychot­ics in first-episode psychosis).^18,22-29 Overall adverse effect profiles remain similar across FEP or multi-episode patients, but tend to be more exaggerated in drug-naïve patients with FEP.

Regarding FGA side effects, McEvoy et al¹⁸ demonstrated the neuroleptic threshold occurs at 50% lower haloperi­dol dosages in patients with first-episode schizophrenia (2.1 mg/d) compared with multi-episode schizophrenia (4.3 mg/d). Other trials suggest SGAs are associated with a lower risk of extrapyramidal side effects (EPS) or use of adjunctive therapies such as anticholinergic drugs or benzo­diazepines.^23-27 An exception to this state­ment is that higher risperidone dosages (≥4 to 6 mg/d) have been found to have higher rates of EPS and use of adjunctive medica­tions to treat these symptoms in FEP.²⁶ This is important because studies report higher discontinuation rates with more severe adverse effects of antipsychotics.

Cardiometabolic effects are of particular concern in first-episode patients because most weight gain happens in the first 3 to 4 months of treatment and remains throughout the first year.^18,24,29,30 Studies have shown that olanzapine, quetiap­ine, and risperidone are associated with more clinically significant weight gain compared with haloperidol and ziprasi­done.^23-25 Olanzapine-associated weight gain has been reported to be twice that of quetiapine and risperidone.¹⁸ Regardless, the EUFEST trial did not find a difference in clinically significant weight gain after 12 months among the antipsychotics studied, including haloperidol and ziprasidone.²⁵

Weight gain associated with these anti­psychotics is accompanied by changes in fasting triglycerides, glucose, total choles­terol,²³ and high-density lipoprotein cho­lesterol as well as an increase in body mass index (BMI) categorization²⁹ (eg, shift from normal to overweight).^18,25 Patients with lower baseline BMI and in racial minor­ity groups might experience more rapid weight gain regardless of antipsychotic selection.^29,30

Hyperprolactinemia could be under-recognized and could contribute to early treatment discontinuation.³¹ Evidence in patients with first-episode schizophrenia suggests similar outcomes as those seen in multi-episode patients, in whom ris­peridone is associated with higher pro­lactin elevations and clinically significant hyperprolactinemia (eg, galactorrhea and gynecomastia) compared with olanzapine, quetiapine, and low-dose haloperidol.^18,23,24 However, there is a lack of studies that assess whether long-term therapy with strong D2 receptor antagonists increases the risk of bone demineralization or path­ological fractures when started before patients’ bones reach maximum density in their mid-20s.³¹

Antipsychotic dosing
Given the high rate of treatment response in FEP and patients’ higher sensitivity to antipsychotic adverse effects, particularly EPS, guidelines recommend antipsychotic dosages lower than those used for multi-episode schizophrenia,¹¹ especially FGAs. Based on trial data, commonly used dos­ages include:
   • haloperidol, ≤5 mg/d^23-25,29
   • olanzapine, 10 mg/d^18,23,25,29
   • risperidone, ≤4 to 6 mg/d.^18,24,29,32

In general, haloperidol and risperidone, 2 to 3 mg/d, were well tolerated and effec­tive in trials. Higher quetiapine dosages of 500 to 600 mg/d could be required.^11,18,25

According to a survey on prescribing practices of antipsychotic selection and dosing in first-episode schizophrenia,4 clinical prescribing practices tend to use unnecessarily high initial antipsychotic dosing compared with trial data. There also is variability in the usual target anti­psychotic dosage ranging from 50% lower dosages to normal dosages in chronic schizophrenia to above FDA-approved maximum dosages for olanzapine (which may be necessary to counteract tobacco-induced cytochrome P450 1A2 enzyme induction).

In addition, these clinicians reported prescribing aripiprazole, an antipsychotic with weaker evidence (eg, case reports, case series, open-label studies) support­ing its efficacy and tolerability in FEP. These prescribing practices could reflect attempts to reduce the DUP and achieve symptom remission, so long as tolerability is not a concern.

Essentially, prescribed dosages should be based on symptom improvement and tolerability. This ideal dosage will vary as illustrated by Kapur et al,³³ who reported that FEP patients (N = 20) given haloper­idol, 1 mg or 2.5 mg/d, had D2 receptor occupancy rates of 38% to 87%, which was significantly dose-related (1 mg/d mean = 59%, 2.5 mg/d mean = 75%). Clinical response and EPS significantly increased as D2 receptor occupancy exceeded 65% and 78%, respectively.

Antipsychotic response
When should you expect to see symp­tom improvement in patients with first-episode schizophrenia?
Emsley et al³⁴ reported a 77.6% response rate among first-episode patients (N = 522) treated with low dosages of risperidone (mean modal dosage [MMD] = 3.3 mg/d) and haloperidol (MMD = 2.9 mg/d). They found variable response times that were evenly dispersed over a 10-week period. Nearly one-quarter (22.5%) did not respond until after week 4 and 11.2% did not respond until after week 8. In a study of FEP patients (N = 112) treated with olanzapine (MMD = 11.8 mg/d) or risperi­done (MMD = 3.9 mg/d), Gallego et al³⁵ reported a cumulative response of 39.6% at week 8 and 65.1% at week 16.

Although there is evidence that, among multi-episode patients, early nonresponse to antipsychotic therapy could predict subsequent nonresponse,³⁶ the evidence is mixed for first-episode schizophrenia. Studies by Emsley et al³⁴ and Gallego et al³⁵ did not find that early nonresponse at weeks 1 or 2 predicted subsequent nonre­sponse at week 4 or later. However, other studies support the idea that early nonre­sponse predicts subsequent nonresponse and early antipsychotic response predicts future response in first-episode patients, with good specificity and sensitivity.^37,38

Overall, treatment response in first-episode schizophrenia is variable. An adequate antipsychotic trial may be lon­ger, 8 to 16 weeks, compared with 4 to 8 weeks in multi-episode patients. Because research suggests that failure to respond to treatment may lead to medication non­adherence,³⁹ it is reasonable to consider switching antipsychotics when a patient experiences minimal or no response to antipsychotic therapy at week 2; however, this should be a patient-specific decision.

How long should you continue therapy after symptom remission?
There is a lack of consensus on the dura­tion of therapy for a patient treated for first-episode schizophrenia because a small percentage (10% to 20%) do not relapse after the first psychotic episode.³ In general, treatment guidelines and expert consensus statements recommend at least 1 to 2 years of treatment before considering a discon­tinuation trial.^7,10-11 Discuss the benefits and risks of maintenance treatment with your patient and obtain informed consent. With patients with minimal insight, obtaining proper consent is not possible and the phy­sician must exercise judgment unilaterally, if necessary, after educating the family.

After at least 12 months of treatment, antipsychotic therapy could continue indefinitely, depending on patient-specific factors. There are no predictors for identi­fying patients who do not require mainte­nance therapy beyond the first psychotic episode. The absence of negative and cog­nitive deficits could provide clues that a patient might be a candidate for antipsy­chotic tapering.

Predicting the treatment course
Research investigating clinical predic­tors or biomarkers that forecast whether a patient will respond to treatment is pre­liminary. Many characteristics have been identified (Table 3^{1,3,4,23,25,40}) and include shorter DUP,¹ poorer premorbid function,³ antipsychotic discontinuation,³ a trusting patient-doctor relationship,⁴¹ and antipsychotic-related adverse effects,^23,25 which are predictive of response, nonre­sponse, relapse, adherence, and nonadher­ence, respectively.
 

Bottom Line
The goals of pharmacological treatment of first-episode schizophrenia are to minimize the duration of untreated psychosis and target full remission of positive symptoms using the lowest possible antipsychotic dosages. Pharmacotherapy should continued for 1 to 2 years, with longer duration considered if it is discussed with the patient and with vigilant monitoring for adverse effects and suboptimal medication nonadherence to prevent relapse.
 

Editor’s note: The second article in this series in the July 2015 issue reviews the rationale and evidence for non-standard, first-line therapies, including long-acting injectable antipsychotics and clozapine.

Related Resources
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.
• Martens L, Baker S. Promoting recovery from first epi­sode psychosis: a guide for families. Centre for Addiction and Mental Health. http://www.camh.ca/en/hospital/ Documents/www.camh.net/AboutCAMH/Guideto CAMH/MentalHealthPrograms/SchizophreniaProgram/ 3936PromotingRecoveryFirstEpisodePsychosisfinal.pdf.

Drug Brand Names
Aripiprazole • Abilify                Lurasidone • Latuda
Asenapine • Saphris                Olanzapine • Zyprexa
Clozapine • Clozaril                 Paliperidone • Invega
Fluphenazine • Prolixin            Quetiapine • Seroquel
Iloperidone • Fanapt               Risperidone • Risperdal
Haloperidol • Haldol                Ziprasidone • Geodon

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.
Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

The less time that passes between the onset of psychosis and initiation of appropriate treatment, the greater the patient’s odds of recovery.¹ However, relapse prevention is a major clinical challenge because >80% of patients will relapse within 5 years, and, on average, 40% to 50% of patients with a first-episode schizophrenia will relapse within 2 years depending on the definition used and patient characteristics.² Although there are several explanations and contributing factors to relapses, non­adherence—partial or complete discontinuation of antipsychotics—is a primary risk factor, contributing to a 5-fold increase in relapse risk.³

As such, optimal antipsychotic selection, dosing, and monitoring play an important role in managing this illness. Patients with first-episode psychosis (FEP) are unusual in some ways, compared with patients with multiple episodes of psychosis and represent a different stage of schizophrenia.

In this 2-part series, we will discuss pharmacotherapy for FEP. This article focuses on antipsychotic selection, dosage, and duration of treat­ment among these patients. The second article, in the July 2015 issue, reviews the rationale and evidence for non-standard, first-line thera­pies, including long-acting injectable antipsychotics and clozapine.

Defining FEP
FEP refers to a patient who has presented, been evaluated, and received treatment for the first psychotic episode associated with a schizophre­nia spectrum diagnosis.⁴ FEP is part of a trajectory marked by tran­ sitional periods. The patient transitions from being “healthy” to a prodromal state characterized by: (1) nonpsychotic behav­ioral disturbances such as depression or obsessive-compulsive disorder, (2) attenu­ated psychotic symptoms not requiring treatment, then converting to (3) psychotic symptoms prompting initial presentation for antipsychotic pharmacotherapy, lead­ing to (4) a formal diagnosis of schizo­phreniform disorder and, subsequently, schizophrenia, requiring treatment to sta­bilize symptoms.

There are 2 critical periods along this continuum: prodromal stage and the dura­tion of untreated psychosis (DUP). The prodromal period is a retrospectively iden­tified time where the patient shows initial nonpsychotic disturbances (eg, cognitive and behavioral symptoms) before exhibit­ing clinical diagnostic criteria for a schizo­phrenia spectrum disorder. Approximately one-third of patients exhibiting these symptoms convert to psychosis within 1 year, and early treatment engagement at this stage has been shown to improve out­comes.⁵ The DUP is the time from when a patient has noticeable psychotic symptoms to initiation of drug treatment. The DUP is a consistent predictor of clinical out­come in schizophrenia, including negative symptoms, quality of life, and functional capacity.¹

Antipsychotic selection
Treatment goals for FEP patients include:
   • minimizing the DUP
   • rapidly stabilizing psychosis
   • achieving full symptomatic remission
   • preventing relapse.

Several treatment guidelines for manag­ing schizophrenia offer variable recommen­dations for initial antipsychotic treatment in patients with first-episode schizophre­nia (Table 1).^6-15 Most recom­mend second-generation antipsychotics (SGAs) over first-generation antipsy­chotics (FGAs)^6,8,9,13,15 with specific recom­mendations on minimizing neurologic and metabolic adverse effects—to which FEP patients are susceptible—by avoid­ing high-potency and neurotoxic FGAs (eg, haloperidol and fluphenazine),⁷ clo­zapine,^11,14 olanzapine,¹¹ or ziprasidone.¹⁴ Two guidelines—the National Institute for Health and Care Excellence and the Scottish Intercollegiate Guidelines Network—do not state a preference for antipsychotic selection.^10,12

Study design and demographics. Research studies of FEP share some simi­larities in study design; however, there is enough variability to make it difficult to compare studies and generalize find­ings (Table 2).¹⁶ The variability of DUP is a limitation when comparing studies because it is a significant predic­tor of clinical outcome. Patients who abuse substances—and often are more challeng­ing to treat¹⁷—typically are excluded from these trials, which could explain the high response rate documented in studies of first-episode schizophrenia.

In addition, some FEP patients included in clinical trials might not be truly antipsy­chotic naïve; an estimated 25% to 75% of patients in these studies are antipsychotic naïve. This is an important consideration when comparing data on adverse effects that occur early in treatment. Additionally, acknowledging the advantages and disad­vantages of how to handle missing data is critical because of the high dropout rate observed in these studies.¹⁸

Efficacy. There is a high response rate to antipsychotic therapy—ranging from 46% to 96%, depending on the study—in patients with first-episode schizophrenia.³ The response mainly is seen in reduction of positive symptoms because typically negative and cognitive symptoms do not respond to antipsychotics. One study reported only 29% of patients achieved both positive and negative symptom remis­sion.¹⁹ It is likely that secondary negative symptoms caused by social withdrawal, reduced speech, and avoidance improve when positive symptoms subside, but pri­mary negative symptoms endure.In general, there is a lack of evidence suggesting that 1 antipsychotic class or agent is more effective than another. Studies mainly assess effectiveness using the primary outcome measure of all-cause discontinuation, such as the Clinical Antipsychotic Trials of Intervention Effectiveness study.²⁰ This outcome mea­sure is a mixture of patient preference, tol­erability, and efficacy that provides a more generalizable gauge on how well the treat­ment works in the clinic rather than tightly regulated settings such as clinical trials. A recent meta-analysis supports no differ­ences in efficacy among antipsychotics in early-episode psychosis.²¹

Tolerability. Because there are no significant differences among antipsychotic classes or agents in terms of efficacy in first-episode schizophrenia, drug selection is guided mainly by (1) the adverse effect profile and (2) what should be avoided depending on patient-specific variables. Evidence sug­gests first-episode patients are more sen­sitive to adverse effects of antipsychotics, particularly neurologic side effects (see this article at CurrentPsychiatry.com for a table comparing adverse effects of antipsychot­ics in first-episode psychosis).^18,22-29 Overall adverse effect profiles remain similar across FEP or multi-episode patients, but tend to be more exaggerated in drug-naïve patients with FEP.

Regarding FGA side effects, McEvoy et al¹⁸ demonstrated the neuroleptic threshold occurs at 50% lower haloperi­dol dosages in patients with first-episode schizophrenia (2.1 mg/d) compared with multi-episode schizophrenia (4.3 mg/d). Other trials suggest SGAs are associated with a lower risk of extrapyramidal side effects (EPS) or use of adjunctive therapies such as anticholinergic drugs or benzo­diazepines.^23-27 An exception to this state­ment is that higher risperidone dosages (≥4 to 6 mg/d) have been found to have higher rates of EPS and use of adjunctive medica­tions to treat these symptoms in FEP.²⁶ This is important because studies report higher discontinuation rates with more severe adverse effects of antipsychotics.

Cardiometabolic effects are of particular concern in first-episode patients because most weight gain happens in the first 3 to 4 months of treatment and remains throughout the first year.^18,24,29,30 Studies have shown that olanzapine, quetiap­ine, and risperidone are associated with more clinically significant weight gain compared with haloperidol and ziprasi­done.^23-25 Olanzapine-associated weight gain has been reported to be twice that of quetiapine and risperidone.¹⁸ Regardless, the EUFEST trial did not find a difference in clinically significant weight gain after 12 months among the antipsychotics studied, including haloperidol and ziprasidone.²⁵

Weight gain associated with these anti­psychotics is accompanied by changes in fasting triglycerides, glucose, total choles­terol,²³ and high-density lipoprotein cho­lesterol as well as an increase in body mass index (BMI) categorization²⁹ (eg, shift from normal to overweight).^18,25 Patients with lower baseline BMI and in racial minor­ity groups might experience more rapid weight gain regardless of antipsychotic selection.^29,30

Hyperprolactinemia could be under-recognized and could contribute to early treatment discontinuation.³¹ Evidence in patients with first-episode schizophrenia suggests similar outcomes as those seen in multi-episode patients, in whom ris­peridone is associated with higher pro­lactin elevations and clinically significant hyperprolactinemia (eg, galactorrhea and gynecomastia) compared with olanzapine, quetiapine, and low-dose haloperidol.^18,23,24 However, there is a lack of studies that assess whether long-term therapy with strong D2 receptor antagonists increases the risk of bone demineralization or path­ological fractures when started before patients’ bones reach maximum density in their mid-20s.³¹

Antipsychotic dosing
Given the high rate of treatment response in FEP and patients’ higher sensitivity to antipsychotic adverse effects, particularly EPS, guidelines recommend antipsychotic dosages lower than those used for multi-episode schizophrenia,¹¹ especially FGAs. Based on trial data, commonly used dos­ages include:
   • haloperidol, ≤5 mg/d^23-25,29
   • olanzapine, 10 mg/d^18,23,25,29
   • risperidone, ≤4 to 6 mg/d.^18,24,29,32

In general, haloperidol and risperidone, 2 to 3 mg/d, were well tolerated and effec­tive in trials. Higher quetiapine dosages of 500 to 600 mg/d could be required.^11,18,25

According to a survey on prescribing practices of antipsychotic selection and dosing in first-episode schizophrenia,4 clinical prescribing practices tend to use unnecessarily high initial antipsychotic dosing compared with trial data. There also is variability in the usual target anti­psychotic dosage ranging from 50% lower dosages to normal dosages in chronic schizophrenia to above FDA-approved maximum dosages for olanzapine (which may be necessary to counteract tobacco-induced cytochrome P450 1A2 enzyme induction).

In addition, these clinicians reported prescribing aripiprazole, an antipsychotic with weaker evidence (eg, case reports, case series, open-label studies) support­ing its efficacy and tolerability in FEP. These prescribing practices could reflect attempts to reduce the DUP and achieve symptom remission, so long as tolerability is not a concern.

Essentially, prescribed dosages should be based on symptom improvement and tolerability. This ideal dosage will vary as illustrated by Kapur et al,³³ who reported that FEP patients (N = 20) given haloper­idol, 1 mg or 2.5 mg/d, had D2 receptor occupancy rates of 38% to 87%, which was significantly dose-related (1 mg/d mean = 59%, 2.5 mg/d mean = 75%). Clinical response and EPS significantly increased as D2 receptor occupancy exceeded 65% and 78%, respectively.

Antipsychotic response
When should you expect to see symp­tom improvement in patients with first-episode schizophrenia?
Emsley et al³⁴ reported a 77.6% response rate among first-episode patients (N = 522) treated with low dosages of risperidone (mean modal dosage [MMD] = 3.3 mg/d) and haloperidol (MMD = 2.9 mg/d). They found variable response times that were evenly dispersed over a 10-week period. Nearly one-quarter (22.5%) did not respond until after week 4 and 11.2% did not respond until after week 8. In a study of FEP patients (N = 112) treated with olanzapine (MMD = 11.8 mg/d) or risperi­done (MMD = 3.9 mg/d), Gallego et al³⁵ reported a cumulative response of 39.6% at week 8 and 65.1% at week 16.

Although there is evidence that, among multi-episode patients, early nonresponse to antipsychotic therapy could predict subsequent nonresponse,³⁶ the evidence is mixed for first-episode schizophrenia. Studies by Emsley et al³⁴ and Gallego et al³⁵ did not find that early nonresponse at weeks 1 or 2 predicted subsequent nonre­sponse at week 4 or later. However, other studies support the idea that early nonre­sponse predicts subsequent nonresponse and early antipsychotic response predicts future response in first-episode patients, with good specificity and sensitivity.^37,38

Overall, treatment response in first-episode schizophrenia is variable. An adequate antipsychotic trial may be lon­ger, 8 to 16 weeks, compared with 4 to 8 weeks in multi-episode patients. Because research suggests that failure to respond to treatment may lead to medication non­adherence,³⁹ it is reasonable to consider switching antipsychotics when a patient experiences minimal or no response to antipsychotic therapy at week 2; however, this should be a patient-specific decision.

How long should you continue therapy after symptom remission?
There is a lack of consensus on the dura­tion of therapy for a patient treated for first-episode schizophrenia because a small percentage (10% to 20%) do not relapse after the first psychotic episode.³ In general, treatment guidelines and expert consensus statements recommend at least 1 to 2 years of treatment before considering a discon­tinuation trial.^7,10-11 Discuss the benefits and risks of maintenance treatment with your patient and obtain informed consent. With patients with minimal insight, obtaining proper consent is not possible and the phy­sician must exercise judgment unilaterally, if necessary, after educating the family.

After at least 12 months of treatment, antipsychotic therapy could continue indefinitely, depending on patient-specific factors. There are no predictors for identi­fying patients who do not require mainte­nance therapy beyond the first psychotic episode. The absence of negative and cog­nitive deficits could provide clues that a patient might be a candidate for antipsy­chotic tapering.

Predicting the treatment course
Research investigating clinical predic­tors or biomarkers that forecast whether a patient will respond to treatment is pre­liminary. Many characteristics have been identified (Table 3^{1,3,4,23,25,40}) and include shorter DUP,¹ poorer premorbid function,³ antipsychotic discontinuation,³ a trusting patient-doctor relationship,⁴¹ and antipsychotic-related adverse effects,^23,25 which are predictive of response, nonre­sponse, relapse, adherence, and nonadher­ence, respectively.
 

Bottom Line
The goals of pharmacological treatment of first-episode schizophrenia are to minimize the duration of untreated psychosis and target full remission of positive symptoms using the lowest possible antipsychotic dosages. Pharmacotherapy should continued for 1 to 2 years, with longer duration considered if it is discussed with the patient and with vigilant monitoring for adverse effects and suboptimal medication nonadherence to prevent relapse.
 

Editor’s note: The second article in this series in the July 2015 issue reviews the rationale and evidence for non-standard, first-line therapies, including long-acting injectable antipsychotics and clozapine.

Related Resources
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.
• Martens L, Baker S. Promoting recovery from first epi­sode psychosis: a guide for families. Centre for Addiction and Mental Health. http://www.camh.ca/en/hospital/ Documents/www.camh.net/AboutCAMH/Guideto CAMH/MentalHealthPrograms/SchizophreniaProgram/ 3936PromotingRecoveryFirstEpisodePsychosisfinal.pdf.

Drug Brand Names
Aripiprazole • Abilify                Lurasidone • Latuda
Asenapine • Saphris                Olanzapine • Zyprexa
Clozapine • Clozaril                 Paliperidone • Invega
Fluphenazine • Prolixin            Quetiapine • Seroquel
Iloperidone • Fanapt               Risperidone • Risperdal
Haloperidol • Haldol                Ziprasidone • Geodon

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.
Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

Recent studies suggest that most older adults main­tain sexual interest well into late life; many, however, experience sexual dysfunction. This article provides psychiatric practitioners with current information regard­ing sexuality and aging, as well as psychiatric and systemic medical comorbidities and sexual side effects of medi­cations. Practice guidelines for assessing and managing sexual dysfunction have been developed for use in many medical specialties, and such guidance would be welcome in psychiatric practice.

This article addresses the myth of “geriatric asexuality” and its potential impact on clinical practice, the effects of age-related physiological changes on sexual activity, the importance of sexuality in the lives of older adults, and sensitive questions clinicians can pose about geriatric sexu­ality. We also will discuss:  
   • the importance of including a sexual assessment in the comprehensive psychiatric evaluation  
   • recognizing sexual dysfunction  
   • providing appropriate management within a multi-disciplinary, collaborative approach.

Sexuality after 65
Regardless of age, sexual activity can provide a sense of com­fort and elicit a positive emotional and physical response.¹ Hillman² defined human sexuality as any combination of sex­ual behavior, emotional intimacy, and sense of sexual identity.

Sexuality in the aging population gen­erally is an understudied area, obscured by the myth of “geriatric asexuality” and subject to numerous psychosocial vari­ables.¹ Previous research, focused on a bio­logical perspective of sexuality, has largely overlooked psychological and social influ­ences.³ It has been assumed that, with age, physical and hormonal changes or chronic illness ordinarily reduce or eliminate sex­ual desire and sexual behavior.³ However, the majority of older adults (defined as age ≥65) report a moderate-to-high level of sexual interest well into late life.^1,3

Sexual function remains a subject often neglected in psychiatry. Sexual dysfunc­tions, as described in the DSM-5,⁴ do not include age-related changes in sexual func­tion. In addition to physiological changes, sexual difficulties can result from relation­ship strain, systemic medical or psychi­atric disorders, and sexual side effects of medications.

CASE REPORT
Mr. C, age 71 and married, is being treated for a major depressive episode that followed a course of shingles and persistent posther­petic neuralgia. Medications are: escitalo­pram, 20 mg/d; pregabalin, 150 mg/d; and ramipril, 5 mg/d. Mr. C is physically active and involved in social activities; he has no substance use history. He attends clinic visits with his wife.

Mr. C reports that despite significant improvement of his depressive and pain symptoms, he now experiences sexual dif­ficulties, which he seems hesitant to discuss in detail. According to his wife, Mr. C appears to lack sexual desire and has difficulty initi­ating and maintaining an erection. She asks Mr. C’s psychiatrist whether she should stop her estrogen treatment, intended to enhance her sexual function, given that the couple is no longer engaging in sexual intercourse.

Mr. C admits to missing physical inti­macy; however, he states, “If I have to make a choice between having sex with my wife and getting this depression out of my head, I’m going to pick getting rid of the depres­sion.” Mrs. C says she is becoming dissatisfied with their marriage and the limited time she and her husband now spend together. Mr. C’s psychiatrist suggests that Mr. C and his wife undergo couples counseling.

Physiological changes with aging
In both women and men, the reproductive system undergoes age-related physiologi­cal changes.

Women. In women, the phase of decline in ovarian function and resulting decline in sex steroid production (estradiol and pro­gesterone) is referred to as the climacteric, with menopause being determined retro­spectively by the cessation of a menstrual period for 1 year.⁵

Menopausal symptoms typically occur between age 40 and 58; the average age of menopause is 51.^6,7 Both estradiol and pro­gesterone levels decline with menopause, and anovulation and ovarian failure ensue. A more gradual decline of female testoster­one levels also occurs with aging, starting in the fourth decade of life.⁸

Clinical manifestations of menopause include vasomotor symptoms (ie, “hot flushes”), sleep disturbances, anxiety and depressive symptoms, decreased bone min­eral density, and increased risk of cardio­vascular disease.^6,7 Loss of estrogen as well as continued loss of testosterone can result in dyspareunia because of atrophy and decreased vulvar and vaginal lubrication, with sexual excitement achieved less quickly, and a decreased intensity of orgasm.⁷

Men. Research has shown that testosterone levels are highest in men in the second and third decades, with a subsequent gradual decline.⁹ Older men with a low testosterone level are described as experiencing “late-onset hypogonadism,” also known by the popularized term “andropause.”¹⁰ This is attributed to decreased activity at the tes­ticular and hypothalamic levels.¹⁰

Nonetheless, only a small fraction of older men with confirmed androgen defi­ciency are clinically symptomatic.^11,12 Low testosterone is associated with decreased libido; it can hinder morning erections, contribute to erectile dysfunction, and result in erections that require physical stimulation.¹³

Notably, erectile dysfunction involves several other etiologic factors: psychiatric (eg, relationship difficulties, depression), neurogenic (eg, spinal cord injury), endo­crine (eg, hyperprolactinemia), arteriogenic (eg, hypertension, type 2 diabetes mellitus), and drug-induced (eg, antidepressants, antihypertensives).¹⁴ A low testosterone level also has been associated with potential cognitive changes, decreased bone mineral density, metabolic syndrome (eg, increased risk of type 2 diabetes mellitus), and cardio­vascular mortality.¹⁰

Effects on sexual activity. How much age-related physiological changes impact sexual practices in the geriatric popula­tion is uncertain. A study following 3,302 women through menopause over 6 years found some decline in sexual activity; how­ever, this decline was not associated with increased sexual pain, decreased desire, or lack of arousal.¹⁵ Men continue to find ways to remain sexually active despite physiolog­ical changes (eg, erectile difficulties), but the etiology of sexual dysfunction in later life remains multi-modal, involving physical, psychological, and relational factors.^16,17

Sexual practices in older adults
Researchers for the National Social Life, Health, and Aging Project (NSHAP) have examined sexual activities, behaviors, and problems in >3,000 older community-dwelling men and women across the United States, using information collected from in-home interviews.18 This study found that sexual activity, defined as any mutually voluntary sexual contact with another person, declines with age; how­ever, even in the oldest age group (age 75 to 85), 39% of men and 17% of women reported being sexually active in the last 12 months. Among these persons, 54% reported sexual activity at least 2 times per month; 23% reported having sex at least once a week; and 32% reported engaging in oral sex. Partner availability predicted sexual activity.

Respondents with self-reported poor physical health were more likely to experi­ence sexual problems (eg, difficulty with erection or lubrication, dyspareunia, and lack of pleasure). The most commonly reported reason for sexual inactivity in those with a spouse or other intimate partner was the male partner’s poor physical health.¹⁸

A longitudinal study, part of the Women’s Healthy Ageing Project, examined changes in sexual function at late menopause com­pared with early menopause. Although the researchers also found an age-related decrease in sexual activity, 50% of their late-menopause respondents (mean age, 70; range, 64 to 77) still reported sexual activity in the previous month, with 35% of this subgroup reporting sexual activity at least once a week; 83% reported sexual thoughts or fantasies.¹⁹ Availability of a partner, absence of a history of depression, moder­ate (compared with no) alcohol consump­tion, and better cognitive function were significantly associated with a higher level of sexual activity.¹⁹

In the Successful Aging Evaluation study, conducted in San Diego County, California, community-dwelling older partnered adults age 50 to 99 (mean age, 75) were surveyed about their sexual health after a cogni­tive screen by telephone²⁰; rating scales for depression, anxiety, and physical function also were included. Results included 41% of men and 35% of women reporting sexual activity at least once a week, and only 21% of men and 24% of women reporting no sex­ual activity in the previous year. Depressive symptoms were most highly correlated with lack of sexual activity.²⁰

Overall, these studies reveal that posi­tive physical and mental health, access to a healthy partner, and a positive attitude toward sex are correlated with sexual activ­ity in later life, whereas barriers to sexual activity include lack of a healthy sexual partner, depression, and chronic systemic medical illnesses, such as coronary artery disease or type 2 diabetes mellitus.^13,17,21-24 Sexual activity and satisfaction have been positively associated with perceived general well-being and self-esteem.^25,26 Conversely, sexual difficulties secondary to disease can be a source of distress for couples.²⁷

Possibly overlooked? It is important to note that sexuality itself is a subjective area. Psychological intimacy is a universal phe­nomenon, and its physical expression may evolve as couples accommodate to age-related bodily changes. Means of achieving physical closeness, other than intercourse (eg, intimate touching, hand holding, kiss­ing, or even acts of caretaking), may not be adequately captured in studies that look specifically at sexual activity.

Taking a sexual history in a geriatric patient
Because sexuality can be an uncomfort­able topic for geriatric patients to discuss, sexual problems in this population often go unrecognized. It has been suggested that psychiatrists are more likely to inquire about sexual activity in middle-aged patients than geriatric patients with the same psychiatric presentation—perhaps illustrating a bias against taking a sexual history from a geriatric patient.²⁸ However, because many older patients can experi­ence depression or anxiety disorders in relation to normal sexual changes or sex­ual dysfunction within the context of their intimate relationships, it is essential to bring these issues to light.

Although a sexual history may not be the focus of a first clinical encounter, consider making such an assessment at a relatively early stage of patient care. The importance of such dialogue is 2-fold:
   • It demonstrates to the patient that talking about sexuality in a respectful and empathic manner is appropriate and can encourage patients to communicate more effectively about sexuality with clinicians and with sexual partners.
   • It helps elicit medical information needed to make an accurate diagnosis and provide adequate management.

How to begin. As a starting point to taking a sexual history, an open-ended invitation for the geriatric patient to share informa­tion may be best, such as “What would you like to tell me about your sexual life?” See further suggestions (Table 1) and examples of more detailed questions to ask once a dialogue has been initiated (Table 2). Additional factors that may contribute to sexual dysfunction are presented in Table 3.^1,27,29,30

CASE CONTINUED
In Mr. C’s case, an assessment of his sexual history, including risk factors for sexual dysfunction, is completed. Results from laboratory investigations, including a total testosterone level, are within normal limits.

Mr. C asks about using medications with fewer sexual side effects (he has been taking 3 medications that can contribute to sexual dysfunction). A gradual cross-taper of esci­talopram, 20 mg/d, to mirtazapine, 45 mg/d, is implemented, along with tapering prega­balin to 50 mg/d.

Mr. C’s psychiatric and pain symptom improvement is maintained. He notices a boost in his sexual desire but has minimal improvement in erectile dysfunction. He is encouraged to speak with his primary care physician about an antihypertensive agent with less impact on sexual function, as well as therapeutic agents for erectile dysfunc­tion; these, he declines.

At a subsequent visit, Mr. C reports feeling less apprehension about sexual performance. He is now willing to consider further medica­tion options with his primary care physician, and agrees to a recommendation for couples psychotherapy.

As illustrated in Mr. C’s case, the recom­mended sexual assessment and manage­ment strategies to consider at a minimum in psychiatric practice are listed in Table 4.

STI risk in geriatric patients
The risk of sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), often is overlooked in sexually active older adults. Although STIs are more common among younger adults, there is recent evidence of increased incidence in the geriatric population31 (with the high­est risk of incident HIV and some STIs in older men who have sex with men³²). These increased rates can be explained, at least in part, by:
   • older men being less likely to use a condom during sexual activity
   • promotion of viral entry in older women through a drier, thinner vaginal wall
   • increased longevity of HIV-positive persons.³¹

Routine STI screening is not warranted in all older adults, but education and prevention strategies in sexually active seniors who are at greater risk of STIs are recommended. Particularly, clinicians should seek opportunities to discuss risk factors and safe sex practices (eg, using condoms, limiting number of sexual part­ners, practicing good hygiene, engaging in preventive care), and provide behavioral counseling where appropriate.^31,33

Additional considerations in geriatric sexuality
Because psychiatric and systemic medical conditions can hinder sexual function, it is essential to identify and manage these conditions. Several neuropsychiatric dis­orders, including mood and neurocogni­tive disorders, can not only cause sexual dysfunction, but also can raise ethical dilemmas for clinicians, such as reduced decisional capacity in cognitively impaired patients to consent to sexual activity.^1,34

In some patients, psychological, envi­ronmental, and pharmacological treatment options may help. A phosphodiesterase type 5 inhibitor for erectile dysfunction can be prescribed by the primary care phy­sician, a psychiatrist, or another specialist, depending on the physician’s expertise and comfort level.

Sequencing of sexual dysfunction. Notably, there is a common paradox in mood disorders. Decreased sexual interest or performance may represent an aspect of anhedonia associated with depres­sion, whereas sexual dysfunction could also result from medication use (particularly that of serotonergic antidepressants, such as selective serotonin reuptake inhibitors and serotonin-norepinephrine inhibitors), even as other depressive symptoms improve. Therefore, it is critical to analyze sequencing of sexual dysfunction—as part of the pre­senting mood symptoms or dysfunction induced by antidepressant treatment.

Geriatric sexuality in the digital age. Because older adults represent a rapidly growing segment of digital device users,³⁵ Internet use is likely to play a role in the future of sexuality and “digital intimacy,” in that older adults can engage in online sexual activities. The Internet also can be a tool to access medical education.

Related Resources
• Burghardt KJ, Gardner KN. Sildenafil for SSRI-induced sexual dysfunction. Current Psychiatry. 2013;12(4):29-32,A.
• Maciel M, Laganà L. Older women’s sexual desire prob­lems: biopsychosocial factors impacting them and barriers to their clinical assessment [published online January 5, 2014]. Biomed Res Int. 2014;2014:107217. doi: 10.1155/2014/107217.

Drug Brand Names
Bupropion • Wellbutrin, Zyban                   Mirtazapine • Remeron
Carbamazepine • Tegretol                         Oxcarbazepine • Trileptal
Clonidine • Catapres                                 Phenobarbital • Luminal
Donepezil • Aricept                                   Phenytoin • Dilantin
Escitalopram • Lexapro                             Pregabalin • Lyrica
Gabapentin • Neurontin                            Ramipril • Altace
Lamotrigine • Lamictal                              Rivastigmine • Exelon
Lithium • Eskalith, Lithobid                       Trazodone • Desyrel
Memantine • Namenda                             Valproic acid • Depakote

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Recent studies suggest that most older adults main­tain sexual interest well into late life; many, however, experience sexual dysfunction. This article provides psychiatric practitioners with current information regard­ing sexuality and aging, as well as psychiatric and systemic medical comorbidities and sexual side effects of medi­cations. Practice guidelines for assessing and managing sexual dysfunction have been developed for use in many medical specialties, and such guidance would be welcome in psychiatric practice.

This article addresses the myth of “geriatric asexuality” and its potential impact on clinical practice, the effects of age-related physiological changes on sexual activity, the importance of sexuality in the lives of older adults, and sensitive questions clinicians can pose about geriatric sexu­ality. We also will discuss:  
   • the importance of including a sexual assessment in the comprehensive psychiatric evaluation  
   • recognizing sexual dysfunction  
   • providing appropriate management within a multi-disciplinary, collaborative approach.

Sexuality after 65
Regardless of age, sexual activity can provide a sense of com­fort and elicit a positive emotional and physical response.¹ Hillman² defined human sexuality as any combination of sex­ual behavior, emotional intimacy, and sense of sexual identity.

Sexuality in the aging population gen­erally is an understudied area, obscured by the myth of “geriatric asexuality” and subject to numerous psychosocial vari­ables.¹ Previous research, focused on a bio­logical perspective of sexuality, has largely overlooked psychological and social influ­ences.³ It has been assumed that, with age, physical and hormonal changes or chronic illness ordinarily reduce or eliminate sex­ual desire and sexual behavior.³ However, the majority of older adults (defined as age ≥65) report a moderate-to-high level of sexual interest well into late life.^1,3

Sexual function remains a subject often neglected in psychiatry. Sexual dysfunc­tions, as described in the DSM-5,⁴ do not include age-related changes in sexual func­tion. In addition to physiological changes, sexual difficulties can result from relation­ship strain, systemic medical or psychi­atric disorders, and sexual side effects of medications.

CASE REPORT
Mr. C, age 71 and married, is being treated for a major depressive episode that followed a course of shingles and persistent posther­petic neuralgia. Medications are: escitalo­pram, 20 mg/d; pregabalin, 150 mg/d; and ramipril, 5 mg/d. Mr. C is physically active and involved in social activities; he has no substance use history. He attends clinic visits with his wife.

Mr. C reports that despite significant improvement of his depressive and pain symptoms, he now experiences sexual dif­ficulties, which he seems hesitant to discuss in detail. According to his wife, Mr. C appears to lack sexual desire and has difficulty initi­ating and maintaining an erection. She asks Mr. C’s psychiatrist whether she should stop her estrogen treatment, intended to enhance her sexual function, given that the couple is no longer engaging in sexual intercourse.

Mr. C admits to missing physical inti­macy; however, he states, “If I have to make a choice between having sex with my wife and getting this depression out of my head, I’m going to pick getting rid of the depres­sion.” Mrs. C says she is becoming dissatisfied with their marriage and the limited time she and her husband now spend together. Mr. C’s psychiatrist suggests that Mr. C and his wife undergo couples counseling.

Physiological changes with aging
In both women and men, the reproductive system undergoes age-related physiologi­cal changes.

Women. In women, the phase of decline in ovarian function and resulting decline in sex steroid production (estradiol and pro­gesterone) is referred to as the climacteric, with menopause being determined retro­spectively by the cessation of a menstrual period for 1 year.⁵

Menopausal symptoms typically occur between age 40 and 58; the average age of menopause is 51.^6,7 Both estradiol and pro­gesterone levels decline with menopause, and anovulation and ovarian failure ensue. A more gradual decline of female testoster­one levels also occurs with aging, starting in the fourth decade of life.⁸

Clinical manifestations of menopause include vasomotor symptoms (ie, “hot flushes”), sleep disturbances, anxiety and depressive symptoms, decreased bone min­eral density, and increased risk of cardio­vascular disease.^6,7 Loss of estrogen as well as continued loss of testosterone can result in dyspareunia because of atrophy and decreased vulvar and vaginal lubrication, with sexual excitement achieved less quickly, and a decreased intensity of orgasm.⁷

Men. Research has shown that testosterone levels are highest in men in the second and third decades, with a subsequent gradual decline.⁹ Older men with a low testosterone level are described as experiencing “late-onset hypogonadism,” also known by the popularized term “andropause.”¹⁰ This is attributed to decreased activity at the tes­ticular and hypothalamic levels.¹⁰

Nonetheless, only a small fraction of older men with confirmed androgen defi­ciency are clinically symptomatic.^11,12 Low testosterone is associated with decreased libido; it can hinder morning erections, contribute to erectile dysfunction, and result in erections that require physical stimulation.¹³

Notably, erectile dysfunction involves several other etiologic factors: psychiatric (eg, relationship difficulties, depression), neurogenic (eg, spinal cord injury), endo­crine (eg, hyperprolactinemia), arteriogenic (eg, hypertension, type 2 diabetes mellitus), and drug-induced (eg, antidepressants, antihypertensives).¹⁴ A low testosterone level also has been associated with potential cognitive changes, decreased bone mineral density, metabolic syndrome (eg, increased risk of type 2 diabetes mellitus), and cardio­vascular mortality.¹⁰

Effects on sexual activity. How much age-related physiological changes impact sexual practices in the geriatric popula­tion is uncertain. A study following 3,302 women through menopause over 6 years found some decline in sexual activity; how­ever, this decline was not associated with increased sexual pain, decreased desire, or lack of arousal.¹⁵ Men continue to find ways to remain sexually active despite physiolog­ical changes (eg, erectile difficulties), but the etiology of sexual dysfunction in later life remains multi-modal, involving physical, psychological, and relational factors.^16,17

Sexual practices in older adults
Researchers for the National Social Life, Health, and Aging Project (NSHAP) have examined sexual activities, behaviors, and problems in >3,000 older community-dwelling men and women across the United States, using information collected from in-home interviews.18 This study found that sexual activity, defined as any mutually voluntary sexual contact with another person, declines with age; how­ever, even in the oldest age group (age 75 to 85), 39% of men and 17% of women reported being sexually active in the last 12 months. Among these persons, 54% reported sexual activity at least 2 times per month; 23% reported having sex at least once a week; and 32% reported engaging in oral sex. Partner availability predicted sexual activity.

Respondents with self-reported poor physical health were more likely to experi­ence sexual problems (eg, difficulty with erection or lubrication, dyspareunia, and lack of pleasure). The most commonly reported reason for sexual inactivity in those with a spouse or other intimate partner was the male partner’s poor physical health.¹⁸

A longitudinal study, part of the Women’s Healthy Ageing Project, examined changes in sexual function at late menopause com­pared with early menopause. Although the researchers also found an age-related decrease in sexual activity, 50% of their late-menopause respondents (mean age, 70; range, 64 to 77) still reported sexual activity in the previous month, with 35% of this subgroup reporting sexual activity at least once a week; 83% reported sexual thoughts or fantasies.¹⁹ Availability of a partner, absence of a history of depression, moder­ate (compared with no) alcohol consump­tion, and better cognitive function were significantly associated with a higher level of sexual activity.¹⁹

In the Successful Aging Evaluation study, conducted in San Diego County, California, community-dwelling older partnered adults age 50 to 99 (mean age, 75) were surveyed about their sexual health after a cogni­tive screen by telephone²⁰; rating scales for depression, anxiety, and physical function also were included. Results included 41% of men and 35% of women reporting sexual activity at least once a week, and only 21% of men and 24% of women reporting no sex­ual activity in the previous year. Depressive symptoms were most highly correlated with lack of sexual activity.²⁰

Overall, these studies reveal that posi­tive physical and mental health, access to a healthy partner, and a positive attitude toward sex are correlated with sexual activ­ity in later life, whereas barriers to sexual activity include lack of a healthy sexual partner, depression, and chronic systemic medical illnesses, such as coronary artery disease or type 2 diabetes mellitus.^13,17,21-24 Sexual activity and satisfaction have been positively associated with perceived general well-being and self-esteem.^25,26 Conversely, sexual difficulties secondary to disease can be a source of distress for couples.²⁷

Possibly overlooked? It is important to note that sexuality itself is a subjective area. Psychological intimacy is a universal phe­nomenon, and its physical expression may evolve as couples accommodate to age-related bodily changes. Means of achieving physical closeness, other than intercourse (eg, intimate touching, hand holding, kiss­ing, or even acts of caretaking), may not be adequately captured in studies that look specifically at sexual activity.

Taking a sexual history in a geriatric patient
Because sexuality can be an uncomfort­able topic for geriatric patients to discuss, sexual problems in this population often go unrecognized. It has been suggested that psychiatrists are more likely to inquire about sexual activity in middle-aged patients than geriatric patients with the same psychiatric presentation—perhaps illustrating a bias against taking a sexual history from a geriatric patient.²⁸ However, because many older patients can experi­ence depression or anxiety disorders in relation to normal sexual changes or sex­ual dysfunction within the context of their intimate relationships, it is essential to bring these issues to light.

Although a sexual history may not be the focus of a first clinical encounter, consider making such an assessment at a relatively early stage of patient care. The importance of such dialogue is 2-fold:
   • It demonstrates to the patient that talking about sexuality in a respectful and empathic manner is appropriate and can encourage patients to communicate more effectively about sexuality with clinicians and with sexual partners.
   • It helps elicit medical information needed to make an accurate diagnosis and provide adequate management.

How to begin. As a starting point to taking a sexual history, an open-ended invitation for the geriatric patient to share informa­tion may be best, such as “What would you like to tell me about your sexual life?” See further suggestions (Table 1) and examples of more detailed questions to ask once a dialogue has been initiated (Table 2). Additional factors that may contribute to sexual dysfunction are presented in Table 3.^1,27,29,30

CASE CONTINUED
In Mr. C’s case, an assessment of his sexual history, including risk factors for sexual dysfunction, is completed. Results from laboratory investigations, including a total testosterone level, are within normal limits.

Mr. C asks about using medications with fewer sexual side effects (he has been taking 3 medications that can contribute to sexual dysfunction). A gradual cross-taper of esci­talopram, 20 mg/d, to mirtazapine, 45 mg/d, is implemented, along with tapering prega­balin to 50 mg/d.

Mr. C’s psychiatric and pain symptom improvement is maintained. He notices a boost in his sexual desire but has minimal improvement in erectile dysfunction. He is encouraged to speak with his primary care physician about an antihypertensive agent with less impact on sexual function, as well as therapeutic agents for erectile dysfunc­tion; these, he declines.

At a subsequent visit, Mr. C reports feeling less apprehension about sexual performance. He is now willing to consider further medica­tion options with his primary care physician, and agrees to a recommendation for couples psychotherapy.

As illustrated in Mr. C’s case, the recom­mended sexual assessment and manage­ment strategies to consider at a minimum in psychiatric practice are listed in Table 4.

STI risk in geriatric patients
The risk of sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), often is overlooked in sexually active older adults. Although STIs are more common among younger adults, there is recent evidence of increased incidence in the geriatric population31 (with the high­est risk of incident HIV and some STIs in older men who have sex with men³²). These increased rates can be explained, at least in part, by:
   • older men being less likely to use a condom during sexual activity
   • promotion of viral entry in older women through a drier, thinner vaginal wall
   • increased longevity of HIV-positive persons.³¹

Routine STI screening is not warranted in all older adults, but education and prevention strategies in sexually active seniors who are at greater risk of STIs are recommended. Particularly, clinicians should seek opportunities to discuss risk factors and safe sex practices (eg, using condoms, limiting number of sexual part­ners, practicing good hygiene, engaging in preventive care), and provide behavioral counseling where appropriate.^31,33

Additional considerations in geriatric sexuality
Because psychiatric and systemic medical conditions can hinder sexual function, it is essential to identify and manage these conditions. Several neuropsychiatric dis­orders, including mood and neurocogni­tive disorders, can not only cause sexual dysfunction, but also can raise ethical dilemmas for clinicians, such as reduced decisional capacity in cognitively impaired patients to consent to sexual activity.^1,34

In some patients, psychological, envi­ronmental, and pharmacological treatment options may help. A phosphodiesterase type 5 inhibitor for erectile dysfunction can be prescribed by the primary care phy­sician, a psychiatrist, or another specialist, depending on the physician’s expertise and comfort level.

Sequencing of sexual dysfunction. Notably, there is a common paradox in mood disorders. Decreased sexual interest or performance may represent an aspect of anhedonia associated with depres­sion, whereas sexual dysfunction could also result from medication use (particularly that of serotonergic antidepressants, such as selective serotonin reuptake inhibitors and serotonin-norepinephrine inhibitors), even as other depressive symptoms improve. Therefore, it is critical to analyze sequencing of sexual dysfunction—as part of the pre­senting mood symptoms or dysfunction induced by antidepressant treatment.

Geriatric sexuality in the digital age. Because older adults represent a rapidly growing segment of digital device users,³⁵ Internet use is likely to play a role in the future of sexuality and “digital intimacy,” in that older adults can engage in online sexual activities. The Internet also can be a tool to access medical education.

Related Resources
• Burghardt KJ, Gardner KN. Sildenafil for SSRI-induced sexual dysfunction. Current Psychiatry. 2013;12(4):29-32,A.
• Maciel M, Laganà L. Older women’s sexual desire prob­lems: biopsychosocial factors impacting them and barriers to their clinical assessment [published online January 5, 2014]. Biomed Res Int. 2014;2014:107217. doi: 10.1155/2014/107217.

Drug Brand Names
Bupropion • Wellbutrin, Zyban                   Mirtazapine • Remeron
Carbamazepine • Tegretol                         Oxcarbazepine • Trileptal
Clonidine • Catapres                                 Phenobarbital • Luminal
Donepezil • Aricept                                   Phenytoin • Dilantin
Escitalopram • Lexapro                             Pregabalin • Lyrica
Gabapentin • Neurontin                            Ramipril • Altace
Lamotrigine • Lamictal                              Rivastigmine • Exelon
Lithium • Eskalith, Lithobid                       Trazodone • Desyrel
Memantine • Namenda                             Valproic acid • Depakote

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Recent studies suggest that most older adults main­tain sexual interest well into late life; many, however, experience sexual dysfunction. This article provides psychiatric practitioners with current information regard­ing sexuality and aging, as well as psychiatric and systemic medical comorbidities and sexual side effects of medi­cations. Practice guidelines for assessing and managing sexual dysfunction have been developed for use in many medical specialties, and such guidance would be welcome in psychiatric practice.

This article addresses the myth of “geriatric asexuality” and its potential impact on clinical practice, the effects of age-related physiological changes on sexual activity, the importance of sexuality in the lives of older adults, and sensitive questions clinicians can pose about geriatric sexu­ality. We also will discuss:  
   • the importance of including a sexual assessment in the comprehensive psychiatric evaluation  
   • recognizing sexual dysfunction  
   • providing appropriate management within a multi-disciplinary, collaborative approach.

Sexuality after 65
Regardless of age, sexual activity can provide a sense of com­fort and elicit a positive emotional and physical response.¹ Hillman² defined human sexuality as any combination of sex­ual behavior, emotional intimacy, and sense of sexual identity.

Sexuality in the aging population gen­erally is an understudied area, obscured by the myth of “geriatric asexuality” and subject to numerous psychosocial vari­ables.¹ Previous research, focused on a bio­logical perspective of sexuality, has largely overlooked psychological and social influ­ences.³ It has been assumed that, with age, physical and hormonal changes or chronic illness ordinarily reduce or eliminate sex­ual desire and sexual behavior.³ However, the majority of older adults (defined as age ≥65) report a moderate-to-high level of sexual interest well into late life.^1,3

Sexual function remains a subject often neglected in psychiatry. Sexual dysfunc­tions, as described in the DSM-5,⁴ do not include age-related changes in sexual func­tion. In addition to physiological changes, sexual difficulties can result from relation­ship strain, systemic medical or psychi­atric disorders, and sexual side effects of medications.

CASE REPORT
Mr. C, age 71 and married, is being treated for a major depressive episode that followed a course of shingles and persistent posther­petic neuralgia. Medications are: escitalo­pram, 20 mg/d; pregabalin, 150 mg/d; and ramipril, 5 mg/d. Mr. C is physically active and involved in social activities; he has no substance use history. He attends clinic visits with his wife.

Mr. C reports that despite significant improvement of his depressive and pain symptoms, he now experiences sexual dif­ficulties, which he seems hesitant to discuss in detail. According to his wife, Mr. C appears to lack sexual desire and has difficulty initi­ating and maintaining an erection. She asks Mr. C’s psychiatrist whether she should stop her estrogen treatment, intended to enhance her sexual function, given that the couple is no longer engaging in sexual intercourse.

Mr. C admits to missing physical inti­macy; however, he states, “If I have to make a choice between having sex with my wife and getting this depression out of my head, I’m going to pick getting rid of the depres­sion.” Mrs. C says she is becoming dissatisfied with their marriage and the limited time she and her husband now spend together. Mr. C’s psychiatrist suggests that Mr. C and his wife undergo couples counseling.

Physiological changes with aging
In both women and men, the reproductive system undergoes age-related physiologi­cal changes.

Women. In women, the phase of decline in ovarian function and resulting decline in sex steroid production (estradiol and pro­gesterone) is referred to as the climacteric, with menopause being determined retro­spectively by the cessation of a menstrual period for 1 year.⁵

Menopausal symptoms typically occur between age 40 and 58; the average age of menopause is 51.^6,7 Both estradiol and pro­gesterone levels decline with menopause, and anovulation and ovarian failure ensue. A more gradual decline of female testoster­one levels also occurs with aging, starting in the fourth decade of life.⁸

Clinical manifestations of menopause include vasomotor symptoms (ie, “hot flushes”), sleep disturbances, anxiety and depressive symptoms, decreased bone min­eral density, and increased risk of cardio­vascular disease.^6,7 Loss of estrogen as well as continued loss of testosterone can result in dyspareunia because of atrophy and decreased vulvar and vaginal lubrication, with sexual excitement achieved less quickly, and a decreased intensity of orgasm.⁷

Men. Research has shown that testosterone levels are highest in men in the second and third decades, with a subsequent gradual decline.⁹ Older men with a low testosterone level are described as experiencing “late-onset hypogonadism,” also known by the popularized term “andropause.”¹⁰ This is attributed to decreased activity at the tes­ticular and hypothalamic levels.¹⁰

Nonetheless, only a small fraction of older men with confirmed androgen defi­ciency are clinically symptomatic.^11,12 Low testosterone is associated with decreased libido; it can hinder morning erections, contribute to erectile dysfunction, and result in erections that require physical stimulation.¹³

Notably, erectile dysfunction involves several other etiologic factors: psychiatric (eg, relationship difficulties, depression), neurogenic (eg, spinal cord injury), endo­crine (eg, hyperprolactinemia), arteriogenic (eg, hypertension, type 2 diabetes mellitus), and drug-induced (eg, antidepressants, antihypertensives).¹⁴ A low testosterone level also has been associated with potential cognitive changes, decreased bone mineral density, metabolic syndrome (eg, increased risk of type 2 diabetes mellitus), and cardio­vascular mortality.¹⁰

Effects on sexual activity. How much age-related physiological changes impact sexual practices in the geriatric popula­tion is uncertain. A study following 3,302 women through menopause over 6 years found some decline in sexual activity; how­ever, this decline was not associated with increased sexual pain, decreased desire, or lack of arousal.¹⁵ Men continue to find ways to remain sexually active despite physiolog­ical changes (eg, erectile difficulties), but the etiology of sexual dysfunction in later life remains multi-modal, involving physical, psychological, and relational factors.^16,17

Sexual practices in older adults
Researchers for the National Social Life, Health, and Aging Project (NSHAP) have examined sexual activities, behaviors, and problems in >3,000 older community-dwelling men and women across the United States, using information collected from in-home interviews.18 This study found that sexual activity, defined as any mutually voluntary sexual contact with another person, declines with age; how­ever, even in the oldest age group (age 75 to 85), 39% of men and 17% of women reported being sexually active in the last 12 months. Among these persons, 54% reported sexual activity at least 2 times per month; 23% reported having sex at least once a week; and 32% reported engaging in oral sex. Partner availability predicted sexual activity.

Respondents with self-reported poor physical health were more likely to experi­ence sexual problems (eg, difficulty with erection or lubrication, dyspareunia, and lack of pleasure). The most commonly reported reason for sexual inactivity in those with a spouse or other intimate partner was the male partner’s poor physical health.¹⁸

A longitudinal study, part of the Women’s Healthy Ageing Project, examined changes in sexual function at late menopause com­pared with early menopause. Although the researchers also found an age-related decrease in sexual activity, 50% of their late-menopause respondents (mean age, 70; range, 64 to 77) still reported sexual activity in the previous month, with 35% of this subgroup reporting sexual activity at least once a week; 83% reported sexual thoughts or fantasies.¹⁹ Availability of a partner, absence of a history of depression, moder­ate (compared with no) alcohol consump­tion, and better cognitive function were significantly associated with a higher level of sexual activity.¹⁹

In the Successful Aging Evaluation study, conducted in San Diego County, California, community-dwelling older partnered adults age 50 to 99 (mean age, 75) were surveyed about their sexual health after a cogni­tive screen by telephone²⁰; rating scales for depression, anxiety, and physical function also were included. Results included 41% of men and 35% of women reporting sexual activity at least once a week, and only 21% of men and 24% of women reporting no sex­ual activity in the previous year. Depressive symptoms were most highly correlated with lack of sexual activity.²⁰

Overall, these studies reveal that posi­tive physical and mental health, access to a healthy partner, and a positive attitude toward sex are correlated with sexual activ­ity in later life, whereas barriers to sexual activity include lack of a healthy sexual partner, depression, and chronic systemic medical illnesses, such as coronary artery disease or type 2 diabetes mellitus.^13,17,21-24 Sexual activity and satisfaction have been positively associated with perceived general well-being and self-esteem.^25,26 Conversely, sexual difficulties secondary to disease can be a source of distress for couples.²⁷

Possibly overlooked? It is important to note that sexuality itself is a subjective area. Psychological intimacy is a universal phe­nomenon, and its physical expression may evolve as couples accommodate to age-related bodily changes. Means of achieving physical closeness, other than intercourse (eg, intimate touching, hand holding, kiss­ing, or even acts of caretaking), may not be adequately captured in studies that look specifically at sexual activity.

Taking a sexual history in a geriatric patient
Because sexuality can be an uncomfort­able topic for geriatric patients to discuss, sexual problems in this population often go unrecognized. It has been suggested that psychiatrists are more likely to inquire about sexual activity in middle-aged patients than geriatric patients with the same psychiatric presentation—perhaps illustrating a bias against taking a sexual history from a geriatric patient.²⁸ However, because many older patients can experi­ence depression or anxiety disorders in relation to normal sexual changes or sex­ual dysfunction within the context of their intimate relationships, it is essential to bring these issues to light.

Although a sexual history may not be the focus of a first clinical encounter, consider making such an assessment at a relatively early stage of patient care. The importance of such dialogue is 2-fold:
   • It demonstrates to the patient that talking about sexuality in a respectful and empathic manner is appropriate and can encourage patients to communicate more effectively about sexuality with clinicians and with sexual partners.
   • It helps elicit medical information needed to make an accurate diagnosis and provide adequate management.

How to begin. As a starting point to taking a sexual history, an open-ended invitation for the geriatric patient to share informa­tion may be best, such as “What would you like to tell me about your sexual life?” See further suggestions (Table 1) and examples of more detailed questions to ask once a dialogue has been initiated (Table 2). Additional factors that may contribute to sexual dysfunction are presented in Table 3.^1,27,29,30

CASE CONTINUED
In Mr. C’s case, an assessment of his sexual history, including risk factors for sexual dysfunction, is completed. Results from laboratory investigations, including a total testosterone level, are within normal limits.

Mr. C asks about using medications with fewer sexual side effects (he has been taking 3 medications that can contribute to sexual dysfunction). A gradual cross-taper of esci­talopram, 20 mg/d, to mirtazapine, 45 mg/d, is implemented, along with tapering prega­balin to 50 mg/d.

Mr. C’s psychiatric and pain symptom improvement is maintained. He notices a boost in his sexual desire but has minimal improvement in erectile dysfunction. He is encouraged to speak with his primary care physician about an antihypertensive agent with less impact on sexual function, as well as therapeutic agents for erectile dysfunc­tion; these, he declines.

At a subsequent visit, Mr. C reports feeling less apprehension about sexual performance. He is now willing to consider further medica­tion options with his primary care physician, and agrees to a recommendation for couples psychotherapy.

As illustrated in Mr. C’s case, the recom­mended sexual assessment and manage­ment strategies to consider at a minimum in psychiatric practice are listed in Table 4.

STI risk in geriatric patients
The risk of sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), often is overlooked in sexually active older adults. Although STIs are more common among younger adults, there is recent evidence of increased incidence in the geriatric population31 (with the high­est risk of incident HIV and some STIs in older men who have sex with men³²). These increased rates can be explained, at least in part, by:
   • older men being less likely to use a condom during sexual activity
   • promotion of viral entry in older women through a drier, thinner vaginal wall
   • increased longevity of HIV-positive persons.³¹

Routine STI screening is not warranted in all older adults, but education and prevention strategies in sexually active seniors who are at greater risk of STIs are recommended. Particularly, clinicians should seek opportunities to discuss risk factors and safe sex practices (eg, using condoms, limiting number of sexual part­ners, practicing good hygiene, engaging in preventive care), and provide behavioral counseling where appropriate.^31,33

Additional considerations in geriatric sexuality
Because psychiatric and systemic medical conditions can hinder sexual function, it is essential to identify and manage these conditions. Several neuropsychiatric dis­orders, including mood and neurocogni­tive disorders, can not only cause sexual dysfunction, but also can raise ethical dilemmas for clinicians, such as reduced decisional capacity in cognitively impaired patients to consent to sexual activity.^1,34

In some patients, psychological, envi­ronmental, and pharmacological treatment options may help. A phosphodiesterase type 5 inhibitor for erectile dysfunction can be prescribed by the primary care phy­sician, a psychiatrist, or another specialist, depending on the physician’s expertise and comfort level.

Sequencing of sexual dysfunction. Notably, there is a common paradox in mood disorders. Decreased sexual interest or performance may represent an aspect of anhedonia associated with depres­sion, whereas sexual dysfunction could also result from medication use (particularly that of serotonergic antidepressants, such as selective serotonin reuptake inhibitors and serotonin-norepinephrine inhibitors), even as other depressive symptoms improve. Therefore, it is critical to analyze sequencing of sexual dysfunction—as part of the pre­senting mood symptoms or dysfunction induced by antidepressant treatment.

Geriatric sexuality in the digital age. Because older adults represent a rapidly growing segment of digital device users,³⁵ Internet use is likely to play a role in the future of sexuality and “digital intimacy,” in that older adults can engage in online sexual activities. The Internet also can be a tool to access medical education.

Related Resources
• Burghardt KJ, Gardner KN. Sildenafil for SSRI-induced sexual dysfunction. Current Psychiatry. 2013;12(4):29-32,A.
• Maciel M, Laganà L. Older women’s sexual desire prob­lems: biopsychosocial factors impacting them and barriers to their clinical assessment [published online January 5, 2014]. Biomed Res Int. 2014;2014:107217. doi: 10.1155/2014/107217.

Drug Brand Names
Bupropion • Wellbutrin, Zyban                   Mirtazapine • Remeron
Carbamazepine • Tegretol                         Oxcarbazepine • Trileptal
Clonidine • Catapres                                 Phenobarbital • Luminal
Donepezil • Aricept                                   Phenytoin • Dilantin
Escitalopram • Lexapro                             Pregabalin • Lyrica
Gabapentin • Neurontin                            Ramipril • Altace
Lamotrigine • Lamictal                              Rivastigmine • Exelon
Lithium • Eskalith, Lithobid                       Trazodone • Desyrel
Memantine • Namenda                             Valproic acid • Depakote

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

More and more time is being allocated to training psychiatric residents in cognitive-behavioral therapy and crafting a cognitive-behavioral formulation. However, the psychodynamic formulation, once considered the backbone of psychiatry, should not be forgotten. The psychodynamic formulation is a cohesive portrait of an individual’s inner world based on the biopsychosocial approach.¹ The purpose in crafting a psychodynamic formulation is to create a succinct and focused case conceptualization that can guide treatment and anticipate possible outcomes.^2,3 To teach this in a simple, prac­tical, and relatable way, we propose an approach that can be summarized with the acronym PRESS.

Psychologically minded
Can the patient be introspective and contemplate his (her) thoughts and feel­ings before acting? Without the capacity to look within—distinct from intelli­gence—a patient could struggle with the psychodynamic approach and could benefit from a more supportive form of psychotherapy.⁴

Relationships
Examine the patient’s relationships with others:
   • Who are the prominent people in his (her) life?
   • What are his interpersonal relations like?
   • How does he (she) recall important relationships from the past?
   • Do these relationships appear to be recurring?⁴

Just as themes and patterns recur, so do relationships. Predict how the patient’s relationship pattern could be recreated in the therapeutic dynamic and how this could influence treatment. Then, by examining this transference and coun­tertransference data, you can illustrate a pattern from past relationships that is being recreated in the doctor-patient relationship.^3,5

Ego strength
Determining how the patient expresses or inhibits wishes and exhibits impulse con­trol can shed light onto how he operates on a daily basis:  
   • Does he have the ability to regulate his impulses?   
   • Is he capable of anticipating the conse­quences of inappropriate action?  
   • Does he show a lack of insight and judgment by exhibiting too many repetitive maladaptive behaviors?

Additionally, how does the patient keep unwanted fantasies, wishes, and memo­ries out of conscious awareness?

Identifying which constellation of defense mechanisms the patient is using can help categorize his level of functioning and personality type, and identify anxiety-provoking thoughts and events.^1,6 Often, one of these situations has consciously or subconsciously triggered the need for psychotherapy.

Stimulus
The hallmark of any psychodynamic formulation starts with a concise sum­marizing statement that describes the fun­damental details about the patient and his motivation for treatment.² Determining the patient’s impetus for treatment is 2-fold: Why does the patient want to receive treat­ment? Why now?

Superego
Review the patient’s ego ideal—what one should not do—and the moral conscience— what one should do.¹ Do there seem to be any deficits (recurrent shoplifting, crimi­nality, etc.)? Who contributed to his sense of right and wrong, and how harsh or lax is it? Is the patient self-defeating or self-punishing? Contrarily, does the patient seem to have little conscience?

Acknowledgment
Franklin Maleson, MD, provided advice and input to the authors.

Disclosures
The authors report no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.

More and more time is being allocated to training psychiatric residents in cognitive-behavioral therapy and crafting a cognitive-behavioral formulation. However, the psychodynamic formulation, once considered the backbone of psychiatry, should not be forgotten. The psychodynamic formulation is a cohesive portrait of an individual’s inner world based on the biopsychosocial approach.¹ The purpose in crafting a psychodynamic formulation is to create a succinct and focused case conceptualization that can guide treatment and anticipate possible outcomes.^2,3 To teach this in a simple, prac­tical, and relatable way, we propose an approach that can be summarized with the acronym PRESS.

Psychologically minded
Can the patient be introspective and contemplate his (her) thoughts and feel­ings before acting? Without the capacity to look within—distinct from intelli­gence—a patient could struggle with the psychodynamic approach and could benefit from a more supportive form of psychotherapy.⁴

Relationships
Examine the patient’s relationships with others:
   • Who are the prominent people in his (her) life?
   • What are his interpersonal relations like?
   • How does he (she) recall important relationships from the past?
   • Do these relationships appear to be recurring?⁴

Just as themes and patterns recur, so do relationships. Predict how the patient’s relationship pattern could be recreated in the therapeutic dynamic and how this could influence treatment. Then, by examining this transference and coun­tertransference data, you can illustrate a pattern from past relationships that is being recreated in the doctor-patient relationship.^3,5

Ego strength
Determining how the patient expresses or inhibits wishes and exhibits impulse con­trol can shed light onto how he operates on a daily basis:  
   • Does he have the ability to regulate his impulses?   
   • Is he capable of anticipating the conse­quences of inappropriate action?  
   • Does he show a lack of insight and judgment by exhibiting too many repetitive maladaptive behaviors?

Additionally, how does the patient keep unwanted fantasies, wishes, and memo­ries out of conscious awareness?

Identifying which constellation of defense mechanisms the patient is using can help categorize his level of functioning and personality type, and identify anxiety-provoking thoughts and events.^1,6 Often, one of these situations has consciously or subconsciously triggered the need for psychotherapy.

Stimulus
The hallmark of any psychodynamic formulation starts with a concise sum­marizing statement that describes the fun­damental details about the patient and his motivation for treatment.² Determining the patient’s impetus for treatment is 2-fold: Why does the patient want to receive treat­ment? Why now?

Superego
Review the patient’s ego ideal—what one should not do—and the moral conscience— what one should do.¹ Do there seem to be any deficits (recurrent shoplifting, crimi­nality, etc.)? Who contributed to his sense of right and wrong, and how harsh or lax is it? Is the patient self-defeating or self-punishing? Contrarily, does the patient seem to have little conscience?

Acknowledgment
Franklin Maleson, MD, provided advice and input to the authors.

Disclosures
The authors report no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.

More and more time is being allocated to training psychiatric residents in cognitive-behavioral therapy and crafting a cognitive-behavioral formulation. However, the psychodynamic formulation, once considered the backbone of psychiatry, should not be forgotten. The psychodynamic formulation is a cohesive portrait of an individual’s inner world based on the biopsychosocial approach.¹ The purpose in crafting a psychodynamic formulation is to create a succinct and focused case conceptualization that can guide treatment and anticipate possible outcomes.^2,3 To teach this in a simple, prac­tical, and relatable way, we propose an approach that can be summarized with the acronym PRESS.

Psychologically minded
Can the patient be introspective and contemplate his (her) thoughts and feel­ings before acting? Without the capacity to look within—distinct from intelli­gence—a patient could struggle with the psychodynamic approach and could benefit from a more supportive form of psychotherapy.⁴

Relationships
Examine the patient’s relationships with others:
   • Who are the prominent people in his (her) life?
   • What are his interpersonal relations like?
   • How does he (she) recall important relationships from the past?
   • Do these relationships appear to be recurring?⁴

Just as themes and patterns recur, so do relationships. Predict how the patient’s relationship pattern could be recreated in the therapeutic dynamic and how this could influence treatment. Then, by examining this transference and coun­tertransference data, you can illustrate a pattern from past relationships that is being recreated in the doctor-patient relationship.^3,5

Ego strength
Determining how the patient expresses or inhibits wishes and exhibits impulse con­trol can shed light onto how he operates on a daily basis:  
   • Does he have the ability to regulate his impulses?   
   • Is he capable of anticipating the conse­quences of inappropriate action?  
   • Does he show a lack of insight and judgment by exhibiting too many repetitive maladaptive behaviors?

Additionally, how does the patient keep unwanted fantasies, wishes, and memo­ries out of conscious awareness?

Identifying which constellation of defense mechanisms the patient is using can help categorize his level of functioning and personality type, and identify anxiety-provoking thoughts and events.^1,6 Often, one of these situations has consciously or subconsciously triggered the need for psychotherapy.

Stimulus
The hallmark of any psychodynamic formulation starts with a concise sum­marizing statement that describes the fun­damental details about the patient and his motivation for treatment.² Determining the patient’s impetus for treatment is 2-fold: Why does the patient want to receive treat­ment? Why now?

Superego
Review the patient’s ego ideal—what one should not do—and the moral conscience— what one should do.¹ Do there seem to be any deficits (recurrent shoplifting, crimi­nality, etc.)? Who contributed to his sense of right and wrong, and how harsh or lax is it? Is the patient self-defeating or self-punishing? Contrarily, does the patient seem to have little conscience?

Acknowledgment
Franklin Maleson, MD, provided advice and input to the authors.

Disclosures
The authors report no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.

WASHINGTON, DC—Football helmet add-ons such as outer soft-shell layers, spray treatments, helmet pads, and fiber sheets may not significantly help lower the risk of concussions in athletes, according to a study presented at the American Academy of Neurology’s 67th Annual Meeting. “Our study suggests that despite many products targeted at reducing concussions in players, there is no magic concussion prevention product on the market at this time,” said study author John Lloyd, PhD, of BRAINS, a company in San Antonio, Florida.

Researchers modified the standard drop test system, approved by the National Operating Committee on Standards for Athletic Equipment, by using a crash test dummy head and neck to more realistically simulate head impact. Sensors were placed in the dummy’s head to measure linear and angular rotational responses to helmet impacts at 10, 12, and 14 miles per hour.

Using this device, BRAINS researchers evaluated four football helmet add-ons: Guardian Cap, UnEqual Technologies’ Concussion Reduction Technology, Shockstrips, and Helmet Glide. Riddell Revolution Speed and Xenith X1 football helmets were outfitted with each of these add-ons and impacted five times from drop heights of 1.0, 1.5, and 2.0 meters. Linear acceleration, angular velocity, and angular accelerations of the head were measured in response to impacts.

The study found that compared with helmets without the add-ons, those fitted with the Guardian Cap, Concussion Reduction Technology, and Shockstrips reduced linear accelerations by about 11%, but only reduced angular accelerations by 2%, while Helmet Glide was shown to have no effect.

“These findings are important because angular accelerations are believed to be the major biomechanical forces involved in concussion,” said Dr. Lloyd. “Few add-on products have undergone even basic biomechanical evaluation. Hopefully, our research will lead to more rigorous testing of helmets and add-ons.”

The study was supported by BRAINS and the Seeing Stars Foundation.

WASHINGTON, DC—Football helmet add-ons such as outer soft-shell layers, spray treatments, helmet pads, and fiber sheets may not significantly help lower the risk of concussions in athletes, according to a study presented at the American Academy of Neurology’s 67th Annual Meeting. “Our study suggests that despite many products targeted at reducing concussions in players, there is no magic concussion prevention product on the market at this time,” said study author John Lloyd, PhD, of BRAINS, a company in San Antonio, Florida.

Researchers modified the standard drop test system, approved by the National Operating Committee on Standards for Athletic Equipment, by using a crash test dummy head and neck to more realistically simulate head impact. Sensors were placed in the dummy’s head to measure linear and angular rotational responses to helmet impacts at 10, 12, and 14 miles per hour.

Using this device, BRAINS researchers evaluated four football helmet add-ons: Guardian Cap, UnEqual Technologies’ Concussion Reduction Technology, Shockstrips, and Helmet Glide. Riddell Revolution Speed and Xenith X1 football helmets were outfitted with each of these add-ons and impacted five times from drop heights of 1.0, 1.5, and 2.0 meters. Linear acceleration, angular velocity, and angular accelerations of the head were measured in response to impacts.

The study found that compared with helmets without the add-ons, those fitted with the Guardian Cap, Concussion Reduction Technology, and Shockstrips reduced linear accelerations by about 11%, but only reduced angular accelerations by 2%, while Helmet Glide was shown to have no effect.

“These findings are important because angular accelerations are believed to be the major biomechanical forces involved in concussion,” said Dr. Lloyd. “Few add-on products have undergone even basic biomechanical evaluation. Hopefully, our research will lead to more rigorous testing of helmets and add-ons.”

The study was supported by BRAINS and the Seeing Stars Foundation.

WASHINGTON, DC—Football helmet add-ons such as outer soft-shell layers, spray treatments, helmet pads, and fiber sheets may not significantly help lower the risk of concussions in athletes, according to a study presented at the American Academy of Neurology’s 67th Annual Meeting. “Our study suggests that despite many products targeted at reducing concussions in players, there is no magic concussion prevention product on the market at this time,” said study author John Lloyd, PhD, of BRAINS, a company in San Antonio, Florida.

Researchers modified the standard drop test system, approved by the National Operating Committee on Standards for Athletic Equipment, by using a crash test dummy head and neck to more realistically simulate head impact. Sensors were placed in the dummy’s head to measure linear and angular rotational responses to helmet impacts at 10, 12, and 14 miles per hour.

Using this device, BRAINS researchers evaluated four football helmet add-ons: Guardian Cap, UnEqual Technologies’ Concussion Reduction Technology, Shockstrips, and Helmet Glide. Riddell Revolution Speed and Xenith X1 football helmets were outfitted with each of these add-ons and impacted five times from drop heights of 1.0, 1.5, and 2.0 meters. Linear acceleration, angular velocity, and angular accelerations of the head were measured in response to impacts.

The study found that compared with helmets without the add-ons, those fitted with the Guardian Cap, Concussion Reduction Technology, and Shockstrips reduced linear accelerations by about 11%, but only reduced angular accelerations by 2%, while Helmet Glide was shown to have no effect.

“These findings are important because angular accelerations are believed to be the major biomechanical forces involved in concussion,” said Dr. Lloyd. “Few add-on products have undergone even basic biomechanical evaluation. Hopefully, our research will lead to more rigorous testing of helmets and add-ons.”

The study was supported by BRAINS and the Seeing Stars Foundation.

This nervous system is located inside the wall of the GI tract, extending from the esophagus to the rectum. Technically, it is known as the enteric nervous system, or ENS, but it has been given other labels, too: “second brain,”² “abdominal brain,” “other brain,” and “back-up brain.” Its neurologic disorders include abdomi­nal epilepsy, abdominal migraine, and autism with intestinal symptoms, such as chronic enterocolitis.³

Impressive brain-like features
The ENS includes 100 million neu­rons (same as the spinal cord) with glia-like support cells. It contains >30 neurotransmitters, including several closely linked to psychopathology (serotonin, dopamine, γ-aminobutyric acid, and acetylcholine). The ENS is not part of the autonomic nervous system. It communicates with the brain via the vagus nerve.

A vast system of gut bacteria
The ENS maintains close links with, and is influenced by, the microbiome, an extensive universe of commensal (that is, symbiotic) bacteria in the gut that play a vital role in immune health, brain function, and signaling systems within the CNS. The role of the micro­biome in neuropsychiatric disorders has become a sizzling area of research.

The numbers of the microbiome are astonishing, including approximately 1,000 species of bacteria; 100 trillion total bacterial organisms (outnum­bering cells of the body by 100-fold); 4 million bacterial genes (compared with 26,000 genes in the host human genome); and a density as high as 1 tril­lion bacteria in a cubic milliliter—higher than any known microbial system.⁴

Significant GI−brain connections
It is of great relevance to psychiatry that 90% of the body’s serotonin and 50% of dopamine are found in the GI brain. Selective serotonin reuptake inhibitors often are associated with GI symptoms, such as nausea and diarrhea; antipsychotics, which are dopamine antagonists, are known for antiemetic effects. Clozapine’s potent anticholiner­gic effects can cause serious ileus.

Things get more interesting when one considers the association of GI dis­orders and psychiatric symptoms:

Irritable bowel syndrome is associated with panic disorder, generalized anxiety disorder, social phobia, dysthymia, and major depression.

Inflammatory bowel disease (IBD)— such as Crohn’s disease and ulcerative colitis (prevalence ranging from 6% in Canada to 14% in the United States to 46% in Mexico⁵)—is commonly associ­ated with mood and anxiety disorders and personality changes. The psychi­atric manifestations of IBD are so com­mon that the authors of a recent article in World Journal of Gastroenterology urged gastroenterologists to collaborate with psychiatrists when managing IBD.⁶

Celiac disease has been repeatedly associated with several neuropsychiat­ric disorders, including ataxia, epilepsy, peripheral neuropathy, headache, anxi­ety, attention-deficit/hyperactivity dis­order, autism spectrum disorder, and schizophrenia.

New, exciting challenges for medical science
There potentially are important impli­cations for possible exploitation of the ENS and the microbiome in the diag­nosis and treatment of neuropsychiatric disorders. For example, consider these speculative challenges:
   • Can intestinal biopsy reveal neu­rotransmitter pathology in schizophrenia?
   • Can early dopamine deficiency predict Parkinson’s disease, enabling early intervention?
   • Can β-amyloid deposits, the degenerative neurologic stigmata of Alzheimer’s disease, be detected in abdominal neurons years before onset of symptoms to allow early intervention?
   • Can the ENS become a therapeutic pathway by targeting the various neu­rotransmitters found there or by engag­ing the enormous human microbiome to manipulate its beneficial properties?
   • Can foods or probiotic supple­ments be prescribed as microbiomal adjuncts to improve the mood and anxi­ety spectrum?

One recommendation I came across is that ingesting 10 to 100 million ben­eficial bacteria, such as Lactobacillus plan­tarum and Bifidobacterium infantis, might be helpful. Such prescriptions obviously are speculative but also are reasonably testable hypotheses of ways to exploit the “other brain” and the microbiome.

We must summon the guts to seize this opportunity
An independent second brain and a remarkable microbiome appear to be significant evolutionary adaptations and advantages for humans. For too long, neuropsychiatric researchers have ignored the ENS and the micro­biome; now, they must focus on how to exploit these entities to yield inno­vative diagnostic and therapeutic advances. Integrating the ENS and the microbiome and enmeshing them into neuropsychiatric research and clinical applications hold great promise.

The field of psychoneurogastroen­terology is in its infancy, but its growth and relevance will be momentous for neuropsychiatry. A major intellectual peristalsis is underway.

This nervous system is located inside the wall of the GI tract, extending from the esophagus to the rectum. Technically, it is known as the enteric nervous system, or ENS, but it has been given other labels, too: “second brain,”² “abdominal brain,” “other brain,” and “back-up brain.” Its neurologic disorders include abdomi­nal epilepsy, abdominal migraine, and autism with intestinal symptoms, such as chronic enterocolitis.³

Impressive brain-like features
The ENS includes 100 million neu­rons (same as the spinal cord) with glia-like support cells. It contains >30 neurotransmitters, including several closely linked to psychopathology (serotonin, dopamine, γ-aminobutyric acid, and acetylcholine). The ENS is not part of the autonomic nervous system. It communicates with the brain via the vagus nerve.

A vast system of gut bacteria
The ENS maintains close links with, and is influenced by, the microbiome, an extensive universe of commensal (that is, symbiotic) bacteria in the gut that play a vital role in immune health, brain function, and signaling systems within the CNS. The role of the micro­biome in neuropsychiatric disorders has become a sizzling area of research.

The numbers of the microbiome are astonishing, including approximately 1,000 species of bacteria; 100 trillion total bacterial organisms (outnum­bering cells of the body by 100-fold); 4 million bacterial genes (compared with 26,000 genes in the host human genome); and a density as high as 1 tril­lion bacteria in a cubic milliliter—higher than any known microbial system.⁴

Significant GI−brain connections
It is of great relevance to psychiatry that 90% of the body’s serotonin and 50% of dopamine are found in the GI brain. Selective serotonin reuptake inhibitors often are associated with GI symptoms, such as nausea and diarrhea; antipsychotics, which are dopamine antagonists, are known for antiemetic effects. Clozapine’s potent anticholiner­gic effects can cause serious ileus.

Things get more interesting when one considers the association of GI dis­orders and psychiatric symptoms:

Irritable bowel syndrome is associated with panic disorder, generalized anxiety disorder, social phobia, dysthymia, and major depression.

Inflammatory bowel disease (IBD)— such as Crohn’s disease and ulcerative colitis (prevalence ranging from 6% in Canada to 14% in the United States to 46% in Mexico⁵)—is commonly associ­ated with mood and anxiety disorders and personality changes. The psychi­atric manifestations of IBD are so com­mon that the authors of a recent article in World Journal of Gastroenterology urged gastroenterologists to collaborate with psychiatrists when managing IBD.⁶

Celiac disease has been repeatedly associated with several neuropsychiat­ric disorders, including ataxia, epilepsy, peripheral neuropathy, headache, anxi­ety, attention-deficit/hyperactivity dis­order, autism spectrum disorder, and schizophrenia.

New, exciting challenges for medical science
There potentially are important impli­cations for possible exploitation of the ENS and the microbiome in the diag­nosis and treatment of neuropsychiatric disorders. For example, consider these speculative challenges:
   • Can intestinal biopsy reveal neu­rotransmitter pathology in schizophrenia?
   • Can early dopamine deficiency predict Parkinson’s disease, enabling early intervention?
   • Can β-amyloid deposits, the degenerative neurologic stigmata of Alzheimer’s disease, be detected in abdominal neurons years before onset of symptoms to allow early intervention?
   • Can the ENS become a therapeutic pathway by targeting the various neu­rotransmitters found there or by engag­ing the enormous human microbiome to manipulate its beneficial properties?
   • Can foods or probiotic supple­ments be prescribed as microbiomal adjuncts to improve the mood and anxi­ety spectrum?

One recommendation I came across is that ingesting 10 to 100 million ben­eficial bacteria, such as Lactobacillus plan­tarum and Bifidobacterium infantis, might be helpful. Such prescriptions obviously are speculative but also are reasonably testable hypotheses of ways to exploit the “other brain” and the microbiome.

We must summon the guts to seize this opportunity
An independent second brain and a remarkable microbiome appear to be significant evolutionary adaptations and advantages for humans. For too long, neuropsychiatric researchers have ignored the ENS and the micro­biome; now, they must focus on how to exploit these entities to yield inno­vative diagnostic and therapeutic advances. Integrating the ENS and the microbiome and enmeshing them into neuropsychiatric research and clinical applications hold great promise.

The field of psychoneurogastroen­terology is in its infancy, but its growth and relevance will be momentous for neuropsychiatry. A major intellectual peristalsis is underway.

This nervous system is located inside the wall of the GI tract, extending from the esophagus to the rectum. Technically, it is known as the enteric nervous system, or ENS, but it has been given other labels, too: “second brain,”² “abdominal brain,” “other brain,” and “back-up brain.” Its neurologic disorders include abdomi­nal epilepsy, abdominal migraine, and autism with intestinal symptoms, such as chronic enterocolitis.³

Impressive brain-like features
The ENS includes 100 million neu­rons (same as the spinal cord) with glia-like support cells. It contains >30 neurotransmitters, including several closely linked to psychopathology (serotonin, dopamine, γ-aminobutyric acid, and acetylcholine). The ENS is not part of the autonomic nervous system. It communicates with the brain via the vagus nerve.

A vast system of gut bacteria
The ENS maintains close links with, and is influenced by, the microbiome, an extensive universe of commensal (that is, symbiotic) bacteria in the gut that play a vital role in immune health, brain function, and signaling systems within the CNS. The role of the micro­biome in neuropsychiatric disorders has become a sizzling area of research.

The numbers of the microbiome are astonishing, including approximately 1,000 species of bacteria; 100 trillion total bacterial organisms (outnum­bering cells of the body by 100-fold); 4 million bacterial genes (compared with 26,000 genes in the host human genome); and a density as high as 1 tril­lion bacteria in a cubic milliliter—higher than any known microbial system.⁴

Significant GI−brain connections
It is of great relevance to psychiatry that 90% of the body’s serotonin and 50% of dopamine are found in the GI brain. Selective serotonin reuptake inhibitors often are associated with GI symptoms, such as nausea and diarrhea; antipsychotics, which are dopamine antagonists, are known for antiemetic effects. Clozapine’s potent anticholiner­gic effects can cause serious ileus.

Things get more interesting when one considers the association of GI dis­orders and psychiatric symptoms:

Irritable bowel syndrome is associated with panic disorder, generalized anxiety disorder, social phobia, dysthymia, and major depression.

Inflammatory bowel disease (IBD)— such as Crohn’s disease and ulcerative colitis (prevalence ranging from 6% in Canada to 14% in the United States to 46% in Mexico⁵)—is commonly associ­ated with mood and anxiety disorders and personality changes. The psychi­atric manifestations of IBD are so com­mon that the authors of a recent article in World Journal of Gastroenterology urged gastroenterologists to collaborate with psychiatrists when managing IBD.⁶

Celiac disease has been repeatedly associated with several neuropsychiat­ric disorders, including ataxia, epilepsy, peripheral neuropathy, headache, anxi­ety, attention-deficit/hyperactivity dis­order, autism spectrum disorder, and schizophrenia.

New, exciting challenges for medical science
There potentially are important impli­cations for possible exploitation of the ENS and the microbiome in the diag­nosis and treatment of neuropsychiatric disorders. For example, consider these speculative challenges:
   • Can intestinal biopsy reveal neu­rotransmitter pathology in schizophrenia?
   • Can early dopamine deficiency predict Parkinson’s disease, enabling early intervention?
   • Can β-amyloid deposits, the degenerative neurologic stigmata of Alzheimer’s disease, be detected in abdominal neurons years before onset of symptoms to allow early intervention?
   • Can the ENS become a therapeutic pathway by targeting the various neu­rotransmitters found there or by engag­ing the enormous human microbiome to manipulate its beneficial properties?
   • Can foods or probiotic supple­ments be prescribed as microbiomal adjuncts to improve the mood and anxi­ety spectrum?

One recommendation I came across is that ingesting 10 to 100 million ben­eficial bacteria, such as Lactobacillus plan­tarum and Bifidobacterium infantis, might be helpful. Such prescriptions obviously are speculative but also are reasonably testable hypotheses of ways to exploit the “other brain” and the microbiome.

We must summon the guts to seize this opportunity
An independent second brain and a remarkable microbiome appear to be significant evolutionary adaptations and advantages for humans. For too long, neuropsychiatric researchers have ignored the ENS and the micro­biome; now, they must focus on how to exploit these entities to yield inno­vative diagnostic and therapeutic advances. Integrating the ENS and the microbiome and enmeshing them into neuropsychiatric research and clinical applications hold great promise.

The field of psychoneurogastroen­terology is in its infancy, but its growth and relevance will be momentous for neuropsychiatry. A major intellectual peristalsis is underway.

Registration area at AACR 2015

PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.

Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.

But less than a quarter of the patients died of comorbidities, and none of them died of old age.

Most patients died of CLL progression or conditions possibly related to CLL.

Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).

The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.

The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.

“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”

Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).

“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”

But Dr Strati and his colleagues found that was not the case for most of the patients they studied.

The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.

“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.

Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.

Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.

In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.

Registration area at AACR 2015

PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.

Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.

But less than a quarter of the patients died of comorbidities, and none of them died of old age.

Most patients died of CLL progression or conditions possibly related to CLL.

Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).

The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.

The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.

“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”

Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).

“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”

But Dr Strati and his colleagues found that was not the case for most of the patients they studied.

The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.

“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.

Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.

Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.

In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.

Registration area at AACR 2015

PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.

Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.

But less than a quarter of the patients died of comorbidities, and none of them died of old age.

Most patients died of CLL progression or conditions possibly related to CLL.

Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).

The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.

The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.

“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”

Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).

“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”

But Dr Strati and his colleagues found that was not the case for most of the patients they studied.

The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.

“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.

Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.

Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.

In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.

Bags of plasma

Photo by Cristina Granados

High-volume trauma centers can provide consistent, rapid delivery of universal-donor plasma to massively hemorrhaging patients without excessive wastage, results of the PROPPR trial suggest.

For this study, researchers assessed the feasibility of the 2013 guidelines issued by the American College of Surgeons, which recommend that universal-donor products be immediately available upon the arrival of severely injured patients.

This recommendation may be outside the capabilities of many facilities, but it is likely to become the expected standard in the near future, the researchers said.

So Deborah Novak, MD, of the University of Arizona in Tucson, and her colleagues tested the feasibility of following the guidelines and reported their findings in Transfusion.

PROPPR was a randomized trial in which the researchers compared survival after the transfusion of 2 different blood component ratios in patients with traumatic massive hemorrhage. Transfusion services supporting the study were expected to provide thawed plasma, platelets, and red blood cells within 10 minutes of a request.

Twelve Level 1 trauma centers were involved in the trial. Participants collected data on the blood components transfused and the amount of time it took to deliver those products, but they focused primarily on plasma.

The researchers evaluated the adequacy of site plans by comparing the blood availability times to study goals and the American College of Surgeons guidelines.

The 680 patients in this trial received about 4700 units of plasma. Eleven of the sites consistently delivered 6 units of thawed, universal-donor plasma to their trauma-receiving unit within the required 10 minutes. The sites were able to deliver 12 units of plasma within 20 minutes.

Three sites used blood group A plasma instead of AB for massive transfusion and did not see any complications. None of the sites experienced shortages of AB plasma that limited enrollment. Two of the sites reported wasting nearly 25% of the AB plasma prepared.

“We hope the descriptions of the various ways in which centers fulfilled the requirement of delivering blood components to the bedside within 10 minutes inspire other facilities to devise the most effective way for their own circumstances,” Dr Novak said.

Bags of plasma

Photo by Cristina Granados

High-volume trauma centers can provide consistent, rapid delivery of universal-donor plasma to massively hemorrhaging patients without excessive wastage, results of the PROPPR trial suggest.

For this study, researchers assessed the feasibility of the 2013 guidelines issued by the American College of Surgeons, which recommend that universal-donor products be immediately available upon the arrival of severely injured patients.

This recommendation may be outside the capabilities of many facilities, but it is likely to become the expected standard in the near future, the researchers said.

So Deborah Novak, MD, of the University of Arizona in Tucson, and her colleagues tested the feasibility of following the guidelines and reported their findings in Transfusion.

PROPPR was a randomized trial in which the researchers compared survival after the transfusion of 2 different blood component ratios in patients with traumatic massive hemorrhage. Transfusion services supporting the study were expected to provide thawed plasma, platelets, and red blood cells within 10 minutes of a request.

Twelve Level 1 trauma centers were involved in the trial. Participants collected data on the blood components transfused and the amount of time it took to deliver those products, but they focused primarily on plasma.

The researchers evaluated the adequacy of site plans by comparing the blood availability times to study goals and the American College of Surgeons guidelines.

The 680 patients in this trial received about 4700 units of plasma. Eleven of the sites consistently delivered 6 units of thawed, universal-donor plasma to their trauma-receiving unit within the required 10 minutes. The sites were able to deliver 12 units of plasma within 20 minutes.

Three sites used blood group A plasma instead of AB for massive transfusion and did not see any complications. None of the sites experienced shortages of AB plasma that limited enrollment. Two of the sites reported wasting nearly 25% of the AB plasma prepared.

“We hope the descriptions of the various ways in which centers fulfilled the requirement of delivering blood components to the bedside within 10 minutes inspire other facilities to devise the most effective way for their own circumstances,” Dr Novak said.

Bags of plasma

Photo by Cristina Granados

High-volume trauma centers can provide consistent, rapid delivery of universal-donor plasma to massively hemorrhaging patients without excessive wastage, results of the PROPPR trial suggest.

For this study, researchers assessed the feasibility of the 2013 guidelines issued by the American College of Surgeons, which recommend that universal-donor products be immediately available upon the arrival of severely injured patients.

This recommendation may be outside the capabilities of many facilities, but it is likely to become the expected standard in the near future, the researchers said.

So Deborah Novak, MD, of the University of Arizona in Tucson, and her colleagues tested the feasibility of following the guidelines and reported their findings in Transfusion.

PROPPR was a randomized trial in which the researchers compared survival after the transfusion of 2 different blood component ratios in patients with traumatic massive hemorrhage. Transfusion services supporting the study were expected to provide thawed plasma, platelets, and red blood cells within 10 minutes of a request.

Twelve Level 1 trauma centers were involved in the trial. Participants collected data on the blood components transfused and the amount of time it took to deliver those products, but they focused primarily on plasma.

The researchers evaluated the adequacy of site plans by comparing the blood availability times to study goals and the American College of Surgeons guidelines.

The 680 patients in this trial received about 4700 units of plasma. Eleven of the sites consistently delivered 6 units of thawed, universal-donor plasma to their trauma-receiving unit within the required 10 minutes. The sites were able to deliver 12 units of plasma within 20 minutes.

Three sites used blood group A plasma instead of AB for massive transfusion and did not see any complications. None of the sites experienced shortages of AB plasma that limited enrollment. Two of the sites reported wasting nearly 25% of the AB plasma prepared.

“We hope the descriptions of the various ways in which centers fulfilled the requirement of delivering blood components to the bedside within 10 minutes inspire other facilities to devise the most effective way for their own circumstances,” Dr Novak said.

Researcher in the lab

Photo courtesy of NIH

MicroRNA (miR) expression may help us predict long-term prognosis in diffuse large B-cell lymphoma (DLBCL), according to a study published in

Leukemia Research.

Investigators identified 8 miRs that were differently expressed in DLBCL patients with poor prognosis and patients with favorable prognosis.

However, many of the miRs that have been linked to DLBCL prognosis in previous studies were not associated with prognosis in this study.

“Our data are in agreement with previous findings showing that miR signature is predictive of prognosis for patients with DLBCL, although with different miRs achieving statistical significance,” said study author Meir Lahav, MD, of Tel Aviv University in Israel.

Dr Lahav and his colleagues analyzed miR signatures from tissue biopsies taken from 83 patients with DLBCL who were treated between 1995 and 2003.

Patients who relapsed within 9 months from the start of treatment were defined as poor prognosis (n=43), and patients with disease-free survival of at least 5 years were defined as good prognosis (n=40).

The investigators analyzed RNA using microarrays developed by Rosetta Genomics. To validate the microarray results, the team used quantitative real-time polymerase chain reaction (qRT-PCR) and an independent set of 13 samples.

They found that 4 miRs were upregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-17-5p, hsa-miR-19b-3p, hsa-miR-20a-5p, and hsa-miR-106a-5p.

And 4 miRs were downregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-150-5p, hsa-miR-342-3p, hsa-miR-181a-5p, and hsa-miR-140-3p.

The investigators said the strongest and most consistent correlation was for miR-342-3p and miR-150-5p, which discriminated between the 2 prognostic groups in the microarray analysis, qRT-PCR, and the independent validation set.

Several miRs that were found to have prognostic value in previous studies did not differentiate the prognostic groups in this study. These were miR-155-5p, miR-21-5p, miR-18a-5p, miR-221-3p, and miR-222-3p. However, one miR—miR-181a-5p—had prognostic value in a previous study and the current study.

The investigators said the differences in miRs might be explained by the fact that this study had a larger sample size and longer follow-up than previous studies.

The differences might also reflect prognostic changes with rituximab treatment, as the patients in this study did not receive rituximab (only CHOP).

Either way, the investigators said these results suggest that analyzing miR expression can potentially improve our ability to predict prognosis in DLBCL and may therefore have a significant clinical impact.

Researcher in the lab

Photo courtesy of NIH

MicroRNA (miR) expression may help us predict long-term prognosis in diffuse large B-cell lymphoma (DLBCL), according to a study published in

Leukemia Research.

Investigators identified 8 miRs that were differently expressed in DLBCL patients with poor prognosis and patients with favorable prognosis.

However, many of the miRs that have been linked to DLBCL prognosis in previous studies were not associated with prognosis in this study.

“Our data are in agreement with previous findings showing that miR signature is predictive of prognosis for patients with DLBCL, although with different miRs achieving statistical significance,” said study author Meir Lahav, MD, of Tel Aviv University in Israel.

Dr Lahav and his colleagues analyzed miR signatures from tissue biopsies taken from 83 patients with DLBCL who were treated between 1995 and 2003.

Patients who relapsed within 9 months from the start of treatment were defined as poor prognosis (n=43), and patients with disease-free survival of at least 5 years were defined as good prognosis (n=40).

The investigators analyzed RNA using microarrays developed by Rosetta Genomics. To validate the microarray results, the team used quantitative real-time polymerase chain reaction (qRT-PCR) and an independent set of 13 samples.

They found that 4 miRs were upregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-17-5p, hsa-miR-19b-3p, hsa-miR-20a-5p, and hsa-miR-106a-5p.

And 4 miRs were downregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-150-5p, hsa-miR-342-3p, hsa-miR-181a-5p, and hsa-miR-140-3p.

The investigators said the strongest and most consistent correlation was for miR-342-3p and miR-150-5p, which discriminated between the 2 prognostic groups in the microarray analysis, qRT-PCR, and the independent validation set.

Several miRs that were found to have prognostic value in previous studies did not differentiate the prognostic groups in this study. These were miR-155-5p, miR-21-5p, miR-18a-5p, miR-221-3p, and miR-222-3p. However, one miR—miR-181a-5p—had prognostic value in a previous study and the current study.

The investigators said the differences in miRs might be explained by the fact that this study had a larger sample size and longer follow-up than previous studies.

The differences might also reflect prognostic changes with rituximab treatment, as the patients in this study did not receive rituximab (only CHOP).

Either way, the investigators said these results suggest that analyzing miR expression can potentially improve our ability to predict prognosis in DLBCL and may therefore have a significant clinical impact.

Researcher in the lab

Photo courtesy of NIH

MicroRNA (miR) expression may help us predict long-term prognosis in diffuse large B-cell lymphoma (DLBCL), according to a study published in

Leukemia Research.

Investigators identified 8 miRs that were differently expressed in DLBCL patients with poor prognosis and patients with favorable prognosis.

However, many of the miRs that have been linked to DLBCL prognosis in previous studies were not associated with prognosis in this study.

“Our data are in agreement with previous findings showing that miR signature is predictive of prognosis for patients with DLBCL, although with different miRs achieving statistical significance,” said study author Meir Lahav, MD, of Tel Aviv University in Israel.

Dr Lahav and his colleagues analyzed miR signatures from tissue biopsies taken from 83 patients with DLBCL who were treated between 1995 and 2003.

Patients who relapsed within 9 months from the start of treatment were defined as poor prognosis (n=43), and patients with disease-free survival of at least 5 years were defined as good prognosis (n=40).

The investigators analyzed RNA using microarrays developed by Rosetta Genomics. To validate the microarray results, the team used quantitative real-time polymerase chain reaction (qRT-PCR) and an independent set of 13 samples.

They found that 4 miRs were upregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-17-5p, hsa-miR-19b-3p, hsa-miR-20a-5p, and hsa-miR-106a-5p.

And 4 miRs were downregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-150-5p, hsa-miR-342-3p, hsa-miR-181a-5p, and hsa-miR-140-3p.

The investigators said the strongest and most consistent correlation was for miR-342-3p and miR-150-5p, which discriminated between the 2 prognostic groups in the microarray analysis, qRT-PCR, and the independent validation set.

Several miRs that were found to have prognostic value in previous studies did not differentiate the prognostic groups in this study. These were miR-155-5p, miR-21-5p, miR-18a-5p, miR-221-3p, and miR-222-3p. However, one miR—miR-181a-5p—had prognostic value in a previous study and the current study.

The investigators said the differences in miRs might be explained by the fact that this study had a larger sample size and longer follow-up than previous studies.

The differences might also reflect prognostic changes with rituximab treatment, as the patients in this study did not receive rituximab (only CHOP).

Either way, the investigators said these results suggest that analyzing miR expression can potentially improve our ability to predict prognosis in DLBCL and may therefore have a significant clinical impact.

Malaria vaccination

Photo by Caitlin Kleiboer

The malaria vaccine candidate RTS,S/AS01 is somewhat effective in young African children for up to 4 years after vaccination, according to final data from a phase 3 trial.

The vaccine proved more effective against clinical and severe malaria in children than in young infants, but efficacy waned over time in both age groups.

On the other hand, a booster dose of RTS,S/AS01 increased the average number of malaria cases prevented in children and infants.

“Despite the falling efficacy over time, there is still a clear benefit from RTS,S/AS01,” said Brian Greenwood, MD, of the London School of Hygiene & Tropical Medicine in the UK.

“An average 1363 cases of clinical malaria were prevented over 4 years of follow-up for every 1000 children vaccinated, and 1774 cases in those who also received a booster shot. Over 3 years of follow-up, an average 558 cases were averted for every 1000 infants vaccinated, and 983 cases in those also given a booster dose.”

Dr Greenwood and his colleagues disclosed these data in The Lancet. The research was funded by GlaxoSmithKline Biologicals SA, the company developing RTS,S/AS01, and the PATH Malaria Vaccine Initiative.

The trial included 15,459 young infants (aged 6 weeks to 12 weeks at first vaccination) and children (5 months to 17 months at first vaccination) from 11 sites across 7 sub-Saharan African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and United Republic of Tanzania) with varying levels of malaria transmission.

Earlier results from this trial, at 18 months of follow-up, showed efficacy of about 46% against clinical malaria in children and around 27% among young infants. Vaccine efficacy is defined as the reduction in the incidence of disease among participants who receive the vaccine compared to the incidence among participants who do not.

Dr Greenwood and his colleagues followed the infants and children for a further 20 to 30 months, respectively, and assessed the impact of a fourth booster dose.

Participants were each vaccinated 3 times with RTS,S/AS01, with or without a booster dose 18 months later, or given 4 doses of a comparator vaccine (control group).

In children who received 3 doses of RTS,S/AS01 plus a booster, the number of clinical episodes of malaria at 4 years was reduced by just over a third (36%). This is a drop in efficacy from the 50% protection against malaria seen in the first year.

Without a booster dose, the vaccine was not significantly effective against severe malaria in this age group. However, in children given a booster dose, the overall protective efficacy against severe malaria was 32% and 35% against malaria-associated hospitalizations.

In infants who received 3 doses of RTS,S/AS01 plus a booster, the vaccine reduced the risk of clinical episodes of malaria by 26% over 3 years of follow-up. There was no significant protection against severe disease in infants.

Meningitis occurred more frequently in children given RTS,S/AS01 than in children given the control vaccine. There were 11 cases of meningitis among children who received a booster, 10 cases among children who did not receive a booster, and 1 case among children in the control group.

RTS,S/AS02 produced more adverse reactions than the control vaccines. Convulsions following vaccination, although uncommon, occurred more frequently in children who received RTS,S/AS01. The incidence of other serious adverse events was similar in all the groups.

“The European Medicines Agency (EMA) will assess the quality, safety, and efficacy of the vaccine based on these final data,” Dr Greenwood said. “If the EMA gives a favorable opinion, WHO could recommend the use of RTS,S/AS01 as early as October this year. If licensed, RTS,S/AS01 would be the first licensed human vaccine against a parasitic disease.”

Malaria vaccination

Photo by Caitlin Kleiboer

The malaria vaccine candidate RTS,S/AS01 is somewhat effective in young African children for up to 4 years after vaccination, according to final data from a phase 3 trial.

The vaccine proved more effective against clinical and severe malaria in children than in young infants, but efficacy waned over time in both age groups.

On the other hand, a booster dose of RTS,S/AS01 increased the average number of malaria cases prevented in children and infants.

“Despite the falling efficacy over time, there is still a clear benefit from RTS,S/AS01,” said Brian Greenwood, MD, of the London School of Hygiene & Tropical Medicine in the UK.

“An average 1363 cases of clinical malaria were prevented over 4 years of follow-up for every 1000 children vaccinated, and 1774 cases in those who also received a booster shot. Over 3 years of follow-up, an average 558 cases were averted for every 1000 infants vaccinated, and 983 cases in those also given a booster dose.”

Dr Greenwood and his colleagues disclosed these data in The Lancet. The research was funded by GlaxoSmithKline Biologicals SA, the company developing RTS,S/AS01, and the PATH Malaria Vaccine Initiative.

The trial included 15,459 young infants (aged 6 weeks to 12 weeks at first vaccination) and children (5 months to 17 months at first vaccination) from 11 sites across 7 sub-Saharan African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and United Republic of Tanzania) with varying levels of malaria transmission.

Earlier results from this trial, at 18 months of follow-up, showed efficacy of about 46% against clinical malaria in children and around 27% among young infants. Vaccine efficacy is defined as the reduction in the incidence of disease among participants who receive the vaccine compared to the incidence among participants who do not.

Dr Greenwood and his colleagues followed the infants and children for a further 20 to 30 months, respectively, and assessed the impact of a fourth booster dose.

Participants were each vaccinated 3 times with RTS,S/AS01, with or without a booster dose 18 months later, or given 4 doses of a comparator vaccine (control group).

In children who received 3 doses of RTS,S/AS01 plus a booster, the number of clinical episodes of malaria at 4 years was reduced by just over a third (36%). This is a drop in efficacy from the 50% protection against malaria seen in the first year.

Without a booster dose, the vaccine was not significantly effective against severe malaria in this age group. However, in children given a booster dose, the overall protective efficacy against severe malaria was 32% and 35% against malaria-associated hospitalizations.

In infants who received 3 doses of RTS,S/AS01 plus a booster, the vaccine reduced the risk of clinical episodes of malaria by 26% over 3 years of follow-up. There was no significant protection against severe disease in infants.

Meningitis occurred more frequently in children given RTS,S/AS01 than in children given the control vaccine. There were 11 cases of meningitis among children who received a booster, 10 cases among children who did not receive a booster, and 1 case among children in the control group.

RTS,S/AS02 produced more adverse reactions than the control vaccines. Convulsions following vaccination, although uncommon, occurred more frequently in children who received RTS,S/AS01. The incidence of other serious adverse events was similar in all the groups.

“The European Medicines Agency (EMA) will assess the quality, safety, and efficacy of the vaccine based on these final data,” Dr Greenwood said. “If the EMA gives a favorable opinion, WHO could recommend the use of RTS,S/AS01 as early as October this year. If licensed, RTS,S/AS01 would be the first licensed human vaccine against a parasitic disease.”

Malaria vaccination

Photo by Caitlin Kleiboer

The malaria vaccine candidate RTS,S/AS01 is somewhat effective in young African children for up to 4 years after vaccination, according to final data from a phase 3 trial.

The vaccine proved more effective against clinical and severe malaria in children than in young infants, but efficacy waned over time in both age groups.

On the other hand, a booster dose of RTS,S/AS01 increased the average number of malaria cases prevented in children and infants.

“Despite the falling efficacy over time, there is still a clear benefit from RTS,S/AS01,” said Brian Greenwood, MD, of the London School of Hygiene & Tropical Medicine in the UK.

“An average 1363 cases of clinical malaria were prevented over 4 years of follow-up for every 1000 children vaccinated, and 1774 cases in those who also received a booster shot. Over 3 years of follow-up, an average 558 cases were averted for every 1000 infants vaccinated, and 983 cases in those also given a booster dose.”

Dr Greenwood and his colleagues disclosed these data in The Lancet. The research was funded by GlaxoSmithKline Biologicals SA, the company developing RTS,S/AS01, and the PATH Malaria Vaccine Initiative.

The trial included 15,459 young infants (aged 6 weeks to 12 weeks at first vaccination) and children (5 months to 17 months at first vaccination) from 11 sites across 7 sub-Saharan African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and United Republic of Tanzania) with varying levels of malaria transmission.

Earlier results from this trial, at 18 months of follow-up, showed efficacy of about 46% against clinical malaria in children and around 27% among young infants. Vaccine efficacy is defined as the reduction in the incidence of disease among participants who receive the vaccine compared to the incidence among participants who do not.

Dr Greenwood and his colleagues followed the infants and children for a further 20 to 30 months, respectively, and assessed the impact of a fourth booster dose.

Participants were each vaccinated 3 times with RTS,S/AS01, with or without a booster dose 18 months later, or given 4 doses of a comparator vaccine (control group).

In children who received 3 doses of RTS,S/AS01 plus a booster, the number of clinical episodes of malaria at 4 years was reduced by just over a third (36%). This is a drop in efficacy from the 50% protection against malaria seen in the first year.

Without a booster dose, the vaccine was not significantly effective against severe malaria in this age group. However, in children given a booster dose, the overall protective efficacy against severe malaria was 32% and 35% against malaria-associated hospitalizations.

In infants who received 3 doses of RTS,S/AS01 plus a booster, the vaccine reduced the risk of clinical episodes of malaria by 26% over 3 years of follow-up. There was no significant protection against severe disease in infants.

Meningitis occurred more frequently in children given RTS,S/AS01 than in children given the control vaccine. There were 11 cases of meningitis among children who received a booster, 10 cases among children who did not receive a booster, and 1 case among children in the control group.

RTS,S/AS02 produced more adverse reactions than the control vaccines. Convulsions following vaccination, although uncommon, occurred more frequently in children who received RTS,S/AS01. The incidence of other serious adverse events was similar in all the groups.

“The European Medicines Agency (EMA) will assess the quality, safety, and efficacy of the vaccine based on these final data,” Dr Greenwood said. “If the EMA gives a favorable opinion, WHO could recommend the use of RTS,S/AS01 as early as October this year. If licensed, RTS,S/AS01 would be the first licensed human vaccine against a parasitic disease.”