Patients with knee osteoarthritis (OA) who have poor sleep habits display greater central sensitization of pain, according to a study published online ahead of print June 4 in Arthritis Care & Research. Study findings also showed that OA patients who catastrophize had increased central sensitization that was associated with greater pain.

“Our study is the largest and most comprehensive examination of the relationship between sleep disturbance, catastrophizing, and central sensitization in knee OA,” stated lead author Claudia Campbell, PhD, an Associate Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine in Baltimore.

The case-controlled study included 208 participants who were categorized according to 4 groups: patients who have OA and insomnia, patients who have OA and normal sleep habits, healthy controls with insomnia, and healthy controls without a pain syndrome and normal sleep. In all, 72% of the study’s participants were female.

Participants completed multimodal sleep assessments (eg, questionnaire, diary, actigraphy, and polysmnography) and extensive evaluation of pain using clinical measures and quantitative sensory testing to evaluate associations between central sensitization, catastrophizing, and insomnia.

Results showed that the participants with knee OA and insomnia had the greatest amount of central sensitization compared with controls. The team found patients with poor sleep and high catastrophizing scores reported increased levels of central sensitization. In turn, central sensitization was significantly associated with increased clinical pain.

“While no causal processes may be determined from this study, our data suggest that those with low sleep efficiency and higher catastrophizing have the greatest central sensitization. Understanding the intricate relationship between sleep, central sensitization, and catastrophizing has important clinical implications for treating those with chronic pain conditions such as knee OA,” Dr. Campbell stated.

Patients with knee osteoarthritis (OA) who have poor sleep habits display greater central sensitization of pain, according to a study published online ahead of print June 4 in Arthritis Care & Research. Study findings also showed that OA patients who catastrophize had increased central sensitization that was associated with greater pain.

“Our study is the largest and most comprehensive examination of the relationship between sleep disturbance, catastrophizing, and central sensitization in knee OA,” stated lead author Claudia Campbell, PhD, an Associate Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine in Baltimore.

The case-controlled study included 208 participants who were categorized according to 4 groups: patients who have OA and insomnia, patients who have OA and normal sleep habits, healthy controls with insomnia, and healthy controls without a pain syndrome and normal sleep. In all, 72% of the study’s participants were female.

Participants completed multimodal sleep assessments (eg, questionnaire, diary, actigraphy, and polysmnography) and extensive evaluation of pain using clinical measures and quantitative sensory testing to evaluate associations between central sensitization, catastrophizing, and insomnia.

Results showed that the participants with knee OA and insomnia had the greatest amount of central sensitization compared with controls. The team found patients with poor sleep and high catastrophizing scores reported increased levels of central sensitization. In turn, central sensitization was significantly associated with increased clinical pain.

“While no causal processes may be determined from this study, our data suggest that those with low sleep efficiency and higher catastrophizing have the greatest central sensitization. Understanding the intricate relationship between sleep, central sensitization, and catastrophizing has important clinical implications for treating those with chronic pain conditions such as knee OA,” Dr. Campbell stated.

Patients with knee osteoarthritis (OA) who have poor sleep habits display greater central sensitization of pain, according to a study published online ahead of print June 4 in Arthritis Care & Research. Study findings also showed that OA patients who catastrophize had increased central sensitization that was associated with greater pain.

“Our study is the largest and most comprehensive examination of the relationship between sleep disturbance, catastrophizing, and central sensitization in knee OA,” stated lead author Claudia Campbell, PhD, an Associate Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine in Baltimore.

The case-controlled study included 208 participants who were categorized according to 4 groups: patients who have OA and insomnia, patients who have OA and normal sleep habits, healthy controls with insomnia, and healthy controls without a pain syndrome and normal sleep. In all, 72% of the study’s participants were female.

Participants completed multimodal sleep assessments (eg, questionnaire, diary, actigraphy, and polysmnography) and extensive evaluation of pain using clinical measures and quantitative sensory testing to evaluate associations between central sensitization, catastrophizing, and insomnia.

Results showed that the participants with knee OA and insomnia had the greatest amount of central sensitization compared with controls. The team found patients with poor sleep and high catastrophizing scores reported increased levels of central sensitization. In turn, central sensitization was significantly associated with increased clinical pain.

“While no causal processes may be determined from this study, our data suggest that those with low sleep efficiency and higher catastrophizing have the greatest central sensitization. Understanding the intricate relationship between sleep, central sensitization, and catastrophizing has important clinical implications for treating those with chronic pain conditions such as knee OA,” Dr. Campbell stated.

First-episode psychosis (FEP) in schizophrenia is char­acterized by high response rates to antipsychotic therapy, followed by frequent antipsychotic discon­tinuation and elevated relapse rates soon after mainte­nance treatment begins.^1,2 With subsequent episodes, time to response progressively increases and likelihood of response decreases.^3,4

To address these issues, this article—the second of 2 parts⁵—describes the rationale and evidence for using non­standard first-line antipsychotic therapies to manage FEP. Specifically, we discuss when clinicians might consider mono­therapy exceeding FDA-approved maximum dosages, combi­nation therapy, long-acting injectable antipsychotics (LAIA), or clozapine.

Monotherapy beyond FDA-approved dosages
Treatment guidelines for FEP recommend oral antipsy­chotic dosages in the lower half of the treatment range and lower than those that are required for multi-episode schizo­phrenia.^6-16 Ultimately, clinicians prescribe individualized dosages for their patients based on symptom improvement and tolerability. The optimal dosage at which to achieve a favorable D2 receptor occupancy likely will vary from patient to patient.¹⁷

To control symptoms, higher dosages may be needed than those used in FEP clinical tri­als, recommended by guidelines for FEP or multi-episode patients, or approved by the FDA. Patients seen in everyday practice may be more complicated (eg, have a comorbid condition or history of nonresponse) than study populations. Higher dosages also may be reasonable to overcome drug−drug interactions (eg, cigarette smoking-mediated cytochrome P450 1A2 induction, resulting in increased olanzapine metabolism),¹⁸ or to establish antipsychotic failure if adequate trials at lower dosages have resulted in a suboptimal response and the patient is not experiencing tolerability or safety concerns.

In a study of low-, full-, and high-dosage antipsychotic therapy in FEP, an additional 15% of patients responded to higher dos­ages of olanzapine and risperidone after failing to respond to a standard dosage.¹⁹ A study of data from the Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP) found that, of participants identified who may benefit from therapy modification, 8.8% were pre­scribed an antipsychotic (often, olanzapine, risperidone, and haloperidol) at a higher-than-recommended dosage.²⁰ Of note, only olanzapine was prescribed at higher than FDA-approved dosages.

Antipsychotic combination therapy
Prescribing combinations of antipsychot­ics—antipsychotic polypharmacy (APP)— has a negative connotation because of limited efficacy and safety data,²¹ and limited endorsement in schizophrenia treatment guidelines.^9,13 Caution with APP is war­ranted; a complex medication regimen may increase the potential for adverse effects, poorer adherence, and adverse drug-drug interactions.⁹ APP has been shown to inde­pendently predict both shorter treatment duration and discontinuation before 1 year.²²

Nonetheless, the clinician and patient may share the decision to implement APP and observe whether benefits outweigh risks in situations such as:
   • to optimize neuroreceptor occupancy and targets (eg, attempting to achieve ade­quate D2 receptor blockade while minimiz­ing side effects secondary to binding other receptors)
   • to manage co-existing symptom domains (eg, mood changes, aggression, negative symptoms, disorganization, and cognitive deficits)
   • to mitigate antipsychotic-induced side effects (eg, initiating aripiprazole to treat hyperprolactinemia induced by another anti­psychotic to which the patient has achieved a favorable response).²³

Clinicians report using APP to treat as many as 50% of patients with a history of multiple psychotic episodes.²³ For FEP patients, 23% of participants in the RAISE-ETP trial who were identified as possibly benefiting from therapy modification were prescribed APP.²⁰ Regrettably, research­ers have not found evidence to support a reported rationale for using APP—that lower dosages of individual antipsychotics when used in combination may avoid high-dosage prescriptions.²⁴

Before implementing APP, thoroughly explore and manage reasons for a patient’s suboptimal response to monotherapy.25 An adequate trial with any antipsychotic should be at the highest tolerated dosage for 12 to 16 weeks. Be mindful that response to an APP trial may be the result of additional time on the original antipsychotic.

Long-acting injectable antipsychotics in FEP
Guideline recommendations. Most older guidelines for schizophrenia treat­ment suggest LAIA after multiple relapses related to medication nonadherence or when a patient prefers injected medica­tion (Table 1).^6-13 Expert consensus guide­lines also recommend considering LAIA in patients who lack insight into their illness. The Texas Medication Algorithm Project (TMAP) guidelines⁷ state LAIA can be con­sidered for inadequate adherence at any stage, whereas the 2010 British Association for Psychopharmacology (BAP) guide­lines⁹ express uncertainty about their use in FEP, because of limited evidence. Both the BAP and National Institute for Health and Care Excellence guidelines¹³ urge cli­nicians to consider LAIA when avoiding nonadherence is a treatment priority.

Barriers to LAIA use include:
   • slow dosage titration and increased time to reach steady state drug level
   • oral supplementation for some (eg, risperidone microspheres and aripiprazole long-acting injectable)
   • logistical challenges for some (eg, 3-hour post-injection monitoring for delir­ium sedation syndrome with olanzapine pamoate)
   • additional planning to coordinate care for scheduled injections
   • higher expenses up front
   • local injection site reactions
   • dosage adjustment difficulties if adverse effects occur.^28,29

Adoption rates of LAIA are low, especially for FEP.³⁰ Most surveys indicate that (1) physi­cians believe LAIA treatment is ineffective for FEP31 and (2) patients do not prefer injectable to oral antipsychotics,³² despite evidence to the contrary.^33,34 A survey of 198 psychiatrists identified 3 factors that influenced their deci­sions against using LAIA patients with FEP:
   • limited availability of SGA depot formu­lations (4, to date, in the United States)
   • frequent rejection by the patient when LAIA is offered without adequate expla­nation or encouragement
   • skepticism of FEP patients (and their family) who lack experience with relapse.³⁵

In reality, when SGA depots were intro­duced in the United Kingdom, prescribing rates of LAIA did not increase. As for patient rejection being a major reason for not pre­scribing LAIA, few patients (5% to 36%) are offered depot injections, particularly in FEP.²⁹ Most patients using LAIA are chronic, multi-episode, violent people who are receiving medications involuntarily.²⁹ Interestingly, this survey did not find 2 factors to be influential in psychiatrists’ decision not to use LAIA in FEP:
   • guidelines do not explicitly recommend depot treatment in FEP
   • treatment in FEP may be limited to 1 year, therefore depot administration is not worthwhile.³⁵

Preliminary evidence. At least a dozen stud­ies have explored LAIA treatment for FEP, with the use of fluphenazine decanoate,³⁶ per­phenazine enanthate³⁷ (discontinued), and risperidone microspheres.^37-48 The research demonstrates the efficacy and safety of LAIA in FEP as measured by these endpoints:
   • improved symptom control^{38,40-43,46,48}
   • adherence^43,44,48
   • reduced relapse rates^37,43 and rehospitalizations^37,47
   • lesser reductions in white matter brain volume⁴⁵
   • no differences in extrapyramidal side effects or prolactin-associated adverse effects.⁴⁸

A few small studies demonstrate signifi­cant differences in outcomes between ris­peridone LAIA and oral comparator groups (Table 3).^43-45 Ongoing studies of LAIA use in FEP are comparing paliperidone palmitate with risperidone microspheres and other oral antipsychotics.^49-51 No stud­ies are examining olanzapine pamoate in FEP, likely because several guidelines do not recommended its use. No studies have been published regarding aripiprazole long-acting injectable in FEP. This LAIA formulation was approved in February 2013, and robust studies of the oral formulation in FEP are limited.⁵²

Relapses begin within a few months of illness stabilization after FEP, and >50% of patients relapse within 1 or 2 years²—the recommended minimum treatment dura­tion for FEP.^8,9,13 The use of LAIA is advis­able in any patient with schizophrenia for whom long-term antipsychotic therapy is indicated.⁵⁶ LAIA administration require­ments objectively track medication adher­ence, which allows clinicians to be proactive in relapse prevention. Not using an inter­vention in FEP that improves adherence and decreases relapse rates contradicts our goal of instituting early, effective treatment to improve long-term functional outcomes (Figure 2).²⁹

Considering clozapine in FEP
Guideline recommendations. Schizo-phrenia treatment guidelines and FDA labeling⁵⁷ reserve clozapine for third-line treatment of refractory schizophrenia after 2 adequate antipsychotic trials have failed despite optimal dosing (Table 1).^6-13 Some guidelines specify 1 of the 2 failed anti­psychotic trials must include an SGA.^{6,7,10,11,13-16} Most say clozapine may be considered in patients with chronic aggression or hostility,^7-9,14,16 or suicidal thoughts and behav­iors.^6-8,14,16 TMAP guidelines recommend a clozapine trial with concomitant substance abuse, persistent positive symptoms during 2 years of consistent medication treatment, and after 5 years of inadequate response (“treatment resistance”), regardless of the number of antipsychotic trials.⁷ ­

Rationale and concerns. Clozapine is a superior choice for treatment-refractory delusions or hallucinations of schizophrenia, because it markedly enhances the response rate to antipsychotic therapy.⁵⁸ Researchers therefore have investigated whether clozap­ine, compared with other antipsychotics, would yield more favorable initial and long-term outcomes when used first-line in FEP.

Preliminary evidence. Five studies have explored the use of clozapine as first-line therapy in FEP (Table 4).^59-63 Interpreting the results is difficult because clozapine trials may be brief (mostly, 12 to 52 weeks); lack a comparator arm; suffer from a high attrition rate; enroll few patients; and lack potentially important outcome measures such as nega­tive symptoms, suicidality, and functional assessment.

At present, clozapine has not been shown superior to other antipsychotics as a first-line treatment for FEP. Research does underscore the importance of a clozapine trial as third-line treatment for FEP patients who have not responded well to 2 SGA trials.⁶³ Many of these nonresponders (77%) have demon­strated a favorable response when promptly switched to clozapine.⁶⁴

Discussion and recommendations. The limited evidence argues against using clo­zapine earlier than as third-line treatment in FEP. Perhaps the high treatment response that characterizes FEP creates a ceiling effect that obscures differences in antipsychotic efficacy at this stage.⁶⁵ Clozapine use as first-line treatment should be re-evaluated with more robust methodology. One approach could be to assess its benefit in FEP by the duration of untreated psychosis.

The odds of achieving remission have been shown to decrease by 15% for each year that psychosis has not been treated.⁵⁹ Studies exploring the use of clozapine as a second-line agent for FEP also are warranted, as anti­psychotic response during subsequent trials is substantially reduced. In fact, the Scottish Intercollegiate Guidelines Network guide­lines recommend this as an area for future research.¹¹

For now, clozapine should continue to be reserved as second- or third-line treatment in a patient with FEP. The risks of clozap­ine’s potentially serious adverse effects (eg, agranulocytosis, seizures, obesity, diabe­tes, dyslipidemia, myocarditis, pancreatitis, hypotension, sialorrhea, severe sedation, ileus) can be justified only in the treatment of severe and persistent psychotic symptoms.⁵⁷

Bottom Line
Nonstandard use of antipsychotic monotherapy dosages beyond the approved FDA limit and combination antipsychotic therapy may be reasonable for select first-episode psychosis (FEP) patients. Strongly consider long-acting injectable antipsychotics in FEP to proactively combat the high relapse rate and more easily identify antipsychotic failure. Continue to use clozapine as second- or third-line therapy in FEP: Studies have not found that it is more efficacious than other antipsychotics for first-line use.

Related Resource
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.

Drug Brand Names
Aripiprazole • Abilify, Abilify Maintena      
Chlorpromazine • Thorazine                     
Clozapine • Clozaril                              
Fluphenazine decanoate • Prolixin-D      
Haloperidol • Haldol                                      
Haloperidol decanoate • Haldol-D       
Olanzapine • Zyprexa
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone microspheres • Risperdal Consta

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.

First-episode psychosis (FEP) in schizophrenia is char­acterized by high response rates to antipsychotic therapy, followed by frequent antipsychotic discon­tinuation and elevated relapse rates soon after mainte­nance treatment begins.^1,2 With subsequent episodes, time to response progressively increases and likelihood of response decreases.^3,4

To address these issues, this article—the second of 2 parts⁵—describes the rationale and evidence for using non­standard first-line antipsychotic therapies to manage FEP. Specifically, we discuss when clinicians might consider mono­therapy exceeding FDA-approved maximum dosages, combi­nation therapy, long-acting injectable antipsychotics (LAIA), or clozapine.

Monotherapy beyond FDA-approved dosages
Treatment guidelines for FEP recommend oral antipsy­chotic dosages in the lower half of the treatment range and lower than those that are required for multi-episode schizo­phrenia.^6-16 Ultimately, clinicians prescribe individualized dosages for their patients based on symptom improvement and tolerability. The optimal dosage at which to achieve a favorable D2 receptor occupancy likely will vary from patient to patient.¹⁷

To control symptoms, higher dosages may be needed than those used in FEP clinical tri­als, recommended by guidelines for FEP or multi-episode patients, or approved by the FDA. Patients seen in everyday practice may be more complicated (eg, have a comorbid condition or history of nonresponse) than study populations. Higher dosages also may be reasonable to overcome drug−drug interactions (eg, cigarette smoking-mediated cytochrome P450 1A2 induction, resulting in increased olanzapine metabolism),¹⁸ or to establish antipsychotic failure if adequate trials at lower dosages have resulted in a suboptimal response and the patient is not experiencing tolerability or safety concerns.

In a study of low-, full-, and high-dosage antipsychotic therapy in FEP, an additional 15% of patients responded to higher dos­ages of olanzapine and risperidone after failing to respond to a standard dosage.¹⁹ A study of data from the Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP) found that, of participants identified who may benefit from therapy modification, 8.8% were pre­scribed an antipsychotic (often, olanzapine, risperidone, and haloperidol) at a higher-than-recommended dosage.²⁰ Of note, only olanzapine was prescribed at higher than FDA-approved dosages.

Antipsychotic combination therapy
Prescribing combinations of antipsychot­ics—antipsychotic polypharmacy (APP)— has a negative connotation because of limited efficacy and safety data,²¹ and limited endorsement in schizophrenia treatment guidelines.^9,13 Caution with APP is war­ranted; a complex medication regimen may increase the potential for adverse effects, poorer adherence, and adverse drug-drug interactions.⁹ APP has been shown to inde­pendently predict both shorter treatment duration and discontinuation before 1 year.²²

Nonetheless, the clinician and patient may share the decision to implement APP and observe whether benefits outweigh risks in situations such as:
   • to optimize neuroreceptor occupancy and targets (eg, attempting to achieve ade­quate D2 receptor blockade while minimiz­ing side effects secondary to binding other receptors)
   • to manage co-existing symptom domains (eg, mood changes, aggression, negative symptoms, disorganization, and cognitive deficits)
   • to mitigate antipsychotic-induced side effects (eg, initiating aripiprazole to treat hyperprolactinemia induced by another anti­psychotic to which the patient has achieved a favorable response).²³

Clinicians report using APP to treat as many as 50% of patients with a history of multiple psychotic episodes.²³ For FEP patients, 23% of participants in the RAISE-ETP trial who were identified as possibly benefiting from therapy modification were prescribed APP.²⁰ Regrettably, research­ers have not found evidence to support a reported rationale for using APP—that lower dosages of individual antipsychotics when used in combination may avoid high-dosage prescriptions.²⁴

Before implementing APP, thoroughly explore and manage reasons for a patient’s suboptimal response to monotherapy.25 An adequate trial with any antipsychotic should be at the highest tolerated dosage for 12 to 16 weeks. Be mindful that response to an APP trial may be the result of additional time on the original antipsychotic.

Long-acting injectable antipsychotics in FEP
Guideline recommendations. Most older guidelines for schizophrenia treat­ment suggest LAIA after multiple relapses related to medication nonadherence or when a patient prefers injected medica­tion (Table 1).^6-13 Expert consensus guide­lines also recommend considering LAIA in patients who lack insight into their illness. The Texas Medication Algorithm Project (TMAP) guidelines⁷ state LAIA can be con­sidered for inadequate adherence at any stage, whereas the 2010 British Association for Psychopharmacology (BAP) guide­lines⁹ express uncertainty about their use in FEP, because of limited evidence. Both the BAP and National Institute for Health and Care Excellence guidelines¹³ urge cli­nicians to consider LAIA when avoiding nonadherence is a treatment priority.

Barriers to LAIA use include:
   • slow dosage titration and increased time to reach steady state drug level
   • oral supplementation for some (eg, risperidone microspheres and aripiprazole long-acting injectable)
   • logistical challenges for some (eg, 3-hour post-injection monitoring for delir­ium sedation syndrome with olanzapine pamoate)
   • additional planning to coordinate care for scheduled injections
   • higher expenses up front
   • local injection site reactions
   • dosage adjustment difficulties if adverse effects occur.^28,29

Adoption rates of LAIA are low, especially for FEP.³⁰ Most surveys indicate that (1) physi­cians believe LAIA treatment is ineffective for FEP31 and (2) patients do not prefer injectable to oral antipsychotics,³² despite evidence to the contrary.^33,34 A survey of 198 psychiatrists identified 3 factors that influenced their deci­sions against using LAIA patients with FEP:
   • limited availability of SGA depot formu­lations (4, to date, in the United States)
   • frequent rejection by the patient when LAIA is offered without adequate expla­nation or encouragement
   • skepticism of FEP patients (and their family) who lack experience with relapse.³⁵

In reality, when SGA depots were intro­duced in the United Kingdom, prescribing rates of LAIA did not increase. As for patient rejection being a major reason for not pre­scribing LAIA, few patients (5% to 36%) are offered depot injections, particularly in FEP.²⁹ Most patients using LAIA are chronic, multi-episode, violent people who are receiving medications involuntarily.²⁹ Interestingly, this survey did not find 2 factors to be influential in psychiatrists’ decision not to use LAIA in FEP:
   • guidelines do not explicitly recommend depot treatment in FEP
   • treatment in FEP may be limited to 1 year, therefore depot administration is not worthwhile.³⁵

Preliminary evidence. At least a dozen stud­ies have explored LAIA treatment for FEP, with the use of fluphenazine decanoate,³⁶ per­phenazine enanthate³⁷ (discontinued), and risperidone microspheres.^37-48 The research demonstrates the efficacy and safety of LAIA in FEP as measured by these endpoints:
   • improved symptom control^{38,40-43,46,48}
   • adherence^43,44,48
   • reduced relapse rates^37,43 and rehospitalizations^37,47
   • lesser reductions in white matter brain volume⁴⁵
   • no differences in extrapyramidal side effects or prolactin-associated adverse effects.⁴⁸

A few small studies demonstrate signifi­cant differences in outcomes between ris­peridone LAIA and oral comparator groups (Table 3).^43-45 Ongoing studies of LAIA use in FEP are comparing paliperidone palmitate with risperidone microspheres and other oral antipsychotics.^49-51 No stud­ies are examining olanzapine pamoate in FEP, likely because several guidelines do not recommended its use. No studies have been published regarding aripiprazole long-acting injectable in FEP. This LAIA formulation was approved in February 2013, and robust studies of the oral formulation in FEP are limited.⁵²

Relapses begin within a few months of illness stabilization after FEP, and >50% of patients relapse within 1 or 2 years²—the recommended minimum treatment dura­tion for FEP.^8,9,13 The use of LAIA is advis­able in any patient with schizophrenia for whom long-term antipsychotic therapy is indicated.⁵⁶ LAIA administration require­ments objectively track medication adher­ence, which allows clinicians to be proactive in relapse prevention. Not using an inter­vention in FEP that improves adherence and decreases relapse rates contradicts our goal of instituting early, effective treatment to improve long-term functional outcomes (Figure 2).²⁹

Considering clozapine in FEP
Guideline recommendations. Schizo-phrenia treatment guidelines and FDA labeling⁵⁷ reserve clozapine for third-line treatment of refractory schizophrenia after 2 adequate antipsychotic trials have failed despite optimal dosing (Table 1).^6-13 Some guidelines specify 1 of the 2 failed anti­psychotic trials must include an SGA.^{6,7,10,11,13-16} Most say clozapine may be considered in patients with chronic aggression or hostility,^7-9,14,16 or suicidal thoughts and behav­iors.^6-8,14,16 TMAP guidelines recommend a clozapine trial with concomitant substance abuse, persistent positive symptoms during 2 years of consistent medication treatment, and after 5 years of inadequate response (“treatment resistance”), regardless of the number of antipsychotic trials.⁷ ­

Rationale and concerns. Clozapine is a superior choice for treatment-refractory delusions or hallucinations of schizophrenia, because it markedly enhances the response rate to antipsychotic therapy.⁵⁸ Researchers therefore have investigated whether clozap­ine, compared with other antipsychotics, would yield more favorable initial and long-term outcomes when used first-line in FEP.

Preliminary evidence. Five studies have explored the use of clozapine as first-line therapy in FEP (Table 4).^59-63 Interpreting the results is difficult because clozapine trials may be brief (mostly, 12 to 52 weeks); lack a comparator arm; suffer from a high attrition rate; enroll few patients; and lack potentially important outcome measures such as nega­tive symptoms, suicidality, and functional assessment.

At present, clozapine has not been shown superior to other antipsychotics as a first-line treatment for FEP. Research does underscore the importance of a clozapine trial as third-line treatment for FEP patients who have not responded well to 2 SGA trials.⁶³ Many of these nonresponders (77%) have demon­strated a favorable response when promptly switched to clozapine.⁶⁴

Discussion and recommendations. The limited evidence argues against using clo­zapine earlier than as third-line treatment in FEP. Perhaps the high treatment response that characterizes FEP creates a ceiling effect that obscures differences in antipsychotic efficacy at this stage.⁶⁵ Clozapine use as first-line treatment should be re-evaluated with more robust methodology. One approach could be to assess its benefit in FEP by the duration of untreated psychosis.

The odds of achieving remission have been shown to decrease by 15% for each year that psychosis has not been treated.⁵⁹ Studies exploring the use of clozapine as a second-line agent for FEP also are warranted, as anti­psychotic response during subsequent trials is substantially reduced. In fact, the Scottish Intercollegiate Guidelines Network guide­lines recommend this as an area for future research.¹¹

For now, clozapine should continue to be reserved as second- or third-line treatment in a patient with FEP. The risks of clozap­ine’s potentially serious adverse effects (eg, agranulocytosis, seizures, obesity, diabe­tes, dyslipidemia, myocarditis, pancreatitis, hypotension, sialorrhea, severe sedation, ileus) can be justified only in the treatment of severe and persistent psychotic symptoms.⁵⁷

Bottom Line
Nonstandard use of antipsychotic monotherapy dosages beyond the approved FDA limit and combination antipsychotic therapy may be reasonable for select first-episode psychosis (FEP) patients. Strongly consider long-acting injectable antipsychotics in FEP to proactively combat the high relapse rate and more easily identify antipsychotic failure. Continue to use clozapine as second- or third-line therapy in FEP: Studies have not found that it is more efficacious than other antipsychotics for first-line use.

Related Resource
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.

Drug Brand Names
Aripiprazole • Abilify, Abilify Maintena      
Chlorpromazine • Thorazine                     
Clozapine • Clozaril                              
Fluphenazine decanoate • Prolixin-D      
Haloperidol • Haldol                                      
Haloperidol decanoate • Haldol-D       
Olanzapine • Zyprexa
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone microspheres • Risperdal Consta

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.

First-episode psychosis (FEP) in schizophrenia is char­acterized by high response rates to antipsychotic therapy, followed by frequent antipsychotic discon­tinuation and elevated relapse rates soon after mainte­nance treatment begins.^1,2 With subsequent episodes, time to response progressively increases and likelihood of response decreases.^3,4

To address these issues, this article—the second of 2 parts⁵—describes the rationale and evidence for using non­standard first-line antipsychotic therapies to manage FEP. Specifically, we discuss when clinicians might consider mono­therapy exceeding FDA-approved maximum dosages, combi­nation therapy, long-acting injectable antipsychotics (LAIA), or clozapine.

Monotherapy beyond FDA-approved dosages
Treatment guidelines for FEP recommend oral antipsy­chotic dosages in the lower half of the treatment range and lower than those that are required for multi-episode schizo­phrenia.^6-16 Ultimately, clinicians prescribe individualized dosages for their patients based on symptom improvement and tolerability. The optimal dosage at which to achieve a favorable D2 receptor occupancy likely will vary from patient to patient.¹⁷

To control symptoms, higher dosages may be needed than those used in FEP clinical tri­als, recommended by guidelines for FEP or multi-episode patients, or approved by the FDA. Patients seen in everyday practice may be more complicated (eg, have a comorbid condition or history of nonresponse) than study populations. Higher dosages also may be reasonable to overcome drug−drug interactions (eg, cigarette smoking-mediated cytochrome P450 1A2 induction, resulting in increased olanzapine metabolism),¹⁸ or to establish antipsychotic failure if adequate trials at lower dosages have resulted in a suboptimal response and the patient is not experiencing tolerability or safety concerns.

In a study of low-, full-, and high-dosage antipsychotic therapy in FEP, an additional 15% of patients responded to higher dos­ages of olanzapine and risperidone after failing to respond to a standard dosage.¹⁹ A study of data from the Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP) found that, of participants identified who may benefit from therapy modification, 8.8% were pre­scribed an antipsychotic (often, olanzapine, risperidone, and haloperidol) at a higher-than-recommended dosage.²⁰ Of note, only olanzapine was prescribed at higher than FDA-approved dosages.

Antipsychotic combination therapy
Prescribing combinations of antipsychot­ics—antipsychotic polypharmacy (APP)— has a negative connotation because of limited efficacy and safety data,²¹ and limited endorsement in schizophrenia treatment guidelines.^9,13 Caution with APP is war­ranted; a complex medication regimen may increase the potential for adverse effects, poorer adherence, and adverse drug-drug interactions.⁹ APP has been shown to inde­pendently predict both shorter treatment duration and discontinuation before 1 year.²²

Nonetheless, the clinician and patient may share the decision to implement APP and observe whether benefits outweigh risks in situations such as:
   • to optimize neuroreceptor occupancy and targets (eg, attempting to achieve ade­quate D2 receptor blockade while minimiz­ing side effects secondary to binding other receptors)
   • to manage co-existing symptom domains (eg, mood changes, aggression, negative symptoms, disorganization, and cognitive deficits)
   • to mitigate antipsychotic-induced side effects (eg, initiating aripiprazole to treat hyperprolactinemia induced by another anti­psychotic to which the patient has achieved a favorable response).²³

Clinicians report using APP to treat as many as 50% of patients with a history of multiple psychotic episodes.²³ For FEP patients, 23% of participants in the RAISE-ETP trial who were identified as possibly benefiting from therapy modification were prescribed APP.²⁰ Regrettably, research­ers have not found evidence to support a reported rationale for using APP—that lower dosages of individual antipsychotics when used in combination may avoid high-dosage prescriptions.²⁴

Before implementing APP, thoroughly explore and manage reasons for a patient’s suboptimal response to monotherapy.25 An adequate trial with any antipsychotic should be at the highest tolerated dosage for 12 to 16 weeks. Be mindful that response to an APP trial may be the result of additional time on the original antipsychotic.

Long-acting injectable antipsychotics in FEP
Guideline recommendations. Most older guidelines for schizophrenia treat­ment suggest LAIA after multiple relapses related to medication nonadherence or when a patient prefers injected medica­tion (Table 1).^6-13 Expert consensus guide­lines also recommend considering LAIA in patients who lack insight into their illness. The Texas Medication Algorithm Project (TMAP) guidelines⁷ state LAIA can be con­sidered for inadequate adherence at any stage, whereas the 2010 British Association for Psychopharmacology (BAP) guide­lines⁹ express uncertainty about their use in FEP, because of limited evidence. Both the BAP and National Institute for Health and Care Excellence guidelines¹³ urge cli­nicians to consider LAIA when avoiding nonadherence is a treatment priority.

Barriers to LAIA use include:
   • slow dosage titration and increased time to reach steady state drug level
   • oral supplementation for some (eg, risperidone microspheres and aripiprazole long-acting injectable)
   • logistical challenges for some (eg, 3-hour post-injection monitoring for delir­ium sedation syndrome with olanzapine pamoate)
   • additional planning to coordinate care for scheduled injections
   • higher expenses up front
   • local injection site reactions
   • dosage adjustment difficulties if adverse effects occur.^28,29

Adoption rates of LAIA are low, especially for FEP.³⁰ Most surveys indicate that (1) physi­cians believe LAIA treatment is ineffective for FEP31 and (2) patients do not prefer injectable to oral antipsychotics,³² despite evidence to the contrary.^33,34 A survey of 198 psychiatrists identified 3 factors that influenced their deci­sions against using LAIA patients with FEP:
   • limited availability of SGA depot formu­lations (4, to date, in the United States)
   • frequent rejection by the patient when LAIA is offered without adequate expla­nation or encouragement
   • skepticism of FEP patients (and their family) who lack experience with relapse.³⁵

In reality, when SGA depots were intro­duced in the United Kingdom, prescribing rates of LAIA did not increase. As for patient rejection being a major reason for not pre­scribing LAIA, few patients (5% to 36%) are offered depot injections, particularly in FEP.²⁹ Most patients using LAIA are chronic, multi-episode, violent people who are receiving medications involuntarily.²⁹ Interestingly, this survey did not find 2 factors to be influential in psychiatrists’ decision not to use LAIA in FEP:
   • guidelines do not explicitly recommend depot treatment in FEP
   • treatment in FEP may be limited to 1 year, therefore depot administration is not worthwhile.³⁵

Preliminary evidence. At least a dozen stud­ies have explored LAIA treatment for FEP, with the use of fluphenazine decanoate,³⁶ per­phenazine enanthate³⁷ (discontinued), and risperidone microspheres.^37-48 The research demonstrates the efficacy and safety of LAIA in FEP as measured by these endpoints:
   • improved symptom control^{38,40-43,46,48}
   • adherence^43,44,48
   • reduced relapse rates^37,43 and rehospitalizations^37,47
   • lesser reductions in white matter brain volume⁴⁵
   • no differences in extrapyramidal side effects or prolactin-associated adverse effects.⁴⁸

A few small studies demonstrate signifi­cant differences in outcomes between ris­peridone LAIA and oral comparator groups (Table 3).^43-45 Ongoing studies of LAIA use in FEP are comparing paliperidone palmitate with risperidone microspheres and other oral antipsychotics.^49-51 No stud­ies are examining olanzapine pamoate in FEP, likely because several guidelines do not recommended its use. No studies have been published regarding aripiprazole long-acting injectable in FEP. This LAIA formulation was approved in February 2013, and robust studies of the oral formulation in FEP are limited.⁵²

Relapses begin within a few months of illness stabilization after FEP, and >50% of patients relapse within 1 or 2 years²—the recommended minimum treatment dura­tion for FEP.^8,9,13 The use of LAIA is advis­able in any patient with schizophrenia for whom long-term antipsychotic therapy is indicated.⁵⁶ LAIA administration require­ments objectively track medication adher­ence, which allows clinicians to be proactive in relapse prevention. Not using an inter­vention in FEP that improves adherence and decreases relapse rates contradicts our goal of instituting early, effective treatment to improve long-term functional outcomes (Figure 2).²⁹

Considering clozapine in FEP
Guideline recommendations. Schizo-phrenia treatment guidelines and FDA labeling⁵⁷ reserve clozapine for third-line treatment of refractory schizophrenia after 2 adequate antipsychotic trials have failed despite optimal dosing (Table 1).^6-13 Some guidelines specify 1 of the 2 failed anti­psychotic trials must include an SGA.^{6,7,10,11,13-16} Most say clozapine may be considered in patients with chronic aggression or hostility,^7-9,14,16 or suicidal thoughts and behav­iors.^6-8,14,16 TMAP guidelines recommend a clozapine trial with concomitant substance abuse, persistent positive symptoms during 2 years of consistent medication treatment, and after 5 years of inadequate response (“treatment resistance”), regardless of the number of antipsychotic trials.⁷ ­

Rationale and concerns. Clozapine is a superior choice for treatment-refractory delusions or hallucinations of schizophrenia, because it markedly enhances the response rate to antipsychotic therapy.⁵⁸ Researchers therefore have investigated whether clozap­ine, compared with other antipsychotics, would yield more favorable initial and long-term outcomes when used first-line in FEP.

Preliminary evidence. Five studies have explored the use of clozapine as first-line therapy in FEP (Table 4).^59-63 Interpreting the results is difficult because clozapine trials may be brief (mostly, 12 to 52 weeks); lack a comparator arm; suffer from a high attrition rate; enroll few patients; and lack potentially important outcome measures such as nega­tive symptoms, suicidality, and functional assessment.

At present, clozapine has not been shown superior to other antipsychotics as a first-line treatment for FEP. Research does underscore the importance of a clozapine trial as third-line treatment for FEP patients who have not responded well to 2 SGA trials.⁶³ Many of these nonresponders (77%) have demon­strated a favorable response when promptly switched to clozapine.⁶⁴

Discussion and recommendations. The limited evidence argues against using clo­zapine earlier than as third-line treatment in FEP. Perhaps the high treatment response that characterizes FEP creates a ceiling effect that obscures differences in antipsychotic efficacy at this stage.⁶⁵ Clozapine use as first-line treatment should be re-evaluated with more robust methodology. One approach could be to assess its benefit in FEP by the duration of untreated psychosis.

The odds of achieving remission have been shown to decrease by 15% for each year that psychosis has not been treated.⁵⁹ Studies exploring the use of clozapine as a second-line agent for FEP also are warranted, as anti­psychotic response during subsequent trials is substantially reduced. In fact, the Scottish Intercollegiate Guidelines Network guide­lines recommend this as an area for future research.¹¹

For now, clozapine should continue to be reserved as second- or third-line treatment in a patient with FEP. The risks of clozap­ine’s potentially serious adverse effects (eg, agranulocytosis, seizures, obesity, diabe­tes, dyslipidemia, myocarditis, pancreatitis, hypotension, sialorrhea, severe sedation, ileus) can be justified only in the treatment of severe and persistent psychotic symptoms.⁵⁷

Bottom Line
Nonstandard use of antipsychotic monotherapy dosages beyond the approved FDA limit and combination antipsychotic therapy may be reasonable for select first-episode psychosis (FEP) patients. Strongly consider long-acting injectable antipsychotics in FEP to proactively combat the high relapse rate and more easily identify antipsychotic failure. Continue to use clozapine as second- or third-line therapy in FEP: Studies have not found that it is more efficacious than other antipsychotics for first-line use.

Related Resource
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.

Drug Brand Names
Aripiprazole • Abilify, Abilify Maintena      
Chlorpromazine • Thorazine                     
Clozapine • Clozaril                              
Fluphenazine decanoate • Prolixin-D      
Haloperidol • Haldol                                      
Haloperidol decanoate • Haldol-D       
Olanzapine • Zyprexa
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone microspheres • Risperdal Consta

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.

Mr. T,  age 23, was given a diagnosis of bipolar disorder 1 year ago. After he experienced inadequate symp­tom relief with valproate, you switched him to extended-release lithium, 1,200 mg/d. Mr. T reported improved mood and stability with this medication adjustment. These posi­tive changes led him to resume activities he enjoyed before onset of bipolar disorder, such as running, reading, and going out to dinner with friends.

Now, Mr. T’s mother calls your office to express concern about her son’s slight

hand tremor, which appeared after 2 days of gas­trointestinal distress. She tells you that Mr. T sprained his ankle while running 1 week ago and has been taking over-the-counter ibu­profen for pain relief, which he did often in the past.

You suspect that Mr. T is experiencing lith­ium toxicity as a result of ibuprofen use.

Although mental health providers can eas­ily recognize the drug−drug interaction between lithium and nonsteroidal anti-inflammatory drugs (NSAIDs) that Mr. T experienced, interpreting the safety of a medication regimen with respect to drug− drug interactions before prescribing often is more daunting. This article reviews the basics of drug−drug interactions, while briefly highlighting common examples in psychiatric medicine (Table 1^1-5). We also provide an outline of additional points to consider when reviewing your patients’ medication regimens and encoun­tering unfamiliar drug−drug interactions.

Types of drug−drug interactions
Drug−drug interactions fall into 2 catego­ries: pharmacodynamic (PD) and pharmaco­kinetic (PK):
   • PD interactions are a result of the com­bined impact of medications on the body when there is no direct effect on absorp­tion, distribution, metabolism, or excretion characteristics, such as 2 medications that act at the same receptor or lead to similar or opposing pharmacologic effects.
   • PK interactions occur when a drug affects the absorption, distribution, metabo­lism, or excretion characteristics of another drug.

Although it is possible that drug−drug interactions will have no clinical effect, when the impact of a PD or PK drug−drug interaction is evident, it likely is the result of additive, synergistic, or antago­nistic consequences on the medications’ intended impact or side-effect profile.

Pharmacodynamic interactions
Serotonin syndrome. The potential for serotonin syndrome occurs when medica­tions that increase synaptic serotonin con­centration are used concomitantly.¹ This can occur through several mechanisms, including increased serotonin release, decreased reuptake, or decreased sero­tonin metabolism. A high serotonin con­centration in the CNS and in the periphery overstimulates serotonin receptors, lead­ing to signs and symptoms that can include diarrhea, fever, delirium, coma, and poten­tially death.

QT prolongation and anticholinergic toxicity are further examples of additive PD drug−drug interactions. Anticholinergic toxicity is possible when multiple medica­tions contribute to inhibition of the neuro-transmitter acetylcholine at muscarinic receptors. This leads to adverse effects such as dry mouth, constipation, confusion, and urinary retention.

QT prolongation, which can lead to arrhythmia, occurs when a patient is taking several medications that can increase the QT interval. Consider close monitoring and using alternative agents with less poten­tial to increase the QT interval in patients at risk of arrhythmias (geriatric patients, those with an increased QT interval at base­line, etc.).

Decreased seizure threshold. The increased risk of seizures with bupropion and other medications that lower the sei­zure threshold is another example of an additive PD drug interaction. Bupropion can increase the risk of seizures in a dose-dependent manner, which increases when bupropion is taken with other drugs that lower the seizure threshold.6 Seizure risk associated with alcohol or benzodiazepine withdrawal also may increase the risk for this interaction.

Of note, the increased risk of seizures with the combination of bupropion and alcohol in the absence of withdrawal is not well studied in humans, but positive corre­lation has been seen in an animal study.⁶

Decreased platelet function. Another example of a PD drug−drug interaction is increased risk of bleeding when a selec­tive serotonin reuptake inhibitor is used with a NSAID or oral anticoagulant. The proposed mechanism for this interaction is that blocking serotonin reuptake on platelets leads to decreased platelet func­tion and an increased risk for prolonged bleeding.7 This is somewhat controversial because, first, it has been noted that drugs with the highest degree of serotonin reup­take inhibition do not always cause the highest risk of bleeding and, second, most of the evidence for this interaction is from observational studies.⁷

This potential interaction could be most important for patients who need an anti­depressant, are on chronic NSAID or anti­coagulant therapy, and are at high risk of bleeding.

Pharmacokinetic interactions
PK interactions in psychiatry often are caused by interference of drug metabo­lizing enzymes. The cytochrome P450 (CYP450) family of metabolizing enzymes in particular is important to the break­down of medications in the body. Many drug−drug interactions involve medica­tions that can inhibit or induce metabolism of other drugs through their effect on the CYP450 system.

Inhibition interactions. When a drug’s metabolism is inhibited, the result is usu­ally increased serum concentration of that medication (because of less break­down) and a more potent impact on the primary mechanism of action or adverse effects. Sometimes, inhibiting metabo­lism can lead to decreased clinical effect. Tamoxifen (an oral agent used to treat breast cancer) and certain analgesics when used in combination with moderate or strong inhibitors of the CYP2D6 subfam­ily of CYP450 metabolizing enzymes are 2 examples of metabolism inhibition lead­ing to decreased efficacy.⁸ Both tamoxi­fen and the analgesics listed in Table 1^1-5 are prodrugs; that is, they must be metabolized to be active. When the enzymes that metabolize these drugs into their active form are inhibited, the concen­tration of active drug decreases.

Induction interactions. Alternatively, there is an increased rate of drug break­down and resulting decrease in effect when drugs that induce the activity of metabolizing enzymes are used with med­ications that are substrates of the same enzyme. Carbamazepine is commonly involved in this type of drug interaction because it is a strong inducer of CYP 1A2, 2B6, 2C19, 2C9, and 3A4, and the p-glyco­protein drug efflux pump.⁹ As a result of this rampant induction, carbamazepine can decrease the serum concentration of oral contraceptives below a reliably effec­tive level. Therefore, it is recommended that women of childbearing potential use other contraceptive methods, such as a progestin implant or an intrauterine device.¹⁰

In addition, the polycyclic aromatic hydrocarbons found in cigarettes induce activity of CYP1A2. Patients who smoke and use medications metabolized by this enzyme, such as clozapine and olanzap­ine, may need a higher dosage.

Drug elimination interactions
The last drug−drug interaction discussed here returns the discussion to Mr. T and involves drug elimination.² The NSAIDs Mr. T was using for pain likely caused decreased renal excretion of lithium. Because lithium is primarily excreted through the kidneys, Mr. T’s NSAID use, possibly in com­bination with dehydration caused by gastro­intestinal distress, resulted in lithium toxicity. This class of analgesics should be avoided or used cautiously in patients taking lithium.

Clinical applications
The relatively common drug−drug interac­tions discussed here are just a fraction of the potential interactions mental health practi­tioners see on a daily basis. Understanding the basics of PD and PK interactions in the setting of patient-specific factors can help to clarify the information found in drug−drug interaction databases, such as Micromedex, Lexicomp, Facts and Comparisons, and Epocrates. Table 2 lists additional insights into drug interactions.

Related Resources
• CredibleMeds. Online resource on QT prolonging drugs. http://crediblemeds.org.
• Madhusoodanan S, Velama U, Parmar J, et al. A current review of cytochrome P450 interactions of psychotropic drugs. Ann Clin Psychiatry. 2014;26(2):120-138.

Drug Brand Names
Benztropine • Cogentin                            Olanzapine • Zyprexa
Bupropion • Wellbutrin                             Oxycodone • Oxycontin
Carbamazepine • Tegretol                        Paroxetine • Paxil
Clozapine • Clozaril                                  Quetiapine • Seroquel
Diphenhydramine • Benadryl                     Sertraline • Zoloft
 Duloxetine • Cymbalta                             Tamoxifen • Soltamox
Fluoxetine • Prozac                                   Trazodone • Desyrel
Lithium • Eskalith, Lithobid                        Valproate • Divalproex
Haloperidol • Haldol                                  Ziprasidone • Geodon
Hydrocodone • Vicodin

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

Mr. T,  age 23, was given a diagnosis of bipolar disorder 1 year ago. After he experienced inadequate symp­tom relief with valproate, you switched him to extended-release lithium, 1,200 mg/d. Mr. T reported improved mood and stability with this medication adjustment. These posi­tive changes led him to resume activities he enjoyed before onset of bipolar disorder, such as running, reading, and going out to dinner with friends.

Now, Mr. T’s mother calls your office to express concern about her son’s slight

hand tremor, which appeared after 2 days of gas­trointestinal distress. She tells you that Mr. T sprained his ankle while running 1 week ago and has been taking over-the-counter ibu­profen for pain relief, which he did often in the past.

You suspect that Mr. T is experiencing lith­ium toxicity as a result of ibuprofen use.

Although mental health providers can eas­ily recognize the drug−drug interaction between lithium and nonsteroidal anti-inflammatory drugs (NSAIDs) that Mr. T experienced, interpreting the safety of a medication regimen with respect to drug− drug interactions before prescribing often is more daunting. This article reviews the basics of drug−drug interactions, while briefly highlighting common examples in psychiatric medicine (Table 1^1-5). We also provide an outline of additional points to consider when reviewing your patients’ medication regimens and encoun­tering unfamiliar drug−drug interactions.

Types of drug−drug interactions
Drug−drug interactions fall into 2 catego­ries: pharmacodynamic (PD) and pharmaco­kinetic (PK):
   • PD interactions are a result of the com­bined impact of medications on the body when there is no direct effect on absorp­tion, distribution, metabolism, or excretion characteristics, such as 2 medications that act at the same receptor or lead to similar or opposing pharmacologic effects.
   • PK interactions occur when a drug affects the absorption, distribution, metabo­lism, or excretion characteristics of another drug.

Although it is possible that drug−drug interactions will have no clinical effect, when the impact of a PD or PK drug−drug interaction is evident, it likely is the result of additive, synergistic, or antago­nistic consequences on the medications’ intended impact or side-effect profile.

Pharmacodynamic interactions
Serotonin syndrome. The potential for serotonin syndrome occurs when medica­tions that increase synaptic serotonin con­centration are used concomitantly.¹ This can occur through several mechanisms, including increased serotonin release, decreased reuptake, or decreased sero­tonin metabolism. A high serotonin con­centration in the CNS and in the periphery overstimulates serotonin receptors, lead­ing to signs and symptoms that can include diarrhea, fever, delirium, coma, and poten­tially death.

QT prolongation and anticholinergic toxicity are further examples of additive PD drug−drug interactions. Anticholinergic toxicity is possible when multiple medica­tions contribute to inhibition of the neuro-transmitter acetylcholine at muscarinic receptors. This leads to adverse effects such as dry mouth, constipation, confusion, and urinary retention.

QT prolongation, which can lead to arrhythmia, occurs when a patient is taking several medications that can increase the QT interval. Consider close monitoring and using alternative agents with less poten­tial to increase the QT interval in patients at risk of arrhythmias (geriatric patients, those with an increased QT interval at base­line, etc.).

Decreased seizure threshold. The increased risk of seizures with bupropion and other medications that lower the sei­zure threshold is another example of an additive PD drug interaction. Bupropion can increase the risk of seizures in a dose-dependent manner, which increases when bupropion is taken with other drugs that lower the seizure threshold.6 Seizure risk associated with alcohol or benzodiazepine withdrawal also may increase the risk for this interaction.

Of note, the increased risk of seizures with the combination of bupropion and alcohol in the absence of withdrawal is not well studied in humans, but positive corre­lation has been seen in an animal study.⁶

Decreased platelet function. Another example of a PD drug−drug interaction is increased risk of bleeding when a selec­tive serotonin reuptake inhibitor is used with a NSAID or oral anticoagulant. The proposed mechanism for this interaction is that blocking serotonin reuptake on platelets leads to decreased platelet func­tion and an increased risk for prolonged bleeding.7 This is somewhat controversial because, first, it has been noted that drugs with the highest degree of serotonin reup­take inhibition do not always cause the highest risk of bleeding and, second, most of the evidence for this interaction is from observational studies.⁷

This potential interaction could be most important for patients who need an anti­depressant, are on chronic NSAID or anti­coagulant therapy, and are at high risk of bleeding.

Pharmacokinetic interactions
PK interactions in psychiatry often are caused by interference of drug metabo­lizing enzymes. The cytochrome P450 (CYP450) family of metabolizing enzymes in particular is important to the break­down of medications in the body. Many drug−drug interactions involve medica­tions that can inhibit or induce metabolism of other drugs through their effect on the CYP450 system.

Inhibition interactions. When a drug’s metabolism is inhibited, the result is usu­ally increased serum concentration of that medication (because of less break­down) and a more potent impact on the primary mechanism of action or adverse effects. Sometimes, inhibiting metabo­lism can lead to decreased clinical effect. Tamoxifen (an oral agent used to treat breast cancer) and certain analgesics when used in combination with moderate or strong inhibitors of the CYP2D6 subfam­ily of CYP450 metabolizing enzymes are 2 examples of metabolism inhibition lead­ing to decreased efficacy.⁸ Both tamoxi­fen and the analgesics listed in Table 1^1-5 are prodrugs; that is, they must be metabolized to be active. When the enzymes that metabolize these drugs into their active form are inhibited, the concen­tration of active drug decreases.

Induction interactions. Alternatively, there is an increased rate of drug break­down and resulting decrease in effect when drugs that induce the activity of metabolizing enzymes are used with med­ications that are substrates of the same enzyme. Carbamazepine is commonly involved in this type of drug interaction because it is a strong inducer of CYP 1A2, 2B6, 2C19, 2C9, and 3A4, and the p-glyco­protein drug efflux pump.⁹ As a result of this rampant induction, carbamazepine can decrease the serum concentration of oral contraceptives below a reliably effec­tive level. Therefore, it is recommended that women of childbearing potential use other contraceptive methods, such as a progestin implant or an intrauterine device.¹⁰

In addition, the polycyclic aromatic hydrocarbons found in cigarettes induce activity of CYP1A2. Patients who smoke and use medications metabolized by this enzyme, such as clozapine and olanzap­ine, may need a higher dosage.

Drug elimination interactions
The last drug−drug interaction discussed here returns the discussion to Mr. T and involves drug elimination.² The NSAIDs Mr. T was using for pain likely caused decreased renal excretion of lithium. Because lithium is primarily excreted through the kidneys, Mr. T’s NSAID use, possibly in com­bination with dehydration caused by gastro­intestinal distress, resulted in lithium toxicity. This class of analgesics should be avoided or used cautiously in patients taking lithium.

Clinical applications
The relatively common drug−drug interac­tions discussed here are just a fraction of the potential interactions mental health practi­tioners see on a daily basis. Understanding the basics of PD and PK interactions in the setting of patient-specific factors can help to clarify the information found in drug−drug interaction databases, such as Micromedex, Lexicomp, Facts and Comparisons, and Epocrates. Table 2 lists additional insights into drug interactions.

Related Resources
• CredibleMeds. Online resource on QT prolonging drugs. http://crediblemeds.org.
• Madhusoodanan S, Velama U, Parmar J, et al. A current review of cytochrome P450 interactions of psychotropic drugs. Ann Clin Psychiatry. 2014;26(2):120-138.

Drug Brand Names
Benztropine • Cogentin                            Olanzapine • Zyprexa
Bupropion • Wellbutrin                             Oxycodone • Oxycontin
Carbamazepine • Tegretol                        Paroxetine • Paxil
Clozapine • Clozaril                                  Quetiapine • Seroquel
Diphenhydramine • Benadryl                     Sertraline • Zoloft
 Duloxetine • Cymbalta                             Tamoxifen • Soltamox
Fluoxetine • Prozac                                   Trazodone • Desyrel
Lithium • Eskalith, Lithobid                        Valproate • Divalproex
Haloperidol • Haldol                                  Ziprasidone • Geodon
Hydrocodone • Vicodin

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

Mr. T,  age 23, was given a diagnosis of bipolar disorder 1 year ago. After he experienced inadequate symp­tom relief with valproate, you switched him to extended-release lithium, 1,200 mg/d. Mr. T reported improved mood and stability with this medication adjustment. These posi­tive changes led him to resume activities he enjoyed before onset of bipolar disorder, such as running, reading, and going out to dinner with friends.

Now, Mr. T’s mother calls your office to express concern about her son’s slight

hand tremor, which appeared after 2 days of gas­trointestinal distress. She tells you that Mr. T sprained his ankle while running 1 week ago and has been taking over-the-counter ibu­profen for pain relief, which he did often in the past.

You suspect that Mr. T is experiencing lith­ium toxicity as a result of ibuprofen use.

Although mental health providers can eas­ily recognize the drug−drug interaction between lithium and nonsteroidal anti-inflammatory drugs (NSAIDs) that Mr. T experienced, interpreting the safety of a medication regimen with respect to drug− drug interactions before prescribing often is more daunting. This article reviews the basics of drug−drug interactions, while briefly highlighting common examples in psychiatric medicine (Table 1^1-5). We also provide an outline of additional points to consider when reviewing your patients’ medication regimens and encoun­tering unfamiliar drug−drug interactions.

Types of drug−drug interactions
Drug−drug interactions fall into 2 catego­ries: pharmacodynamic (PD) and pharmaco­kinetic (PK):
   • PD interactions are a result of the com­bined impact of medications on the body when there is no direct effect on absorp­tion, distribution, metabolism, or excretion characteristics, such as 2 medications that act at the same receptor or lead to similar or opposing pharmacologic effects.
   • PK interactions occur when a drug affects the absorption, distribution, metabo­lism, or excretion characteristics of another drug.

Although it is possible that drug−drug interactions will have no clinical effect, when the impact of a PD or PK drug−drug interaction is evident, it likely is the result of additive, synergistic, or antago­nistic consequences on the medications’ intended impact or side-effect profile.

Pharmacodynamic interactions
Serotonin syndrome. The potential for serotonin syndrome occurs when medica­tions that increase synaptic serotonin con­centration are used concomitantly.¹ This can occur through several mechanisms, including increased serotonin release, decreased reuptake, or decreased sero­tonin metabolism. A high serotonin con­centration in the CNS and in the periphery overstimulates serotonin receptors, lead­ing to signs and symptoms that can include diarrhea, fever, delirium, coma, and poten­tially death.

QT prolongation and anticholinergic toxicity are further examples of additive PD drug−drug interactions. Anticholinergic toxicity is possible when multiple medica­tions contribute to inhibition of the neuro-transmitter acetylcholine at muscarinic receptors. This leads to adverse effects such as dry mouth, constipation, confusion, and urinary retention.

QT prolongation, which can lead to arrhythmia, occurs when a patient is taking several medications that can increase the QT interval. Consider close monitoring and using alternative agents with less poten­tial to increase the QT interval in patients at risk of arrhythmias (geriatric patients, those with an increased QT interval at base­line, etc.).

Decreased seizure threshold. The increased risk of seizures with bupropion and other medications that lower the sei­zure threshold is another example of an additive PD drug interaction. Bupropion can increase the risk of seizures in a dose-dependent manner, which increases when bupropion is taken with other drugs that lower the seizure threshold.6 Seizure risk associated with alcohol or benzodiazepine withdrawal also may increase the risk for this interaction.

Of note, the increased risk of seizures with the combination of bupropion and alcohol in the absence of withdrawal is not well studied in humans, but positive corre­lation has been seen in an animal study.⁶

Decreased platelet function. Another example of a PD drug−drug interaction is increased risk of bleeding when a selec­tive serotonin reuptake inhibitor is used with a NSAID or oral anticoagulant. The proposed mechanism for this interaction is that blocking serotonin reuptake on platelets leads to decreased platelet func­tion and an increased risk for prolonged bleeding.7 This is somewhat controversial because, first, it has been noted that drugs with the highest degree of serotonin reup­take inhibition do not always cause the highest risk of bleeding and, second, most of the evidence for this interaction is from observational studies.⁷

This potential interaction could be most important for patients who need an anti­depressant, are on chronic NSAID or anti­coagulant therapy, and are at high risk of bleeding.

Pharmacokinetic interactions
PK interactions in psychiatry often are caused by interference of drug metabo­lizing enzymes. The cytochrome P450 (CYP450) family of metabolizing enzymes in particular is important to the break­down of medications in the body. Many drug−drug interactions involve medica­tions that can inhibit or induce metabolism of other drugs through their effect on the CYP450 system.

Inhibition interactions. When a drug’s metabolism is inhibited, the result is usu­ally increased serum concentration of that medication (because of less break­down) and a more potent impact on the primary mechanism of action or adverse effects. Sometimes, inhibiting metabo­lism can lead to decreased clinical effect. Tamoxifen (an oral agent used to treat breast cancer) and certain analgesics when used in combination with moderate or strong inhibitors of the CYP2D6 subfam­ily of CYP450 metabolizing enzymes are 2 examples of metabolism inhibition lead­ing to decreased efficacy.⁸ Both tamoxi­fen and the analgesics listed in Table 1^1-5 are prodrugs; that is, they must be metabolized to be active. When the enzymes that metabolize these drugs into their active form are inhibited, the concen­tration of active drug decreases.

Induction interactions. Alternatively, there is an increased rate of drug break­down and resulting decrease in effect when drugs that induce the activity of metabolizing enzymes are used with med­ications that are substrates of the same enzyme. Carbamazepine is commonly involved in this type of drug interaction because it is a strong inducer of CYP 1A2, 2B6, 2C19, 2C9, and 3A4, and the p-glyco­protein drug efflux pump.⁹ As a result of this rampant induction, carbamazepine can decrease the serum concentration of oral contraceptives below a reliably effec­tive level. Therefore, it is recommended that women of childbearing potential use other contraceptive methods, such as a progestin implant or an intrauterine device.¹⁰

In addition, the polycyclic aromatic hydrocarbons found in cigarettes induce activity of CYP1A2. Patients who smoke and use medications metabolized by this enzyme, such as clozapine and olanzap­ine, may need a higher dosage.

Drug elimination interactions
The last drug−drug interaction discussed here returns the discussion to Mr. T and involves drug elimination.² The NSAIDs Mr. T was using for pain likely caused decreased renal excretion of lithium. Because lithium is primarily excreted through the kidneys, Mr. T’s NSAID use, possibly in com­bination with dehydration caused by gastro­intestinal distress, resulted in lithium toxicity. This class of analgesics should be avoided or used cautiously in patients taking lithium.

Clinical applications
The relatively common drug−drug interac­tions discussed here are just a fraction of the potential interactions mental health practi­tioners see on a daily basis. Understanding the basics of PD and PK interactions in the setting of patient-specific factors can help to clarify the information found in drug−drug interaction databases, such as Micromedex, Lexicomp, Facts and Comparisons, and Epocrates. Table 2 lists additional insights into drug interactions.

Related Resources
• CredibleMeds. Online resource on QT prolonging drugs. http://crediblemeds.org.
• Madhusoodanan S, Velama U, Parmar J, et al. A current review of cytochrome P450 interactions of psychotropic drugs. Ann Clin Psychiatry. 2014;26(2):120-138.

Drug Brand Names
Benztropine • Cogentin                            Olanzapine • Zyprexa
Bupropion • Wellbutrin                             Oxycodone • Oxycontin
Carbamazepine • Tegretol                        Paroxetine • Paxil
Clozapine • Clozaril                                  Quetiapine • Seroquel
Diphenhydramine • Benadryl                     Sertraline • Zoloft
 Duloxetine • Cymbalta                             Tamoxifen • Soltamox
Fluoxetine • Prozac                                   Trazodone • Desyrel
Lithium • Eskalith, Lithobid                        Valproate • Divalproex
Haloperidol • Haldol                                  Ziprasidone • Geodon
Hydrocodone • Vicodin

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

People with serious mental illness (SMI) have a life expectancy that is 25 years less than the general population, according to the Centers for Disease Control and Prevention.¹ This disparity is partially a consequence of the lack of primary and preventive medical care for those with psychiatric illness. Decades of research have shown that people with SMI experience higher medical morbidity and mortality in addition to facing the stigma of mental illness.

This article aims to advance the idea that longitudinal “cross educa­tion” between primary care providers (PCPs) and behavioral health providers (BHPs) is essential in addressing this problem. BHPs include psychiatry clinics, which often are part of a university or large health sys­tems; county-based community mental health programs; and indepen­dent mental health clinics that contract with public and private health plans to provide mental health services.

Although suicide and injury account for 40% of the excess mortality in schizophrenia, 60% can be attributed to cardiovascular disease, diabetes, respiratory diseases, and infection.² Patients with SMI have 2 to 3 times the risk of diabetes, dyslipidemia, hypertension, and obesity.^3,4 Furthermore, those with SMI consume more than one-third of tobacco products,⁵ and 50% to 80% of people with SMI smoke tobacco, an important reversible risk factor for cardiovascular disease.

Figure 1 shows that people with SMI are at higher risk of dying from a chronic medical condition, such as cardiovascular disease, diabetes, chronic obstructive pulmonary disease, and hepatitis C^6-8—many of which can be managed by primary and preventive medical interven­tions. These and other conditions often are not diagnosed or effectively managed in patients with SMI.

The high prevalence of metabolic syn­drome and tobacco dependence among people with SMI accelerates development of cardiovascular disease, as shown by several studies. Bobes et al⁹ found that the preva­lence of metabolic syndrome and cardiovas­cular risk among patients with SMI is similar to what is found in the general population at 10 to 15 years of greater age. Osborn et al¹⁰ demonstrated that people with SMI age 18 to 49 had a higher relative risk of death from coronary heart disease, stroke, and lung can­cer than age-matched controls (Figure 2).

Iatrogenic causes of morbidity
Many psychiatric medications, especially second-generation antipsychotics (SGAs), could exacerbate cardiovascular and meta­bolic conditions by increasing the risk of weight gain, insulin resistance, and dyslip­idemia. Antipsychotics that generally are considered to be more effective for refrac­tory psychotic illness (eg, clozapine and olanzapine) are associated with the highest risk of metabolic syndrome. Simon et al¹¹ found a dose-response relationship between olanzapine and clozapine serum concentra­tions and worsening metabolic outcomes. Valproic acid also can cause significant weight gain and could require monitor­ing similar to what is done with to SGAs, although there has been less clinical and research attention to this mood stabilizer.

The American Diabetes Association et al¹² have published guidelines on monitoring antipsychotic-induced obesity and diabetes, but adoption of these guidelines has been slow. Mackin et al¹³ found that providers are slow to recognize the elevated rate of obesity and dyslipidemia among psychiat­ric patients, possibly because of “an alarm­ingly poor rate of monitoring of metabolic parameters.”

Treating adverse metabolic outcomes also seems to lag behind. The same study13 found that physical health parameters among psy­chiatric patients continue to become worse even when appropriate health care profes­sionals were notified. Rates of nontreatment for diabetes, dyslipidemia, and hyperten­sion were 30%, 60%, and 88% respectively, according to Nasrallah et al.¹⁴

Randomized controlled studies have shown that obesity and metabolic syndrome can be effectively managed using lifestyle and pharmacotherapeutic approaches,^15,16 but more research is needed to test long-term outcomes and how to best incorporate these interventions. Newcomer et al¹⁷ found that gradually switching an antipsychotic with high risk of metabolic adverse effects to one with lower risk could reduce adverse meta­bolic outcomes; however, some patients returned to their prior antipsychotic because other medications did not effectively treat their schizophrenia symptoms. Therefore, physicians must pay careful attention to the trade-off between benefits and risks of anti­psychotics and make treatment decisions on an individual basis.

Barriers to medical care
Research has demonstrated that patients with SMI receive less screening and fewer preventive medical services, especially blood pressure monitoring, vaccina­tions, mammography, lipid monitoring, and osteoporosis screening, compared with the general population (Table).¹⁸ Some barriers to preventive services could exist because of demographic fac­tors and medical insurance coverage¹⁹ or medical providers’ discomfort with symp­toms of SMI,²⁰ although Mitchell et al²¹ found that disparities in mammography screening could not be explained by the presence of emotional distress in women with SMI.

Therefore, not only are patients with SMI less likely to receive preventive care, they are also less likely to receive poten­tially lifesaving treatments for SMI. Because those with SMI might not be able to advocate for themselves in these mat­ters, psychiatric clinicians can improve their patients’ lives by advocating for appropriate medical care despite multiple barriers.

Bridging the gap: Managing mental health in primary care
Research from the 1970s and 1980s demon­strated that most persons who sought help for depression or anxiety received treatment from their PCP, many of whom felt limited by their lack of behavioral health training. Moreover, many patients failed to receive a psychiatric diagnosis or adequate treatment, despite efforts to educate primary care phy­sicians on appropriate diagnosis and treat­ment of mental illness.

Katon et al²⁵ at the University of Washington developed the collaborative care model in the early 1990s to help improve treatment of depression in primary care set­tings. This model involved:
   • case load review by psychiatrists
   • use of nurses and other support staff to help monitor patients’ adherence and treatment response
   • use of standardized tools such as the Patient Health Questionnaire to moni­tor symptoms
   • enhancement of patient education with pamphlets or classes.

Studies evaluating the success of collab­orative care models found overall improved outcomes, making it the only evidence-based model for integration of behavioral health and primary care.²⁶ As a result, the collaborative care model has been imple­mented across the United States in primary care clinics and specialty care settings, such as obstetrics and gynecology.²⁷

Regrettably, access to primary care has been hampered by:  
   • population growth  
   • a shortage of PCPs  
   • enrollment of a flood of new patients into the health care marketplace as a result of mandates of the Affordable Care Act (ACA).

In many settings, a psychiatrist might be the patient’s only consistent care provider, and could be thought of as a “primary care psychiatrist.”

To resolve this predicament, mental health professionals need to recognize the unique medical conditions faced by people with SMI, and also might need to provide treatment of common medical conditions, either directly or through collaborative arrangements. Psychiatrists who are capa­ble of managing core medical issues likely will witness improved psychiatric and overall health outcomes in their patients. Consequently, psychiatrists and mental health professionals are increasingly called on to be advocates to improve access to medical services in patients with SMI and to participate in health systems reform.

Managing medical conditions in mental health settings
Although traditional collaborative care involves mental health providers working at primary care sites, other models have emerged that manage chronic disease in behavioral health settings. Federally funded grants for primary behavioral health care integration have allowed community men­tal health centers to partner with federally qualified health centers to provide on-site primary care services.²⁸

In these models, care managers in mental health clinics:
   • link patients to primary care services
   • encourage lifestyle changes to improve their overall health
   • identify and overcome barriers to receiving care
   • track clinical outcomes in a registry format.

Currently, 126 mental health sites in the United States have received these grants and are working toward greater integration of primary care.

In addition, the ACA provided funding for “health homes” in non-primary care settings, which includes SMI. These health homes cannot provide direct primary care, but can deliver comprehensive care man­agement, care coordination, health pro­motion, comprehensive transitional care services between facilities, individual and family support, and referral to commu­nity social support services. In these health homes, a PCP can act as a consultant to help establish priorities for disease management and improving health status.²⁹ The PCP consultant also can support psychiatric staff and collaborate with providers who want to provide some direct care of medical conditions.³⁰

Last, some behavioral health sites are choosing to apply for Federally Qualified Health Clinic status or add primary care services to their clinics, with the hope that sustainable funding will become available. Without additional funding to cover the limited reimbursement provided by pub­lic payers, such as Medicaid and Medicare, these models might be unsustainable. Current innovations in health care fund­ing reform hopefully will offer solutions for sites to provide medical care in the natural “medical home” of the SMI population.

Bottom Line
Psychiatric providers are in a favorable position to develop and oversee a partnership with primary care physicians with the goal of addressing significant and often lethal health disparities among those with mental illness. Psychiatric providers must use evidence-based practices that include assessment and prevention of cardiopulmonary, metabolic, infectious, and oncologic disorders. True primary care–behavioral health integration must include longitudinal “cross education” and changes in health care policy, with an emphasis on decreasing morbidity and mortality in psychiatric patients.

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

People with serious mental illness (SMI) have a life expectancy that is 25 years less than the general population, according to the Centers for Disease Control and Prevention.¹ This disparity is partially a consequence of the lack of primary and preventive medical care for those with psychiatric illness. Decades of research have shown that people with SMI experience higher medical morbidity and mortality in addition to facing the stigma of mental illness.

This article aims to advance the idea that longitudinal “cross educa­tion” between primary care providers (PCPs) and behavioral health providers (BHPs) is essential in addressing this problem. BHPs include psychiatry clinics, which often are part of a university or large health sys­tems; county-based community mental health programs; and indepen­dent mental health clinics that contract with public and private health plans to provide mental health services.

Although suicide and injury account for 40% of the excess mortality in schizophrenia, 60% can be attributed to cardiovascular disease, diabetes, respiratory diseases, and infection.² Patients with SMI have 2 to 3 times the risk of diabetes, dyslipidemia, hypertension, and obesity.^3,4 Furthermore, those with SMI consume more than one-third of tobacco products,⁵ and 50% to 80% of people with SMI smoke tobacco, an important reversible risk factor for cardiovascular disease.

Figure 1 shows that people with SMI are at higher risk of dying from a chronic medical condition, such as cardiovascular disease, diabetes, chronic obstructive pulmonary disease, and hepatitis C^6-8—many of which can be managed by primary and preventive medical interven­tions. These and other conditions often are not diagnosed or effectively managed in patients with SMI.

The high prevalence of metabolic syn­drome and tobacco dependence among people with SMI accelerates development of cardiovascular disease, as shown by several studies. Bobes et al⁹ found that the preva­lence of metabolic syndrome and cardiovas­cular risk among patients with SMI is similar to what is found in the general population at 10 to 15 years of greater age. Osborn et al¹⁰ demonstrated that people with SMI age 18 to 49 had a higher relative risk of death from coronary heart disease, stroke, and lung can­cer than age-matched controls (Figure 2).

Iatrogenic causes of morbidity
Many psychiatric medications, especially second-generation antipsychotics (SGAs), could exacerbate cardiovascular and meta­bolic conditions by increasing the risk of weight gain, insulin resistance, and dyslip­idemia. Antipsychotics that generally are considered to be more effective for refrac­tory psychotic illness (eg, clozapine and olanzapine) are associated with the highest risk of metabolic syndrome. Simon et al¹¹ found a dose-response relationship between olanzapine and clozapine serum concentra­tions and worsening metabolic outcomes. Valproic acid also can cause significant weight gain and could require monitor­ing similar to what is done with to SGAs, although there has been less clinical and research attention to this mood stabilizer.

The American Diabetes Association et al¹² have published guidelines on monitoring antipsychotic-induced obesity and diabetes, but adoption of these guidelines has been slow. Mackin et al¹³ found that providers are slow to recognize the elevated rate of obesity and dyslipidemia among psychiat­ric patients, possibly because of “an alarm­ingly poor rate of monitoring of metabolic parameters.”

Treating adverse metabolic outcomes also seems to lag behind. The same study13 found that physical health parameters among psy­chiatric patients continue to become worse even when appropriate health care profes­sionals were notified. Rates of nontreatment for diabetes, dyslipidemia, and hyperten­sion were 30%, 60%, and 88% respectively, according to Nasrallah et al.¹⁴

Randomized controlled studies have shown that obesity and metabolic syndrome can be effectively managed using lifestyle and pharmacotherapeutic approaches,^15,16 but more research is needed to test long-term outcomes and how to best incorporate these interventions. Newcomer et al¹⁷ found that gradually switching an antipsychotic with high risk of metabolic adverse effects to one with lower risk could reduce adverse meta­bolic outcomes; however, some patients returned to their prior antipsychotic because other medications did not effectively treat their schizophrenia symptoms. Therefore, physicians must pay careful attention to the trade-off between benefits and risks of anti­psychotics and make treatment decisions on an individual basis.

Barriers to medical care
Research has demonstrated that patients with SMI receive less screening and fewer preventive medical services, especially blood pressure monitoring, vaccina­tions, mammography, lipid monitoring, and osteoporosis screening, compared with the general population (Table).¹⁸ Some barriers to preventive services could exist because of demographic fac­tors and medical insurance coverage¹⁹ or medical providers’ discomfort with symp­toms of SMI,²⁰ although Mitchell et al²¹ found that disparities in mammography screening could not be explained by the presence of emotional distress in women with SMI.

Therefore, not only are patients with SMI less likely to receive preventive care, they are also less likely to receive poten­tially lifesaving treatments for SMI. Because those with SMI might not be able to advocate for themselves in these mat­ters, psychiatric clinicians can improve their patients’ lives by advocating for appropriate medical care despite multiple barriers.

Bridging the gap: Managing mental health in primary care
Research from the 1970s and 1980s demon­strated that most persons who sought help for depression or anxiety received treatment from their PCP, many of whom felt limited by their lack of behavioral health training. Moreover, many patients failed to receive a psychiatric diagnosis or adequate treatment, despite efforts to educate primary care phy­sicians on appropriate diagnosis and treat­ment of mental illness.

Katon et al²⁵ at the University of Washington developed the collaborative care model in the early 1990s to help improve treatment of depression in primary care set­tings. This model involved:
   • case load review by psychiatrists
   • use of nurses and other support staff to help monitor patients’ adherence and treatment response
   • use of standardized tools such as the Patient Health Questionnaire to moni­tor symptoms
   • enhancement of patient education with pamphlets or classes.

Studies evaluating the success of collab­orative care models found overall improved outcomes, making it the only evidence-based model for integration of behavioral health and primary care.²⁶ As a result, the collaborative care model has been imple­mented across the United States in primary care clinics and specialty care settings, such as obstetrics and gynecology.²⁷

Regrettably, access to primary care has been hampered by:  
   • population growth  
   • a shortage of PCPs  
   • enrollment of a flood of new patients into the health care marketplace as a result of mandates of the Affordable Care Act (ACA).

In many settings, a psychiatrist might be the patient’s only consistent care provider, and could be thought of as a “primary care psychiatrist.”

To resolve this predicament, mental health professionals need to recognize the unique medical conditions faced by people with SMI, and also might need to provide treatment of common medical conditions, either directly or through collaborative arrangements. Psychiatrists who are capa­ble of managing core medical issues likely will witness improved psychiatric and overall health outcomes in their patients. Consequently, psychiatrists and mental health professionals are increasingly called on to be advocates to improve access to medical services in patients with SMI and to participate in health systems reform.

Managing medical conditions in mental health settings
Although traditional collaborative care involves mental health providers working at primary care sites, other models have emerged that manage chronic disease in behavioral health settings. Federally funded grants for primary behavioral health care integration have allowed community men­tal health centers to partner with federally qualified health centers to provide on-site primary care services.²⁸

In these models, care managers in mental health clinics:
   • link patients to primary care services
   • encourage lifestyle changes to improve their overall health
   • identify and overcome barriers to receiving care
   • track clinical outcomes in a registry format.

Currently, 126 mental health sites in the United States have received these grants and are working toward greater integration of primary care.

In addition, the ACA provided funding for “health homes” in non-primary care settings, which includes SMI. These health homes cannot provide direct primary care, but can deliver comprehensive care man­agement, care coordination, health pro­motion, comprehensive transitional care services between facilities, individual and family support, and referral to commu­nity social support services. In these health homes, a PCP can act as a consultant to help establish priorities for disease management and improving health status.²⁹ The PCP consultant also can support psychiatric staff and collaborate with providers who want to provide some direct care of medical conditions.³⁰

Last, some behavioral health sites are choosing to apply for Federally Qualified Health Clinic status or add primary care services to their clinics, with the hope that sustainable funding will become available. Without additional funding to cover the limited reimbursement provided by pub­lic payers, such as Medicaid and Medicare, these models might be unsustainable. Current innovations in health care fund­ing reform hopefully will offer solutions for sites to provide medical care in the natural “medical home” of the SMI population.

Bottom Line
Psychiatric providers are in a favorable position to develop and oversee a partnership with primary care physicians with the goal of addressing significant and often lethal health disparities among those with mental illness. Psychiatric providers must use evidence-based practices that include assessment and prevention of cardiopulmonary, metabolic, infectious, and oncologic disorders. True primary care–behavioral health integration must include longitudinal “cross education” and changes in health care policy, with an emphasis on decreasing morbidity and mortality in psychiatric patients.

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

People with serious mental illness (SMI) have a life expectancy that is 25 years less than the general population, according to the Centers for Disease Control and Prevention.¹ This disparity is partially a consequence of the lack of primary and preventive medical care for those with psychiatric illness. Decades of research have shown that people with SMI experience higher medical morbidity and mortality in addition to facing the stigma of mental illness.

This article aims to advance the idea that longitudinal “cross educa­tion” between primary care providers (PCPs) and behavioral health providers (BHPs) is essential in addressing this problem. BHPs include psychiatry clinics, which often are part of a university or large health sys­tems; county-based community mental health programs; and indepen­dent mental health clinics that contract with public and private health plans to provide mental health services.

Although suicide and injury account for 40% of the excess mortality in schizophrenia, 60% can be attributed to cardiovascular disease, diabetes, respiratory diseases, and infection.² Patients with SMI have 2 to 3 times the risk of diabetes, dyslipidemia, hypertension, and obesity.^3,4 Furthermore, those with SMI consume more than one-third of tobacco products,⁵ and 50% to 80% of people with SMI smoke tobacco, an important reversible risk factor for cardiovascular disease.

Figure 1 shows that people with SMI are at higher risk of dying from a chronic medical condition, such as cardiovascular disease, diabetes, chronic obstructive pulmonary disease, and hepatitis C^6-8—many of which can be managed by primary and preventive medical interven­tions. These and other conditions often are not diagnosed or effectively managed in patients with SMI.

The high prevalence of metabolic syn­drome and tobacco dependence among people with SMI accelerates development of cardiovascular disease, as shown by several studies. Bobes et al⁹ found that the preva­lence of metabolic syndrome and cardiovas­cular risk among patients with SMI is similar to what is found in the general population at 10 to 15 years of greater age. Osborn et al¹⁰ demonstrated that people with SMI age 18 to 49 had a higher relative risk of death from coronary heart disease, stroke, and lung can­cer than age-matched controls (Figure 2).

Iatrogenic causes of morbidity
Many psychiatric medications, especially second-generation antipsychotics (SGAs), could exacerbate cardiovascular and meta­bolic conditions by increasing the risk of weight gain, insulin resistance, and dyslip­idemia. Antipsychotics that generally are considered to be more effective for refrac­tory psychotic illness (eg, clozapine and olanzapine) are associated with the highest risk of metabolic syndrome. Simon et al¹¹ found a dose-response relationship between olanzapine and clozapine serum concentra­tions and worsening metabolic outcomes. Valproic acid also can cause significant weight gain and could require monitor­ing similar to what is done with to SGAs, although there has been less clinical and research attention to this mood stabilizer.

The American Diabetes Association et al¹² have published guidelines on monitoring antipsychotic-induced obesity and diabetes, but adoption of these guidelines has been slow. Mackin et al¹³ found that providers are slow to recognize the elevated rate of obesity and dyslipidemia among psychiat­ric patients, possibly because of “an alarm­ingly poor rate of monitoring of metabolic parameters.”

Treating adverse metabolic outcomes also seems to lag behind. The same study13 found that physical health parameters among psy­chiatric patients continue to become worse even when appropriate health care profes­sionals were notified. Rates of nontreatment for diabetes, dyslipidemia, and hyperten­sion were 30%, 60%, and 88% respectively, according to Nasrallah et al.¹⁴

Randomized controlled studies have shown that obesity and metabolic syndrome can be effectively managed using lifestyle and pharmacotherapeutic approaches,^15,16 but more research is needed to test long-term outcomes and how to best incorporate these interventions. Newcomer et al¹⁷ found that gradually switching an antipsychotic with high risk of metabolic adverse effects to one with lower risk could reduce adverse meta­bolic outcomes; however, some patients returned to their prior antipsychotic because other medications did not effectively treat their schizophrenia symptoms. Therefore, physicians must pay careful attention to the trade-off between benefits and risks of anti­psychotics and make treatment decisions on an individual basis.

Barriers to medical care
Research has demonstrated that patients with SMI receive less screening and fewer preventive medical services, especially blood pressure monitoring, vaccina­tions, mammography, lipid monitoring, and osteoporosis screening, compared with the general population (Table).¹⁸ Some barriers to preventive services could exist because of demographic fac­tors and medical insurance coverage¹⁹ or medical providers’ discomfort with symp­toms of SMI,²⁰ although Mitchell et al²¹ found that disparities in mammography screening could not be explained by the presence of emotional distress in women with SMI.

Therefore, not only are patients with SMI less likely to receive preventive care, they are also less likely to receive poten­tially lifesaving treatments for SMI. Because those with SMI might not be able to advocate for themselves in these mat­ters, psychiatric clinicians can improve their patients’ lives by advocating for appropriate medical care despite multiple barriers.

Bridging the gap: Managing mental health in primary care
Research from the 1970s and 1980s demon­strated that most persons who sought help for depression or anxiety received treatment from their PCP, many of whom felt limited by their lack of behavioral health training. Moreover, many patients failed to receive a psychiatric diagnosis or adequate treatment, despite efforts to educate primary care phy­sicians on appropriate diagnosis and treat­ment of mental illness.

Katon et al²⁵ at the University of Washington developed the collaborative care model in the early 1990s to help improve treatment of depression in primary care set­tings. This model involved:
   • case load review by psychiatrists
   • use of nurses and other support staff to help monitor patients’ adherence and treatment response
   • use of standardized tools such as the Patient Health Questionnaire to moni­tor symptoms
   • enhancement of patient education with pamphlets or classes.

Studies evaluating the success of collab­orative care models found overall improved outcomes, making it the only evidence-based model for integration of behavioral health and primary care.²⁶ As a result, the collaborative care model has been imple­mented across the United States in primary care clinics and specialty care settings, such as obstetrics and gynecology.²⁷

Regrettably, access to primary care has been hampered by:  
   • population growth  
   • a shortage of PCPs  
   • enrollment of a flood of new patients into the health care marketplace as a result of mandates of the Affordable Care Act (ACA).

In many settings, a psychiatrist might be the patient’s only consistent care provider, and could be thought of as a “primary care psychiatrist.”

To resolve this predicament, mental health professionals need to recognize the unique medical conditions faced by people with SMI, and also might need to provide treatment of common medical conditions, either directly or through collaborative arrangements. Psychiatrists who are capa­ble of managing core medical issues likely will witness improved psychiatric and overall health outcomes in their patients. Consequently, psychiatrists and mental health professionals are increasingly called on to be advocates to improve access to medical services in patients with SMI and to participate in health systems reform.

Managing medical conditions in mental health settings
Although traditional collaborative care involves mental health providers working at primary care sites, other models have emerged that manage chronic disease in behavioral health settings. Federally funded grants for primary behavioral health care integration have allowed community men­tal health centers to partner with federally qualified health centers to provide on-site primary care services.²⁸

In these models, care managers in mental health clinics:
   • link patients to primary care services
   • encourage lifestyle changes to improve their overall health
   • identify and overcome barriers to receiving care
   • track clinical outcomes in a registry format.

Currently, 126 mental health sites in the United States have received these grants and are working toward greater integration of primary care.

In addition, the ACA provided funding for “health homes” in non-primary care settings, which includes SMI. These health homes cannot provide direct primary care, but can deliver comprehensive care man­agement, care coordination, health pro­motion, comprehensive transitional care services between facilities, individual and family support, and referral to commu­nity social support services. In these health homes, a PCP can act as a consultant to help establish priorities for disease management and improving health status.²⁹ The PCP consultant also can support psychiatric staff and collaborate with providers who want to provide some direct care of medical conditions.³⁰

Last, some behavioral health sites are choosing to apply for Federally Qualified Health Clinic status or add primary care services to their clinics, with the hope that sustainable funding will become available. Without additional funding to cover the limited reimbursement provided by pub­lic payers, such as Medicaid and Medicare, these models might be unsustainable. Current innovations in health care fund­ing reform hopefully will offer solutions for sites to provide medical care in the natural “medical home” of the SMI population.

Bottom Line
Psychiatric providers are in a favorable position to develop and oversee a partnership with primary care physicians with the goal of addressing significant and often lethal health disparities among those with mental illness. Psychiatric providers must use evidence-based practices that include assessment and prevention of cardiopulmonary, metabolic, infectious, and oncologic disorders. True primary care–behavioral health integration must include longitudinal “cross education” and changes in health care policy, with an emphasis on decreasing morbidity and mortality in psychiatric patients.

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

Antihemophilic factor

TORONTO—The antihemophilic factor turoctocog alfa is safe and effective long-term, according to interim data from the phase 3 guardian 2 trial.

With more than 4 years of safety data, researchers have found turoctocog alfa to be well-tolerated in patients with hemophilia A.

The median annualized bleeding rate for patients on prophylactic treatment was 1.56 bleeds per patient per year. For patients who received turoctocog alfa on demand, a single injection stopped all bleeds.

And none of the patients developed factor VIII (FVIII) inhibitors.

Margareth Ozelo, MD, PhD, of the University of Campinas in Sao Paulo, Brazil and her colleagues presented these data at the ISTH 2015 Congress (abstract PO251-WED). The research is sponsored by Novo Nordisk, the company developing turoctocog alfa (as NovoEight).

Turoctocog alfa is a B-domain truncated recombinant human coagulation FVIII product indicated for the treatment and prevention of bleeding in patients with hemophilia A. The ongoing guardian 2 trial is a prospective safety and efficacy extension trial of the guardian 1 and guardian 3 studies.

Two hundred patients received turoctocog alfa in guardian 2. They had severe hemophilia A (FVIII activity ≤ 1%), no history of inhibitors, and had completed guardian 1, guardian 3, or a third pharmacokinetics trial. The patients’ mean age at first turoctocog alfa injection was 22.3 ± 14.4 years.

In guardian 1 and guardian 3, all patients switched from other FVIII products to turoctocog alfa prophylaxis every second day (adults/adolescents, 20–40 IU/kg; children, 25–50 IU/kg), or 3 times weekly (adults/adolescents, 20–50 IU/kg; children 25–60 IU/kg). Patients also received turoctocog alfa when bleeds arose.

Of the 200 patients enrolled on guardian 2, 133 were still participating in the trial at the interim cutoff date, December 31, 2013.

The interim analysis includes data for 451.6 patient-years and 72,320 days of exposure to turoctocog alfa. The total number of exposure days was 364.5

(range, 1-762) per patient for prophylaxis and 23.8 (range, 1-90) per patient for on-demand treatment.

The mean number of turoctocog alfa doses was 368.3 (range, 1-766) per patient for prophylaxis and 24.2 (range, 1-90) per patient for on-demand treatment.

Safety results

At the interim cutoff, none of the patients had developed FVIII inhibitors. Adverse events occurred in 84% of patients (n=168). The most common were

headache, nasopharyngitis, upper respiratory tract infection, and arthralgia.

Eight adverse events were considered possibly or probably related to turoctocog alfa in 5 patients (2.5%). These events were mild or moderate and included local swelling (n=1), increased aspartate aminotransferase (n=1), increased alanine aminotransferase (n=1), pain in extremity (n=1), musculoskeletal pain (n=1), lichenoid keratosis (n=1), and arthropathy (n=2).

There were 29 serious adverse events that were considered unlikely to be treatment-related. This included a death from subdural hemorrhage.

Efficacy results

For patients on prophylactic treatment (n=197), the median annualized bleeding rate was 1.56 bleeds per patient per year for all bleeds. It was 0.50 for

spontaneous bleeds, 0.49 for traumatic bleeds, 0.93 for joint bleeds, and 0.35 for nonjoint bleeds.

The success rate for treating bleeds during prophylaxis was 89.4%, and 90% of all bleeding episodes were successfully treated with 1 or 2 infusions of

turoctocog alfa. As for on-demand treatment, a single injection stopped all 73 bleeds.

“These interim results provide an extension to the body of evidence supporting the long-term use of NovoEight,” Dr Ozelo said. “For people with hemophilia A, finding treatments that are effective at preventing bleeding episodes long-term is essential.”

Antihemophilic factor

TORONTO—The antihemophilic factor turoctocog alfa is safe and effective long-term, according to interim data from the phase 3 guardian 2 trial.

With more than 4 years of safety data, researchers have found turoctocog alfa to be well-tolerated in patients with hemophilia A.

The median annualized bleeding rate for patients on prophylactic treatment was 1.56 bleeds per patient per year. For patients who received turoctocog alfa on demand, a single injection stopped all bleeds.

And none of the patients developed factor VIII (FVIII) inhibitors.

Margareth Ozelo, MD, PhD, of the University of Campinas in Sao Paulo, Brazil and her colleagues presented these data at the ISTH 2015 Congress (abstract PO251-WED). The research is sponsored by Novo Nordisk, the company developing turoctocog alfa (as NovoEight).

Turoctocog alfa is a B-domain truncated recombinant human coagulation FVIII product indicated for the treatment and prevention of bleeding in patients with hemophilia A. The ongoing guardian 2 trial is a prospective safety and efficacy extension trial of the guardian 1 and guardian 3 studies.

Two hundred patients received turoctocog alfa in guardian 2. They had severe hemophilia A (FVIII activity ≤ 1%), no history of inhibitors, and had completed guardian 1, guardian 3, or a third pharmacokinetics trial. The patients’ mean age at first turoctocog alfa injection was 22.3 ± 14.4 years.

In guardian 1 and guardian 3, all patients switched from other FVIII products to turoctocog alfa prophylaxis every second day (adults/adolescents, 20–40 IU/kg; children, 25–50 IU/kg), or 3 times weekly (adults/adolescents, 20–50 IU/kg; children 25–60 IU/kg). Patients also received turoctocog alfa when bleeds arose.

Of the 200 patients enrolled on guardian 2, 133 were still participating in the trial at the interim cutoff date, December 31, 2013.

The interim analysis includes data for 451.6 patient-years and 72,320 days of exposure to turoctocog alfa. The total number of exposure days was 364.5

(range, 1-762) per patient for prophylaxis and 23.8 (range, 1-90) per patient for on-demand treatment.

The mean number of turoctocog alfa doses was 368.3 (range, 1-766) per patient for prophylaxis and 24.2 (range, 1-90) per patient for on-demand treatment.

Safety results

At the interim cutoff, none of the patients had developed FVIII inhibitors. Adverse events occurred in 84% of patients (n=168). The most common were

headache, nasopharyngitis, upper respiratory tract infection, and arthralgia.

Eight adverse events were considered possibly or probably related to turoctocog alfa in 5 patients (2.5%). These events were mild or moderate and included local swelling (n=1), increased aspartate aminotransferase (n=1), increased alanine aminotransferase (n=1), pain in extremity (n=1), musculoskeletal pain (n=1), lichenoid keratosis (n=1), and arthropathy (n=2).

There were 29 serious adverse events that were considered unlikely to be treatment-related. This included a death from subdural hemorrhage.

Efficacy results

For patients on prophylactic treatment (n=197), the median annualized bleeding rate was 1.56 bleeds per patient per year for all bleeds. It was 0.50 for

spontaneous bleeds, 0.49 for traumatic bleeds, 0.93 for joint bleeds, and 0.35 for nonjoint bleeds.

The success rate for treating bleeds during prophylaxis was 89.4%, and 90% of all bleeding episodes were successfully treated with 1 or 2 infusions of

turoctocog alfa. As for on-demand treatment, a single injection stopped all 73 bleeds.

“These interim results provide an extension to the body of evidence supporting the long-term use of NovoEight,” Dr Ozelo said. “For people with hemophilia A, finding treatments that are effective at preventing bleeding episodes long-term is essential.”

Antihemophilic factor

TORONTO—The antihemophilic factor turoctocog alfa is safe and effective long-term, according to interim data from the phase 3 guardian 2 trial.

With more than 4 years of safety data, researchers have found turoctocog alfa to be well-tolerated in patients with hemophilia A.

The median annualized bleeding rate for patients on prophylactic treatment was 1.56 bleeds per patient per year. For patients who received turoctocog alfa on demand, a single injection stopped all bleeds.

And none of the patients developed factor VIII (FVIII) inhibitors.

Margareth Ozelo, MD, PhD, of the University of Campinas in Sao Paulo, Brazil and her colleagues presented these data at the ISTH 2015 Congress (abstract PO251-WED). The research is sponsored by Novo Nordisk, the company developing turoctocog alfa (as NovoEight).

Turoctocog alfa is a B-domain truncated recombinant human coagulation FVIII product indicated for the treatment and prevention of bleeding in patients with hemophilia A. The ongoing guardian 2 trial is a prospective safety and efficacy extension trial of the guardian 1 and guardian 3 studies.

Two hundred patients received turoctocog alfa in guardian 2. They had severe hemophilia A (FVIII activity ≤ 1%), no history of inhibitors, and had completed guardian 1, guardian 3, or a third pharmacokinetics trial. The patients’ mean age at first turoctocog alfa injection was 22.3 ± 14.4 years.

In guardian 1 and guardian 3, all patients switched from other FVIII products to turoctocog alfa prophylaxis every second day (adults/adolescents, 20–40 IU/kg; children, 25–50 IU/kg), or 3 times weekly (adults/adolescents, 20–50 IU/kg; children 25–60 IU/kg). Patients also received turoctocog alfa when bleeds arose.

Of the 200 patients enrolled on guardian 2, 133 were still participating in the trial at the interim cutoff date, December 31, 2013.

The interim analysis includes data for 451.6 patient-years and 72,320 days of exposure to turoctocog alfa. The total number of exposure days was 364.5

(range, 1-762) per patient for prophylaxis and 23.8 (range, 1-90) per patient for on-demand treatment.

The mean number of turoctocog alfa doses was 368.3 (range, 1-766) per patient for prophylaxis and 24.2 (range, 1-90) per patient for on-demand treatment.

Safety results

At the interim cutoff, none of the patients had developed FVIII inhibitors. Adverse events occurred in 84% of patients (n=168). The most common were

headache, nasopharyngitis, upper respiratory tract infection, and arthralgia.

Eight adverse events were considered possibly or probably related to turoctocog alfa in 5 patients (2.5%). These events were mild or moderate and included local swelling (n=1), increased aspartate aminotransferase (n=1), increased alanine aminotransferase (n=1), pain in extremity (n=1), musculoskeletal pain (n=1), lichenoid keratosis (n=1), and arthropathy (n=2).

There were 29 serious adverse events that were considered unlikely to be treatment-related. This included a death from subdural hemorrhage.

Efficacy results

For patients on prophylactic treatment (n=197), the median annualized bleeding rate was 1.56 bleeds per patient per year for all bleeds. It was 0.50 for

spontaneous bleeds, 0.49 for traumatic bleeds, 0.93 for joint bleeds, and 0.35 for nonjoint bleeds.

The success rate for treating bleeds during prophylaxis was 89.4%, and 90% of all bleeding episodes were successfully treated with 1 or 2 infusions of

turoctocog alfa. As for on-demand treatment, a single injection stopped all 73 bleeds.

“These interim results provide an extension to the body of evidence supporting the long-term use of NovoEight,” Dr Ozelo said. “For people with hemophilia A, finding treatments that are effective at preventing bleeding episodes long-term is essential.”

Farmer spraying insecticide

Photo by John Messina

The insecticide gamma-hexachlorocyclohexane (lindane) is carcinogenic, according to experts from the International Agency for Research on Cancer (IARC), the specialized cancer agency of the World Health Organization.

The experts said they found sufficient evidence that lindane, which is banned or restricted in most countries, can cause non-Hodgkin lymphoma (NHL).

The group also discovered that 2 other chemicals might cause NHL.

The evidence suggests the insecticide dichlorodiphenyltrichloroethane (DDT) is probably carcinogenic, and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is possibly carcinogenic.

A summary of these findings is available in The Lancet Oncology, and the experts’ detailed assessments will be published as Volume 113 of the IARC Monographs.

The group, which consisted of 26 experts convened by the IARC Monographs Programme, reviewed the latest scientific literature on lindane, DDT, and 2,4-D and used their findings to classify these 3 chemicals according to carcinogenicity.

The classification (Group 1, Group 2A, etc.) indicates the strength of the evidence that a substance causes cancer, not the level of risk associated with exposure. The Monographs Programme identifies cancer hazards even when risks are very low at current exposure levels, because new uses or unforeseen exposures could engender risks that are significantly higher.

Lindane

The experts classified lindane as carcinogenic to humans (Group 1), saying they found sufficient evidence that it can cause NHL. Large epidemiological studies of agricultural exposures in the US and Canada showed a 60% increased risk of NHL in people exposed to lindane.

Lindane has been used extensively for insect control, including in agriculture and for the treatment of human lice and scabies. High exposures have occurred among agricultural workers and pesticide applicators. However, the use of lindane is now banned or restricted in most countries.

DDT

The experts classified DDT as probably carcinogenic to humans (Group 2A), saying they found sufficient evidence that DDT causes cancer in experimental animals and limited evidence of DDT’s carcinogenicity in humans.

Epidemiological studies have shown positive associations between exposure to DDT and NHL, testicular cancer, and liver cancer.

There was also strong experimental evidence that DDT can suppress the immune system and disrupt sex hormones. However, overall, there was no association between breast cancer and DDT levels measured in samples of blood or fat.

DDT was introduced for the control of insect-borne diseases during World War II and was later applied widely to eradicate malaria and in agriculture. Most uses of DDT were banned in the 1970s. However, DDT and its breakdown products are highly persistent and can be found in the environment and in animal and human tissues throughout the world.

Exposure to DDT still occurs, mainly through diet. The remaining and essential use of DDT is for disease vector control, mainly for malaria. This use is strictly restricted under the Stockholm Convention.

2,4-D

The experts classified 2,4-D as possibly carcinogenic to humans (Group 2B), saying they had inadequate evidence in humans and limited evidence in experimental animals.

There is strong evidence that 2,4-D induces oxidative stress and moderate evidence that 2,4-D causes immunosuppression, based on in vivo and in vitro studies. However, epidemiological studies did not show strong or consistent increases in the risk of NHL or other cancers in relation to 2,4-D exposure.

Since its introduction in 1945, 2,4-D has been widely used to control weeds in agriculture, forestry, and urban and residential settings. Occupational exposures to 2,4-D can occur during manufacturing and application, and the general population can be exposed through food, water, dust, or residential application, and during spraying.

Farmer spraying insecticide

Photo by John Messina

The insecticide gamma-hexachlorocyclohexane (lindane) is carcinogenic, according to experts from the International Agency for Research on Cancer (IARC), the specialized cancer agency of the World Health Organization.

The experts said they found sufficient evidence that lindane, which is banned or restricted in most countries, can cause non-Hodgkin lymphoma (NHL).

The group also discovered that 2 other chemicals might cause NHL.

The evidence suggests the insecticide dichlorodiphenyltrichloroethane (DDT) is probably carcinogenic, and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is possibly carcinogenic.

A summary of these findings is available in The Lancet Oncology, and the experts’ detailed assessments will be published as Volume 113 of the IARC Monographs.

The group, which consisted of 26 experts convened by the IARC Monographs Programme, reviewed the latest scientific literature on lindane, DDT, and 2,4-D and used their findings to classify these 3 chemicals according to carcinogenicity.

The classification (Group 1, Group 2A, etc.) indicates the strength of the evidence that a substance causes cancer, not the level of risk associated with exposure. The Monographs Programme identifies cancer hazards even when risks are very low at current exposure levels, because new uses or unforeseen exposures could engender risks that are significantly higher.

Lindane

The experts classified lindane as carcinogenic to humans (Group 1), saying they found sufficient evidence that it can cause NHL. Large epidemiological studies of agricultural exposures in the US and Canada showed a 60% increased risk of NHL in people exposed to lindane.

Lindane has been used extensively for insect control, including in agriculture and for the treatment of human lice and scabies. High exposures have occurred among agricultural workers and pesticide applicators. However, the use of lindane is now banned or restricted in most countries.

DDT

The experts classified DDT as probably carcinogenic to humans (Group 2A), saying they found sufficient evidence that DDT causes cancer in experimental animals and limited evidence of DDT’s carcinogenicity in humans.

Epidemiological studies have shown positive associations between exposure to DDT and NHL, testicular cancer, and liver cancer.

There was also strong experimental evidence that DDT can suppress the immune system and disrupt sex hormones. However, overall, there was no association between breast cancer and DDT levels measured in samples of blood or fat.

DDT was introduced for the control of insect-borne diseases during World War II and was later applied widely to eradicate malaria and in agriculture. Most uses of DDT were banned in the 1970s. However, DDT and its breakdown products are highly persistent and can be found in the environment and in animal and human tissues throughout the world.

Exposure to DDT still occurs, mainly through diet. The remaining and essential use of DDT is for disease vector control, mainly for malaria. This use is strictly restricted under the Stockholm Convention.

2,4-D

The experts classified 2,4-D as possibly carcinogenic to humans (Group 2B), saying they had inadequate evidence in humans and limited evidence in experimental animals.

There is strong evidence that 2,4-D induces oxidative stress and moderate evidence that 2,4-D causes immunosuppression, based on in vivo and in vitro studies. However, epidemiological studies did not show strong or consistent increases in the risk of NHL or other cancers in relation to 2,4-D exposure.

Since its introduction in 1945, 2,4-D has been widely used to control weeds in agriculture, forestry, and urban and residential settings. Occupational exposures to 2,4-D can occur during manufacturing and application, and the general population can be exposed through food, water, dust, or residential application, and during spraying.

Farmer spraying insecticide

Photo by John Messina

The insecticide gamma-hexachlorocyclohexane (lindane) is carcinogenic, according to experts from the International Agency for Research on Cancer (IARC), the specialized cancer agency of the World Health Organization.

The experts said they found sufficient evidence that lindane, which is banned or restricted in most countries, can cause non-Hodgkin lymphoma (NHL).

The group also discovered that 2 other chemicals might cause NHL.

The evidence suggests the insecticide dichlorodiphenyltrichloroethane (DDT) is probably carcinogenic, and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is possibly carcinogenic.

A summary of these findings is available in The Lancet Oncology, and the experts’ detailed assessments will be published as Volume 113 of the IARC Monographs.

The group, which consisted of 26 experts convened by the IARC Monographs Programme, reviewed the latest scientific literature on lindane, DDT, and 2,4-D and used their findings to classify these 3 chemicals according to carcinogenicity.

The classification (Group 1, Group 2A, etc.) indicates the strength of the evidence that a substance causes cancer, not the level of risk associated with exposure. The Monographs Programme identifies cancer hazards even when risks are very low at current exposure levels, because new uses or unforeseen exposures could engender risks that are significantly higher.

Lindane

The experts classified lindane as carcinogenic to humans (Group 1), saying they found sufficient evidence that it can cause NHL. Large epidemiological studies of agricultural exposures in the US and Canada showed a 60% increased risk of NHL in people exposed to lindane.

Lindane has been used extensively for insect control, including in agriculture and for the treatment of human lice and scabies. High exposures have occurred among agricultural workers and pesticide applicators. However, the use of lindane is now banned or restricted in most countries.

DDT

The experts classified DDT as probably carcinogenic to humans (Group 2A), saying they found sufficient evidence that DDT causes cancer in experimental animals and limited evidence of DDT’s carcinogenicity in humans.

Epidemiological studies have shown positive associations between exposure to DDT and NHL, testicular cancer, and liver cancer.

There was also strong experimental evidence that DDT can suppress the immune system and disrupt sex hormones. However, overall, there was no association between breast cancer and DDT levels measured in samples of blood or fat.

DDT was introduced for the control of insect-borne diseases during World War II and was later applied widely to eradicate malaria and in agriculture. Most uses of DDT were banned in the 1970s. However, DDT and its breakdown products are highly persistent and can be found in the environment and in animal and human tissues throughout the world.

Exposure to DDT still occurs, mainly through diet. The remaining and essential use of DDT is for disease vector control, mainly for malaria. This use is strictly restricted under the Stockholm Convention.

2,4-D

The experts classified 2,4-D as possibly carcinogenic to humans (Group 2B), saying they had inadequate evidence in humans and limited evidence in experimental animals.

There is strong evidence that 2,4-D induces oxidative stress and moderate evidence that 2,4-D causes immunosuppression, based on in vivo and in vitro studies. However, epidemiological studies did not show strong or consistent increases in the risk of NHL or other cancers in relation to 2,4-D exposure.

Since its introduction in 1945, 2,4-D has been widely used to control weeds in agriculture, forestry, and urban and residential settings. Occupational exposures to 2,4-D can occur during manufacturing and application, and the general population can be exposed through food, water, dust, or residential application, and during spraying.

VANCOUVER, B.C. – The interleukin-17A inhibitor secukinumab demonstrated the greatest improvement in nail psoriasis ever reported from a randomized, placebo-controlled trial in the phase IIIb TRANSFIGURE study, Dr. Kristian Reich reported at the World Congress of Dermatology.

At 198 patients, TRANSFIGURE is the largest-ever prospective study in patients with moderate to severe chronic plaque psoriasis and significant nail involvement. And while only the 16-week results are available thus far, when TRANSFIGURE is completed after a planned 132 weeks of treatment, it will also be the longest-ever study in the treatment of nail psoriasis, noted Dr. Reich, a dermatologist in group practice in Hamburg, Germany.

Elsewhere at WCD 2015, Dr. Alice B. Gottlieb presented the week 16 results of the phase IIIb GESTURE study, in which 205 psoriasis patients with moderate to severe psoriasis of the palms and soles were randomized to subcutaneous secukinumab (Cosentyx) at 150 or 300 mg or placebo. Dosing was weekly for the first 5 weeks and monthly thereafter.

The primary endpoint, a palmoplantar Investigator’s Global Assessment scale score of 0 or 1 – clear or almost clear – at week 16 was 33.3% with secukinumab at 300 mg, 22.1% at 150 mg, and 1.5% with placebo. The average reduction in palmoplantar PASI (Psoriasis Area Severity Index) score from baseline was 54.6% with high-dose and 35.3% with low-dose secukinumab, compared with 4.1% in placebo-treated controls, reported Dr. Gottlieb, professor and chair of dermatology at Tufts University, Boston.

Like the TRANSFIGURE trial, GESTURE will continue for 132 weeks, with the initial placebo-treated controls being randomized to secukinumab at 150 or 300 mg after week 16.

Dr. Reich reported that by 16 weeks in TRANSFIGURE, mean scores on the Nail Psoriasis Severity Index had improved by 45.3%, compared with baseline, in patients on secukinumab 300 mg, 37.9% in those on secukinumab 150 mg, and 10.8% with placebo.

The results on the skin were dramatic: a PASI 75 rate of 87.1% with secukinumab 300 mg, 77% with secukinumab 150 mg, and 5.1% with placebo. The PASI 100 response rate – meaning totally clear skin – was 31.9% with high-dose and 25.2% with lower-dose secukinumab, while there was a zero PASI 100 rate in controls.

The only adverse events more common than with placebo were nasopharyngitis and upper respiratory infections.

Dr. Reich predicted that as the ongoing TRANSFIGURE study continues well beyond 16 weeks, the nail psoriasis response rates will climb, since nails are so slow growing.

TRANSFIGURE and GESTURE are sponsored by Novartis, which markets secukinumab. Dr. Reich and Dr. Gottlieb reported having financial relationships with Novartis and numerous other pharmaceutical companies.

bjancin@frontlinemedcom

VANCOUVER, B.C. – The interleukin-17A inhibitor secukinumab demonstrated the greatest improvement in nail psoriasis ever reported from a randomized, placebo-controlled trial in the phase IIIb TRANSFIGURE study, Dr. Kristian Reich reported at the World Congress of Dermatology.

At 198 patients, TRANSFIGURE is the largest-ever prospective study in patients with moderate to severe chronic plaque psoriasis and significant nail involvement. And while only the 16-week results are available thus far, when TRANSFIGURE is completed after a planned 132 weeks of treatment, it will also be the longest-ever study in the treatment of nail psoriasis, noted Dr. Reich, a dermatologist in group practice in Hamburg, Germany.

Elsewhere at WCD 2015, Dr. Alice B. Gottlieb presented the week 16 results of the phase IIIb GESTURE study, in which 205 psoriasis patients with moderate to severe psoriasis of the palms and soles were randomized to subcutaneous secukinumab (Cosentyx) at 150 or 300 mg or placebo. Dosing was weekly for the first 5 weeks and monthly thereafter.

The primary endpoint, a palmoplantar Investigator’s Global Assessment scale score of 0 or 1 – clear or almost clear – at week 16 was 33.3% with secukinumab at 300 mg, 22.1% at 150 mg, and 1.5% with placebo. The average reduction in palmoplantar PASI (Psoriasis Area Severity Index) score from baseline was 54.6% with high-dose and 35.3% with low-dose secukinumab, compared with 4.1% in placebo-treated controls, reported Dr. Gottlieb, professor and chair of dermatology at Tufts University, Boston.

Like the TRANSFIGURE trial, GESTURE will continue for 132 weeks, with the initial placebo-treated controls being randomized to secukinumab at 150 or 300 mg after week 16.

Dr. Reich reported that by 16 weeks in TRANSFIGURE, mean scores on the Nail Psoriasis Severity Index had improved by 45.3%, compared with baseline, in patients on secukinumab 300 mg, 37.9% in those on secukinumab 150 mg, and 10.8% with placebo.

The results on the skin were dramatic: a PASI 75 rate of 87.1% with secukinumab 300 mg, 77% with secukinumab 150 mg, and 5.1% with placebo. The PASI 100 response rate – meaning totally clear skin – was 31.9% with high-dose and 25.2% with lower-dose secukinumab, while there was a zero PASI 100 rate in controls.

The only adverse events more common than with placebo were nasopharyngitis and upper respiratory infections.

Dr. Reich predicted that as the ongoing TRANSFIGURE study continues well beyond 16 weeks, the nail psoriasis response rates will climb, since nails are so slow growing.

TRANSFIGURE and GESTURE are sponsored by Novartis, which markets secukinumab. Dr. Reich and Dr. Gottlieb reported having financial relationships with Novartis and numerous other pharmaceutical companies.

bjancin@frontlinemedcom

VANCOUVER, B.C. – The interleukin-17A inhibitor secukinumab demonstrated the greatest improvement in nail psoriasis ever reported from a randomized, placebo-controlled trial in the phase IIIb TRANSFIGURE study, Dr. Kristian Reich reported at the World Congress of Dermatology.

At 198 patients, TRANSFIGURE is the largest-ever prospective study in patients with moderate to severe chronic plaque psoriasis and significant nail involvement. And while only the 16-week results are available thus far, when TRANSFIGURE is completed after a planned 132 weeks of treatment, it will also be the longest-ever study in the treatment of nail psoriasis, noted Dr. Reich, a dermatologist in group practice in Hamburg, Germany.

Elsewhere at WCD 2015, Dr. Alice B. Gottlieb presented the week 16 results of the phase IIIb GESTURE study, in which 205 psoriasis patients with moderate to severe psoriasis of the palms and soles were randomized to subcutaneous secukinumab (Cosentyx) at 150 or 300 mg or placebo. Dosing was weekly for the first 5 weeks and monthly thereafter.

The primary endpoint, a palmoplantar Investigator’s Global Assessment scale score of 0 or 1 – clear or almost clear – at week 16 was 33.3% with secukinumab at 300 mg, 22.1% at 150 mg, and 1.5% with placebo. The average reduction in palmoplantar PASI (Psoriasis Area Severity Index) score from baseline was 54.6% with high-dose and 35.3% with low-dose secukinumab, compared with 4.1% in placebo-treated controls, reported Dr. Gottlieb, professor and chair of dermatology at Tufts University, Boston.

Like the TRANSFIGURE trial, GESTURE will continue for 132 weeks, with the initial placebo-treated controls being randomized to secukinumab at 150 or 300 mg after week 16.

Dr. Reich reported that by 16 weeks in TRANSFIGURE, mean scores on the Nail Psoriasis Severity Index had improved by 45.3%, compared with baseline, in patients on secukinumab 300 mg, 37.9% in those on secukinumab 150 mg, and 10.8% with placebo.

The results on the skin were dramatic: a PASI 75 rate of 87.1% with secukinumab 300 mg, 77% with secukinumab 150 mg, and 5.1% with placebo. The PASI 100 response rate – meaning totally clear skin – was 31.9% with high-dose and 25.2% with lower-dose secukinumab, while there was a zero PASI 100 rate in controls.

The only adverse events more common than with placebo were nasopharyngitis and upper respiratory infections.

Dr. Reich predicted that as the ongoing TRANSFIGURE study continues well beyond 16 weeks, the nail psoriasis response rates will climb, since nails are so slow growing.

TRANSFIGURE and GESTURE are sponsored by Novartis, which markets secukinumab. Dr. Reich and Dr. Gottlieb reported having financial relationships with Novartis and numerous other pharmaceutical companies.

bjancin@frontlinemedcom

Thrombus

Image by Andre E.X. Brown

The European Commission (EC) has approved edoxaban (Lixiana), an oral factor Xa inhibitor, for use in patients with venous thromboembolism (VTE) or nonvalvular atrial fibrillation (NVAF).

The drug can now be used to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE).

It can also be used to prevent stroke and systemic embolism in adults with NVAF who have one or more risk factors for stroke or systemic embolism, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke, or transient ischemic attack.

The EC’s decision affects all 28 European Union member states, plus Iceland, Norway, and Liechtenstein. Edoxaban is already approved for use in the US, Japan, and Switzerland.

The EC based its approval of edoxaban on results of 2 phase 3 clinical trials, ENGAGE AF-TIMI 48 and Hokusai-VTE.

Hokusai-VTE

In the Hokusai-VTE trial, researchers evaluated edoxaban in 4921 patients with DVT and 3319 with PE. Patients received initial treatment with low-molecular-weight heparin and were then randomized to receive edoxaban or warfarin daily for 3 to 12 months.

Overall, edoxaban proved as effective as warfarin. Recurrent, symptomatic VTE occurred in 3.2% and 3.5% of patients, respectively (P<0.001 for non-inferiority).

In addition, the incidence of clinically relevant bleeding was significantly lower in the edoxaban arm than the warfarin arm—8.5% and 10.3%, respectively (P=0.004 for superiority).

ENGAGE-AF TIMI 48

In the ENGAGE AF-TIMI 48 trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.

The trial included 21,105 patients who were randomized to receive warfarin (n=7036), edoxaban at 60 mg (n=7035), or edoxaban at 30 mg (n=7034).

Edoxaban was at least non-inferior to warfarin with regard to efficacy. The annual incidence of stroke or systemic embolism was 1.50% with warfarin, 1.18% with edoxaban at 60 mg (P<0.001 for non-inferiority), and 1.61% with edoxaban at 30 mg (P=0.005 for non-inferiority).

In addition, edoxaban was associated with a significantly lower rate of major and fatal bleeding. The annual incidence of major bleeding was 3.43% with warfarin, 2.75% with edoxaban at 60 mg (P<0.001), and 1.61% with edoxaban at 30 mg (P<0.001).

Fatal bleeds occurred at an annual rate of 0.38% with warfarin, 0.21% with edoxaban at 60 mg (P=0.006), and 0.13% with edoxaban at 30 mg (P<0.001).

Edoxaban is under development by Daiichi Sankyo Co., Ltd.

Thrombus

Image by Andre E.X. Brown

The European Commission (EC) has approved edoxaban (Lixiana), an oral factor Xa inhibitor, for use in patients with venous thromboembolism (VTE) or nonvalvular atrial fibrillation (NVAF).

The drug can now be used to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE).

It can also be used to prevent stroke and systemic embolism in adults with NVAF who have one or more risk factors for stroke or systemic embolism, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke, or transient ischemic attack.

The EC’s decision affects all 28 European Union member states, plus Iceland, Norway, and Liechtenstein. Edoxaban is already approved for use in the US, Japan, and Switzerland.

The EC based its approval of edoxaban on results of 2 phase 3 clinical trials, ENGAGE AF-TIMI 48 and Hokusai-VTE.

Hokusai-VTE

In the Hokusai-VTE trial, researchers evaluated edoxaban in 4921 patients with DVT and 3319 with PE. Patients received initial treatment with low-molecular-weight heparin and were then randomized to receive edoxaban or warfarin daily for 3 to 12 months.

Overall, edoxaban proved as effective as warfarin. Recurrent, symptomatic VTE occurred in 3.2% and 3.5% of patients, respectively (P<0.001 for non-inferiority).

In addition, the incidence of clinically relevant bleeding was significantly lower in the edoxaban arm than the warfarin arm—8.5% and 10.3%, respectively (P=0.004 for superiority).

ENGAGE-AF TIMI 48

In the ENGAGE AF-TIMI 48 trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.

The trial included 21,105 patients who were randomized to receive warfarin (n=7036), edoxaban at 60 mg (n=7035), or edoxaban at 30 mg (n=7034).

Edoxaban was at least non-inferior to warfarin with regard to efficacy. The annual incidence of stroke or systemic embolism was 1.50% with warfarin, 1.18% with edoxaban at 60 mg (P<0.001 for non-inferiority), and 1.61% with edoxaban at 30 mg (P=0.005 for non-inferiority).

In addition, edoxaban was associated with a significantly lower rate of major and fatal bleeding. The annual incidence of major bleeding was 3.43% with warfarin, 2.75% with edoxaban at 60 mg (P<0.001), and 1.61% with edoxaban at 30 mg (P<0.001).

Fatal bleeds occurred at an annual rate of 0.38% with warfarin, 0.21% with edoxaban at 60 mg (P=0.006), and 0.13% with edoxaban at 30 mg (P<0.001).

Edoxaban is under development by Daiichi Sankyo Co., Ltd.

Thrombus

Image by Andre E.X. Brown

The European Commission (EC) has approved edoxaban (Lixiana), an oral factor Xa inhibitor, for use in patients with venous thromboembolism (VTE) or nonvalvular atrial fibrillation (NVAF).

The drug can now be used to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE).

It can also be used to prevent stroke and systemic embolism in adults with NVAF who have one or more risk factors for stroke or systemic embolism, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke, or transient ischemic attack.

The EC’s decision affects all 28 European Union member states, plus Iceland, Norway, and Liechtenstein. Edoxaban is already approved for use in the US, Japan, and Switzerland.

The EC based its approval of edoxaban on results of 2 phase 3 clinical trials, ENGAGE AF-TIMI 48 and Hokusai-VTE.

Hokusai-VTE

In the Hokusai-VTE trial, researchers evaluated edoxaban in 4921 patients with DVT and 3319 with PE. Patients received initial treatment with low-molecular-weight heparin and were then randomized to receive edoxaban or warfarin daily for 3 to 12 months.

Overall, edoxaban proved as effective as warfarin. Recurrent, symptomatic VTE occurred in 3.2% and 3.5% of patients, respectively (P<0.001 for non-inferiority).

In addition, the incidence of clinically relevant bleeding was significantly lower in the edoxaban arm than the warfarin arm—8.5% and 10.3%, respectively (P=0.004 for superiority).

ENGAGE-AF TIMI 48

In the ENGAGE AF-TIMI 48 trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.

The trial included 21,105 patients who were randomized to receive warfarin (n=7036), edoxaban at 60 mg (n=7035), or edoxaban at 30 mg (n=7034).

Edoxaban was at least non-inferior to warfarin with regard to efficacy. The annual incidence of stroke or systemic embolism was 1.50% with warfarin, 1.18% with edoxaban at 60 mg (P<0.001 for non-inferiority), and 1.61% with edoxaban at 30 mg (P=0.005 for non-inferiority).

In addition, edoxaban was associated with a significantly lower rate of major and fatal bleeding. The annual incidence of major bleeding was 3.43% with warfarin, 2.75% with edoxaban at 60 mg (P<0.001), and 1.61% with edoxaban at 30 mg (P<0.001).

Fatal bleeds occurred at an annual rate of 0.38% with warfarin, 0.21% with edoxaban at 60 mg (P=0.006), and 0.13% with edoxaban at 30 mg (P<0.001).

Edoxaban is under development by Daiichi Sankyo Co., Ltd.

VANCOUVER, B.C. – Occupational hand eczema is worse and more persistent in smokers than nonsmokers, a large prospective cohort study found.

“Tobacco smoking is associated with work absenteeism and with not staying in the workforce due to occupational hand eczema. Smoking confers a worse prognosis and interferes with the outcome of prevention programs,” Dr. Richard Brans said at the World Congress of Dermatology.

Hand eczema is the most common occupational skin disease. Smoking might worsen signs and symptoms by inducing proinflammatory effects in the skin, said Dr. Brans, a dermatologist at the University of Osnabrück, Germany.

To better assess the link between smoking and hand eczema, he and his associates carried out a prospective 3-year study of 1,095 patients from throughout Germany. The patients initially had attended a 6-week residential treatment program for hand eczema that was followed by a 3-week outpatient program. Smokers comprised about half of the patients and resembled nonsmokers in terms of gender, general atopy, and degree of professional or occupational exposures, such as wetting or soiling the hands at work, Dr. Brans said. However, smokers were significantly younger than nonsmokers and were more likely to have allergic contact dermatitis, he noted.

The inpatient phase of the program markedly benefited both smokers and nonsmokers, but notably, smokers had significantly worse symptoms and signs of hand eczema at all time points assessed, Dr. Brans said. Furthermore, smokers missed an average of 37 days of work because of occupational hand eczema in the year before the program, compared with only 25 days for nonsmokers (P = .001), and smokers continued to miss more days of work because of hand eczema in the year after completing the program (P = .023), he reported. Significantly more smokers also left their professions because of their hand eczema, even after completing the prevention program (P = .021), he added.

The study found no link between number of cigarettes smoked per day and severity of hand eczema, Dr. Brans said. Smoking history was self-reported, and the study design excluded patients who changed their smoking behavior during follow-up, he noted. In addition, the researchers did not assess whether other factors associated with smoking might have confounded the association between smoking and severity of hand eczema, he said.

Dr. Brans reported no relevant disclosures.

VANCOUVER, B.C. – Occupational hand eczema is worse and more persistent in smokers than nonsmokers, a large prospective cohort study found.

“Tobacco smoking is associated with work absenteeism and with not staying in the workforce due to occupational hand eczema. Smoking confers a worse prognosis and interferes with the outcome of prevention programs,” Dr. Richard Brans said at the World Congress of Dermatology.

Hand eczema is the most common occupational skin disease. Smoking might worsen signs and symptoms by inducing proinflammatory effects in the skin, said Dr. Brans, a dermatologist at the University of Osnabrück, Germany.

To better assess the link between smoking and hand eczema, he and his associates carried out a prospective 3-year study of 1,095 patients from throughout Germany. The patients initially had attended a 6-week residential treatment program for hand eczema that was followed by a 3-week outpatient program. Smokers comprised about half of the patients and resembled nonsmokers in terms of gender, general atopy, and degree of professional or occupational exposures, such as wetting or soiling the hands at work, Dr. Brans said. However, smokers were significantly younger than nonsmokers and were more likely to have allergic contact dermatitis, he noted.

The inpatient phase of the program markedly benefited both smokers and nonsmokers, but notably, smokers had significantly worse symptoms and signs of hand eczema at all time points assessed, Dr. Brans said. Furthermore, smokers missed an average of 37 days of work because of occupational hand eczema in the year before the program, compared with only 25 days for nonsmokers (P = .001), and smokers continued to miss more days of work because of hand eczema in the year after completing the program (P = .023), he reported. Significantly more smokers also left their professions because of their hand eczema, even after completing the prevention program (P = .021), he added.

The study found no link between number of cigarettes smoked per day and severity of hand eczema, Dr. Brans said. Smoking history was self-reported, and the study design excluded patients who changed their smoking behavior during follow-up, he noted. In addition, the researchers did not assess whether other factors associated with smoking might have confounded the association between smoking and severity of hand eczema, he said.

Dr. Brans reported no relevant disclosures.

VANCOUVER, B.C. – Occupational hand eczema is worse and more persistent in smokers than nonsmokers, a large prospective cohort study found.

“Tobacco smoking is associated with work absenteeism and with not staying in the workforce due to occupational hand eczema. Smoking confers a worse prognosis and interferes with the outcome of prevention programs,” Dr. Richard Brans said at the World Congress of Dermatology.

Hand eczema is the most common occupational skin disease. Smoking might worsen signs and symptoms by inducing proinflammatory effects in the skin, said Dr. Brans, a dermatologist at the University of Osnabrück, Germany.

To better assess the link between smoking and hand eczema, he and his associates carried out a prospective 3-year study of 1,095 patients from throughout Germany. The patients initially had attended a 6-week residential treatment program for hand eczema that was followed by a 3-week outpatient program. Smokers comprised about half of the patients and resembled nonsmokers in terms of gender, general atopy, and degree of professional or occupational exposures, such as wetting or soiling the hands at work, Dr. Brans said. However, smokers were significantly younger than nonsmokers and were more likely to have allergic contact dermatitis, he noted.

The inpatient phase of the program markedly benefited both smokers and nonsmokers, but notably, smokers had significantly worse symptoms and signs of hand eczema at all time points assessed, Dr. Brans said. Furthermore, smokers missed an average of 37 days of work because of occupational hand eczema in the year before the program, compared with only 25 days for nonsmokers (P = .001), and smokers continued to miss more days of work because of hand eczema in the year after completing the program (P = .023), he reported. Significantly more smokers also left their professions because of their hand eczema, even after completing the prevention program (P = .021), he added.

The study found no link between number of cigarettes smoked per day and severity of hand eczema, Dr. Brans said. Smoking history was self-reported, and the study design excluded patients who changed their smoking behavior during follow-up, he noted. In addition, the researchers did not assess whether other factors associated with smoking might have confounded the association between smoking and severity of hand eczema, he said.

Dr. Brans reported no relevant disclosures.

For the first time since the middle of the 20th century, cardiovascular disease is not the main cause of death overall in the United Kingdom, according to 2012 data published in Heart.

Cancer narrowly took the lead, with 29% of mortalities in 2012 having resulted from this disease, compared to the 28% of deaths that resulted from cardiovascular disease (CVD). But CVD remains the largest killer of women in the U.K.

In 2012, 28% of all female deaths and 32% of all male deaths were caused by CVD. The highest cause of mortality for men was cancer, with 32% of male deaths having resulted from that disease. A slightly smaller percentage of female deaths – 27% – was caused by cancer than by CVD. The Office for National Statistics (ONS), the National Records of Scotland, and the Northern Ireland Statistics and Research Agency provided the data.

Of the CVD deaths, 46%, or just under 73,500, were from coronary heart disease (CHD) and 26%, or about 41,000, were from stroke.

CVD caused more than a quarter of premature deaths – defined as deaths occurring in people younger than 75 – in men and 18% of premature deaths in women. CHD was the most common cause of premature death in U.K. men.

CVD death rates also varied per region of the United Kingdom, with higher percentages of the populations of Scotland and the north of England having died of CVD than the percentage of people living in the south of England who died from the disease, according to age-standardized death rates by local authorities. Glasgow City, Scotland, had the highest CVD mortality, with 144/100,0000 people having died prematurely and 400/100,000 people having died of the disease.

“The improvements in survival [of people with CVD] mean that there is now a high prevalence of people living with CVD,” according to Prachi Bhatnagar, Ph.D., and her colleagues.

The numbers of people suffering from CHD, stroke, atrial fibrillation and heart failure in the U.K. in 2012 and 2013 were approximately 2.3 million, 1.2 million, 1 million and 480,000, respectively, Quality of Outcomes Framework data suggest. The number of operations carried out to treat CHD is increasing in the United Kingdom, with greater than 90,000 percutaneous coronary interventions (PCIs) having been carried out in 2012 – more than twice as many as had been performed a decade earlier.

“CVD remains a substantial burden to the U.K., both in terms of health and economic costs,” according to the researchers.

Read the full study in Heart (doi:10.1136/heartjnl-2015-307516).

[email protected]

For the first time since the middle of the 20th century, cardiovascular disease is not the main cause of death overall in the United Kingdom, according to 2012 data published in Heart.

Cancer narrowly took the lead, with 29% of mortalities in 2012 having resulted from this disease, compared to the 28% of deaths that resulted from cardiovascular disease (CVD). But CVD remains the largest killer of women in the U.K.

In 2012, 28% of all female deaths and 32% of all male deaths were caused by CVD. The highest cause of mortality for men was cancer, with 32% of male deaths having resulted from that disease. A slightly smaller percentage of female deaths – 27% – was caused by cancer than by CVD. The Office for National Statistics (ONS), the National Records of Scotland, and the Northern Ireland Statistics and Research Agency provided the data.

Of the CVD deaths, 46%, or just under 73,500, were from coronary heart disease (CHD) and 26%, or about 41,000, were from stroke.

CVD caused more than a quarter of premature deaths – defined as deaths occurring in people younger than 75 – in men and 18% of premature deaths in women. CHD was the most common cause of premature death in U.K. men.

CVD death rates also varied per region of the United Kingdom, with higher percentages of the populations of Scotland and the north of England having died of CVD than the percentage of people living in the south of England who died from the disease, according to age-standardized death rates by local authorities. Glasgow City, Scotland, had the highest CVD mortality, with 144/100,0000 people having died prematurely and 400/100,000 people having died of the disease.

“The improvements in survival [of people with CVD] mean that there is now a high prevalence of people living with CVD,” according to Prachi Bhatnagar, Ph.D., and her colleagues.

The numbers of people suffering from CHD, stroke, atrial fibrillation and heart failure in the U.K. in 2012 and 2013 were approximately 2.3 million, 1.2 million, 1 million and 480,000, respectively, Quality of Outcomes Framework data suggest. The number of operations carried out to treat CHD is increasing in the United Kingdom, with greater than 90,000 percutaneous coronary interventions (PCIs) having been carried out in 2012 – more than twice as many as had been performed a decade earlier.

“CVD remains a substantial burden to the U.K., both in terms of health and economic costs,” according to the researchers.

Read the full study in Heart (doi:10.1136/heartjnl-2015-307516).

[email protected]

For the first time since the middle of the 20th century, cardiovascular disease is not the main cause of death overall in the United Kingdom, according to 2012 data published in Heart.

Cancer narrowly took the lead, with 29% of mortalities in 2012 having resulted from this disease, compared to the 28% of deaths that resulted from cardiovascular disease (CVD). But CVD remains the largest killer of women in the U.K.

In 2012, 28% of all female deaths and 32% of all male deaths were caused by CVD. The highest cause of mortality for men was cancer, with 32% of male deaths having resulted from that disease. A slightly smaller percentage of female deaths – 27% – was caused by cancer than by CVD. The Office for National Statistics (ONS), the National Records of Scotland, and the Northern Ireland Statistics and Research Agency provided the data.

Of the CVD deaths, 46%, or just under 73,500, were from coronary heart disease (CHD) and 26%, or about 41,000, were from stroke.

CVD caused more than a quarter of premature deaths – defined as deaths occurring in people younger than 75 – in men and 18% of premature deaths in women. CHD was the most common cause of premature death in U.K. men.

CVD death rates also varied per region of the United Kingdom, with higher percentages of the populations of Scotland and the north of England having died of CVD than the percentage of people living in the south of England who died from the disease, according to age-standardized death rates by local authorities. Glasgow City, Scotland, had the highest CVD mortality, with 144/100,0000 people having died prematurely and 400/100,000 people having died of the disease.

“The improvements in survival [of people with CVD] mean that there is now a high prevalence of people living with CVD,” according to Prachi Bhatnagar, Ph.D., and her colleagues.

The numbers of people suffering from CHD, stroke, atrial fibrillation and heart failure in the U.K. in 2012 and 2013 were approximately 2.3 million, 1.2 million, 1 million and 480,000, respectively, Quality of Outcomes Framework data suggest. The number of operations carried out to treat CHD is increasing in the United Kingdom, with greater than 90,000 percutaneous coronary interventions (PCIs) having been carried out in 2012 – more than twice as many as had been performed a decade earlier.

“CVD remains a substantial burden to the U.K., both in terms of health and economic costs,” according to the researchers.

Read the full study in Heart (doi:10.1136/heartjnl-2015-307516).

[email protected]