Jonathan M. Meyer, MD

Pimavanserin is a potent 5-HT2A inverse agonist and 5-HT2C inverse agonist, with 5-fold greater affinity for the 5-HT2A receptor.¹ Although antagonists block agonist actions at the receptor site, inverse agonists reduce the level of baseline constitutive activity seen in many G protein-coupled receptors. This medication is FDA approved for treating hallucinations and delusions associated with Parkinson’s disease (PD) psychosis (Table 1).¹

In the pivotal 6-week clinical trial, pimavanserin significantly reduced positive symptoms seen in PD patients with psychosis (effect size = 0.50), with no evident impairment of motor function.² Only 2 adverse effects occurred in ≥5% of pimavanserin-treated patients and at ≥2 times the rate of placebo: peripheral edema (7% vs 3% for placebo) and confusion (6% vs 3% for placebo). There was a mean increase in the QTc of 7.3 milliseconds compared with placebo in the pivotal phase III study.

Clinical implications

Despite numerous developments in the pharmacotherapeutics of psychotic disorders, patients with psychosis related to PD previously responded in a robust manner to only 1 antipsychotic, low-dosage clozapine (mean effect size, 0.80),² with numerous failed trials for other atypical antipsychotics, including quetiapine.^3,4 The pathophysiology of psychosis in PD patients is not related to dopamine agonist treatment, but is caused by the accumulation of cortical Lewy body burden, which results in loss of serotonergic signaling from dorsal raphe neurons. The net effect is up-regulation of postsynaptic 5-HT2A receptors.⁵ Psychosis is the most common cause of nursing home placement among PD patients without dementia.⁶

Receptor blocking. Based on the finding that clozapine in low dosages acts at 5-HT2A receptors,⁷ pimavanserin was designed to be a potent 5-HT2A inverse agonist, with more than 5-fold higher selectivity over 5-HT2C receptors, and no appreciable affinity for other serotonergic, adrenergic, dopaminergic, muscarinic, or histaminergic receptors⁸ (Table 2). The concept that 5-HT2A receptor stimulation can cause psychosis with prominent visual hallucinations is known from studies of LSD and other hallucinogenic compounds whose activity is blocked by 5-HT2A antagonists.

As an agent devoid of dopamine D2 antagonism, pimavanserin carries no risk of exacerbating motor symptoms, which was commonly seen with most atypical antipsychotics studied for psychosis in PD patients, except for clozapine and quetiapine.³ Although quetiapine did not cause motor effects, it proved ineffective in multiple studies (n = 153), likely because of the near absence of potent 5-HT2A binding.⁴

Pimavanserin also lacks:

• the hematologic monitoring requirement of clozapine
• clozapine’s risks of sedation, orthostasis, and anticholinergic and metabolic adverse effects.

Pimavanserin is significantly more potent than other non-antipsychotic psychotropics at the 5-HT2Areceptor, including doxepin (26 nM), trazodone (36 nM), and mirtazapine (60 nM).

Use in psychosis associated with PD. Recommended dosage is 34 mg once daily without titration (with or without food), based on results from a phase III clinical trial² (because of the FDA breakthrough therapy designation for this compound, only 1 phase III trial was required). Pimavanserin produced significant improvement on the PD-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD), a 9-item instrument extracted from the larger SAPS used in schizophrenia research. Specifically, pimavanserin was effective for both the hallucinations and delusions components of the SAPS-PD.

Pharmacologic profile, adverse effects. Pimavanserin lacks affinity for receptors other than 5-HT2A and 5-HT2C, leading to an absence of significant anticholinergic effects, orthostasis, or sedation in clinical trials.² In all short-term clinical trials, the only common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were peripheral edema (7% vs 2% placebo) and confusional state (6% vs 3% placebo).² More than 300 patients have been treated for >6 months, >270 have been treated for at least 12 months, and >150 have been treated for at least 24 months with no adverse effects other than those seen in the short-term trials.¹

There is a measurable impact on cardiac conduction seen in phase III data and in the thorough QT study. In the thorough QT study, 252 healthy participants received multiple dosages in a randomized, double-blind manner with positive controls.¹ The maximum mean change from baseline was 13.5 milliseconds at dosages twice the recommended dosage, and the upper limit of the 90% CI was only slightly greater at 16.6 milliseconds. Subsequent kinetic analyses suggested concentration-dependent QTc interval prolongation in the therapeutic range, with a recommendation to halve the daily dosage in patients taking potent cytochrome P450 (CYP) 3A4 inhibitors.

In the 6-week, placebo-controlled effectiveness studies, mean increases in QTc interval were in the range of 5 to 8 milliseconds. There were sporadic reports of QTcF values ≥500 milliseconds, or changes from baseline QTc values ≥60 milliseconds in pimavanserin-treated participants, although the incidence generally was the same for pimavanserin and placebo groups. There were no reports of torsades de pointes or any differences from placebo in the incidence of adverse reactions associated with delayed ventricular repolarization.

How it works

The theory behind development of pimavanserin rests in the finding that low-dosage clozapine (6.25 to 50 mg/d) was effective for PD patients with psychosis (effect size 0.80).⁸ Although clozapine has high affinity for multiple sites, including histamine H1 receptors (Ki = 1.13 nM), α-1A and a α-2C adrenergic receptors (Ki = 1.62 nM and 6 nM, respectively), 5-HT2A receptors (Ki = 5.35 nM), and muscarinic M1 receptors (Ki = 6 nM), the hypothesized primary mechanism of clozapine’s effectiveness for PD psychosis at low dosages focused on the 5-HT2Areceptor. This idea was based on the knowledge that hallucinogens such as mescaline, psilocybin, and LSD are 5-HT2A agonists.⁹ This hallucinogenic activity can be blocked with 5-HT2A antagonists. Because of pimavanserin’s binding profile, the compound was studied as a treatment for psychosis in PD patients.

Pharmacokinetics

Pimavanserin demonstrates dose-proportional pharmacokinetics after a single oral dose as much as 7.5 times the recommended dosage. The pharmacokinetics of pimavanserin were similar in study participants (mean age, 72.4) and healthy controls, and a high-fat meal had no impact on the maximum blood levels (Cmax) or total drug exposure (area under the curve [AUC]).

The mean plasma half-lives for pimavanserin and its metabolite N-desmethyl-pimavanserin (AC-279) are 57 hours and 200 hours, respectively. Although the metabolite appears active in in vitro assays, it does not cross the blood-brain barrier to any appreciable extent, therefore contributing little to the clinical effect. The median time to maximum concentration (Tmax) of pimavanserin is 6 hours with a range of 4 to 24 hours, while the median Tmax of the primary metabolite AC-279 is 6 hours. The bioavailability of pimavanserin in an oral tablet or solution essentially is identical.

Pimavanserin is primarily metabolized via CYP3A4 to AC-279, and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, indinavir) increase pimavanserin Cmax by 1.5-fold, and AUC by 3-fold. In patients taking strong CYP3A4 inhibitors, the dosage of pimavanserin should be reduced by 50% to 17 mg/d. Conversely, patients on CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin) should be monitored for lack of efficacy; consider a dosage increase as necessary. Neither pimavanserin nor its metabolite, AC-279, are inhibitors or inducers of major CYP enzymes or drug transporters.

Efficacy in PD psychosis

Study 1. This 6-week, fixed dosage, double-blind, placebo-controlled trial was performed in adult PD patients age ≥40 with PD psychosis.² Participants had to have (1) a PD diagnosis for at least 1 year and (2) psychotic symptoms that developed after diagnosis. Psychotic symptoms had to be present for at least 1 month, occurring at least weekly in the month before screening, and severe enough to warrant antipsychotic treatment. Baseline Mini-Mental State Examination score had to be ≥21 out of 30, with no evidence of delirium. Patients with dementia preceding or concurrent with the PD diagnosis were excluded. Antipsychotic treatments were not permitted during the trial.

After a 2-week nonpharmacotherapeutic lead-in phase that included a brief, daily psychosocial intervention by a caregiver, 199 patients who still met severity criteria were randomly allocated in a 1:1 manner to pimavanserin (34 mg of active drug, reported in the paper as 40 mg of pimavanserin tartrate) or matched placebo. Based on kinetic modeling and earlier clinical data, lower dosages (ie, 17 mg) were not explored, because they achieved only 50% of the steady state plasma levels thought to be required for efficacy.

The primary outcome was assessed by central, independent raters using the PD-adapted SAPS-PD. The efficacy analysis included 95 pimavanserin-treated individuals and 90 taking placebo. Baseline SAPS-PD scores were 14.7 ± 5.55 in the placebo group, and 15.9 ± 6.12 in the pimavanserin arm. Participants had a mean age of 72.4 and 94% white ethnicity across both cohorts; 42% of the placebo group and 33% of the pimavanserin group were female. Antipsychotic exposure in the 21 days prior to study entry were reported in 17% (n = 15) and 19% (n = 18) of the placebo and pimavanserin groups, respectively, with the most common agent being quetiapine (13 of 15, placebo, 16 of 18, pimavanserin). Approximately one-third of all participants were taking a cholinesterase inhibitor throughout the study.

Efficacy outcome. Pimavanserin was associated with a 5.79-point decrease in SAPS-PD scores compared with 2.73-point decrease for placebo (difference −3.06, 95% CI −4.91 to −1.20; P = .001). The effect size for this difference (Cohen’s d) was 0.50. The significant effect of pimavanserin vs placebo also was seen in separate analyses of the SAPS-PD subscore for hallucinations and delusions (effect size 0.50), and individually for hallucinations (effect size 0.45) and delusions (effect size 0.33). Separation from placebo appeared after the second week of pimavanserin treatment, and continued through the end of the study. There is unpublished data showing efficacy through week 10, and longer term, uncontrolled data consistent with sustained response. An exploratory analysis of caregiver burden demonstrated an effect size of 0.50.

Tolerability

The discontinuation rate because of adverse events for pimavanserin and placebo-treated patients was 10 patients in the pimavanserin group (4 due to psychotic symptoms within 10 days of starting the study drug) compared with 2 in the placebo group. There was no evidence of motor worsening in either group, demonstrated by the score on part II of the Unified Parkinson’s Disease Rating Scale (UPDRS) that captures self-reported activities of daily living, or on UPDRS part III (motor examination). Pimavanserin has no contraindications.

Unique clinical issues

Binding properties. Pimavanserin possesses potent 5-HT2A inverse agonist properties required to manage psychosis in PD patients, but lacks clozapine’s affinities for α-1 adrenergic, muscarinic, or histaminergic receptors that contribute to clozapine’s poor tolerability. Moreover, pimavanserin has no appreciable affinity for dopaminergic receptors, and therefore does not induce motor adverse effects.

Clozapine aside, all available atypical antipsychotics have proved ineffective for psychosis in PD patients, and most caused significant motor worsening.³ Although quetiapine does not cause motor effects, it has been shown to be ineffective for psychosis in PD patients in multiple trials.⁴

The effect size for clozapine response is large (0.80) in PD patients with psychosis, but tolerability issues and administrative burdens regarding patient and prescriber registration and routine hematological monitoring pose significant clinical barriers. Clozapine also lacks an FDA indication for this purpose, which may pose a hurdle to its use in certain treatment settings.

Why Rx? The reasons to prescribe pimavanserin for PD patients with psychosis likely include:

• absence of tolerability issues seen with the only other effective agent, clozapine
• lack of motor effects
• lack of administrative and monitoring burden related to clozapine prescribing
• only agent with FDA approval for hallucinations and delusions in PD patients with psychosis.

Dosing

The recommended dosage of pimavanserin is 34 mg/d administered as a single dose with or without food. There is no need for titration, and none was performed in the pivotal clinical trial. Given the long half-life (57 hours), steady state is not achieved until day 12, therefore initiation with a lower dosage might prolong the time to efficacy. There is no dosage adjustment required in patients with mild or moderate renal impairment, but pimavanserin treatment is not recommended in patients with severe renal impairment. Pimavanserin has not been evaluated in patients with hepatic impairment (using Child-Pugh criteria), and is not recommended for these patients.

Other key aspects of dosing to keep in mind.

• Because pimavanserin is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a strong CYP3A4 inhibitor; the recommended dosage is 17 mg/d when administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of pimavanserin with CYP3A4 inducers, patients should be monitored for lack of efficacy during concomitant use with a CYP3A4 inducer, and consideration given to a dosage increase.

Use in pregnancy and lactation. There are no data on the use of pimavanserin in pregnant women, but no developmental effects were seen when the drug was administered orally at 10 or 12 times the maximum recommended human dosage to rats or rabbits during organogenesis. Pimavanserin was not teratogenic in pregnant rats and rabbits. There is no information regarding the presence of pimavanserin in human breast milk.

Geriatric patients. No dosage adjustment is required for older patients. The study population in the pivotal trial was mean age 72.4 years.

Summing up

Before development of pimavanserin, clozapine was the only effective treatment for psychosis in PD patients. Despite clozapine’s robust effects across several trials, patients often were given ineffective medications, such as quetiapine, because of the administrative and tolerability barriers posed by clozapine use. Because psychosis is the most common cause of nursing home placement in non-demented PD patients, an agent with demonstrated efficacy and without the adverse effect profile of clozapine or monitoring requirements represents an enormous advance in the treatment of psychosis in PD patients.

Pimavanserin is a potent 5-HT2A inverse agonist and 5-HT2C inverse agonist, with 5-fold greater affinity for the 5-HT2A receptor.¹ Although antagonists block agonist actions at the receptor site, inverse agonists reduce the level of baseline constitutive activity seen in many G protein-coupled receptors. This medication is FDA approved for treating hallucinations and delusions associated with Parkinson’s disease (PD) psychosis (Table 1).¹

In the pivotal 6-week clinical trial, pimavanserin significantly reduced positive symptoms seen in PD patients with psychosis (effect size = 0.50), with no evident impairment of motor function.² Only 2 adverse effects occurred in ≥5% of pimavanserin-treated patients and at ≥2 times the rate of placebo: peripheral edema (7% vs 3% for placebo) and confusion (6% vs 3% for placebo). There was a mean increase in the QTc of 7.3 milliseconds compared with placebo in the pivotal phase III study.

Clinical implications

Despite numerous developments in the pharmacotherapeutics of psychotic disorders, patients with psychosis related to PD previously responded in a robust manner to only 1 antipsychotic, low-dosage clozapine (mean effect size, 0.80),² with numerous failed trials for other atypical antipsychotics, including quetiapine.^3,4 The pathophysiology of psychosis in PD patients is not related to dopamine agonist treatment, but is caused by the accumulation of cortical Lewy body burden, which results in loss of serotonergic signaling from dorsal raphe neurons. The net effect is up-regulation of postsynaptic 5-HT2A receptors.⁵ Psychosis is the most common cause of nursing home placement among PD patients without dementia.⁶

Receptor blocking. Based on the finding that clozapine in low dosages acts at 5-HT2A receptors,⁷ pimavanserin was designed to be a potent 5-HT2A inverse agonist, with more than 5-fold higher selectivity over 5-HT2C receptors, and no appreciable affinity for other serotonergic, adrenergic, dopaminergic, muscarinic, or histaminergic receptors⁸ (Table 2). The concept that 5-HT2A receptor stimulation can cause psychosis with prominent visual hallucinations is known from studies of LSD and other hallucinogenic compounds whose activity is blocked by 5-HT2A antagonists.

As an agent devoid of dopamine D2 antagonism, pimavanserin carries no risk of exacerbating motor symptoms, which was commonly seen with most atypical antipsychotics studied for psychosis in PD patients, except for clozapine and quetiapine.³ Although quetiapine did not cause motor effects, it proved ineffective in multiple studies (n = 153), likely because of the near absence of potent 5-HT2A binding.⁴

Pimavanserin also lacks:

• the hematologic monitoring requirement of clozapine
• clozapine’s risks of sedation, orthostasis, and anticholinergic and metabolic adverse effects.

Pimavanserin is significantly more potent than other non-antipsychotic psychotropics at the 5-HT2Areceptor, including doxepin (26 nM), trazodone (36 nM), and mirtazapine (60 nM).

Use in psychosis associated with PD. Recommended dosage is 34 mg once daily without titration (with or without food), based on results from a phase III clinical trial² (because of the FDA breakthrough therapy designation for this compound, only 1 phase III trial was required). Pimavanserin produced significant improvement on the PD-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD), a 9-item instrument extracted from the larger SAPS used in schizophrenia research. Specifically, pimavanserin was effective for both the hallucinations and delusions components of the SAPS-PD.

Pharmacologic profile, adverse effects. Pimavanserin lacks affinity for receptors other than 5-HT2A and 5-HT2C, leading to an absence of significant anticholinergic effects, orthostasis, or sedation in clinical trials.² In all short-term clinical trials, the only common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were peripheral edema (7% vs 2% placebo) and confusional state (6% vs 3% placebo).² More than 300 patients have been treated for >6 months, >270 have been treated for at least 12 months, and >150 have been treated for at least 24 months with no adverse effects other than those seen in the short-term trials.¹

There is a measurable impact on cardiac conduction seen in phase III data and in the thorough QT study. In the thorough QT study, 252 healthy participants received multiple dosages in a randomized, double-blind manner with positive controls.¹ The maximum mean change from baseline was 13.5 milliseconds at dosages twice the recommended dosage, and the upper limit of the 90% CI was only slightly greater at 16.6 milliseconds. Subsequent kinetic analyses suggested concentration-dependent QTc interval prolongation in the therapeutic range, with a recommendation to halve the daily dosage in patients taking potent cytochrome P450 (CYP) 3A4 inhibitors.

In the 6-week, placebo-controlled effectiveness studies, mean increases in QTc interval were in the range of 5 to 8 milliseconds. There were sporadic reports of QTcF values ≥500 milliseconds, or changes from baseline QTc values ≥60 milliseconds in pimavanserin-treated participants, although the incidence generally was the same for pimavanserin and placebo groups. There were no reports of torsades de pointes or any differences from placebo in the incidence of adverse reactions associated with delayed ventricular repolarization.

How it works

The theory behind development of pimavanserin rests in the finding that low-dosage clozapine (6.25 to 50 mg/d) was effective for PD patients with psychosis (effect size 0.80).⁸ Although clozapine has high affinity for multiple sites, including histamine H1 receptors (Ki = 1.13 nM), α-1A and a α-2C adrenergic receptors (Ki = 1.62 nM and 6 nM, respectively), 5-HT2A receptors (Ki = 5.35 nM), and muscarinic M1 receptors (Ki = 6 nM), the hypothesized primary mechanism of clozapine’s effectiveness for PD psychosis at low dosages focused on the 5-HT2Areceptor. This idea was based on the knowledge that hallucinogens such as mescaline, psilocybin, and LSD are 5-HT2A agonists.⁹ This hallucinogenic activity can be blocked with 5-HT2A antagonists. Because of pimavanserin’s binding profile, the compound was studied as a treatment for psychosis in PD patients.

Pharmacokinetics

Pimavanserin demonstrates dose-proportional pharmacokinetics after a single oral dose as much as 7.5 times the recommended dosage. The pharmacokinetics of pimavanserin were similar in study participants (mean age, 72.4) and healthy controls, and a high-fat meal had no impact on the maximum blood levels (Cmax) or total drug exposure (area under the curve [AUC]).

The mean plasma half-lives for pimavanserin and its metabolite N-desmethyl-pimavanserin (AC-279) are 57 hours and 200 hours, respectively. Although the metabolite appears active in in vitro assays, it does not cross the blood-brain barrier to any appreciable extent, therefore contributing little to the clinical effect. The median time to maximum concentration (Tmax) of pimavanserin is 6 hours with a range of 4 to 24 hours, while the median Tmax of the primary metabolite AC-279 is 6 hours. The bioavailability of pimavanserin in an oral tablet or solution essentially is identical.

Pimavanserin is primarily metabolized via CYP3A4 to AC-279, and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, indinavir) increase pimavanserin Cmax by 1.5-fold, and AUC by 3-fold. In patients taking strong CYP3A4 inhibitors, the dosage of pimavanserin should be reduced by 50% to 17 mg/d. Conversely, patients on CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin) should be monitored for lack of efficacy; consider a dosage increase as necessary. Neither pimavanserin nor its metabolite, AC-279, are inhibitors or inducers of major CYP enzymes or drug transporters.

Efficacy in PD psychosis

Study 1. This 6-week, fixed dosage, double-blind, placebo-controlled trial was performed in adult PD patients age ≥40 with PD psychosis.² Participants had to have (1) a PD diagnosis for at least 1 year and (2) psychotic symptoms that developed after diagnosis. Psychotic symptoms had to be present for at least 1 month, occurring at least weekly in the month before screening, and severe enough to warrant antipsychotic treatment. Baseline Mini-Mental State Examination score had to be ≥21 out of 30, with no evidence of delirium. Patients with dementia preceding or concurrent with the PD diagnosis were excluded. Antipsychotic treatments were not permitted during the trial.

After a 2-week nonpharmacotherapeutic lead-in phase that included a brief, daily psychosocial intervention by a caregiver, 199 patients who still met severity criteria were randomly allocated in a 1:1 manner to pimavanserin (34 mg of active drug, reported in the paper as 40 mg of pimavanserin tartrate) or matched placebo. Based on kinetic modeling and earlier clinical data, lower dosages (ie, 17 mg) were not explored, because they achieved only 50% of the steady state plasma levels thought to be required for efficacy.

The primary outcome was assessed by central, independent raters using the PD-adapted SAPS-PD. The efficacy analysis included 95 pimavanserin-treated individuals and 90 taking placebo. Baseline SAPS-PD scores were 14.7 ± 5.55 in the placebo group, and 15.9 ± 6.12 in the pimavanserin arm. Participants had a mean age of 72.4 and 94% white ethnicity across both cohorts; 42% of the placebo group and 33% of the pimavanserin group were female. Antipsychotic exposure in the 21 days prior to study entry were reported in 17% (n = 15) and 19% (n = 18) of the placebo and pimavanserin groups, respectively, with the most common agent being quetiapine (13 of 15, placebo, 16 of 18, pimavanserin). Approximately one-third of all participants were taking a cholinesterase inhibitor throughout the study.

Efficacy outcome. Pimavanserin was associated with a 5.79-point decrease in SAPS-PD scores compared with 2.73-point decrease for placebo (difference −3.06, 95% CI −4.91 to −1.20; P = .001). The effect size for this difference (Cohen’s d) was 0.50. The significant effect of pimavanserin vs placebo also was seen in separate analyses of the SAPS-PD subscore for hallucinations and delusions (effect size 0.50), and individually for hallucinations (effect size 0.45) and delusions (effect size 0.33). Separation from placebo appeared after the second week of pimavanserin treatment, and continued through the end of the study. There is unpublished data showing efficacy through week 10, and longer term, uncontrolled data consistent with sustained response. An exploratory analysis of caregiver burden demonstrated an effect size of 0.50.

Tolerability

The discontinuation rate because of adverse events for pimavanserin and placebo-treated patients was 10 patients in the pimavanserin group (4 due to psychotic symptoms within 10 days of starting the study drug) compared with 2 in the placebo group. There was no evidence of motor worsening in either group, demonstrated by the score on part II of the Unified Parkinson’s Disease Rating Scale (UPDRS) that captures self-reported activities of daily living, or on UPDRS part III (motor examination). Pimavanserin has no contraindications.

Unique clinical issues

Binding properties. Pimavanserin possesses potent 5-HT2A inverse agonist properties required to manage psychosis in PD patients, but lacks clozapine’s affinities for α-1 adrenergic, muscarinic, or histaminergic receptors that contribute to clozapine’s poor tolerability. Moreover, pimavanserin has no appreciable affinity for dopaminergic receptors, and therefore does not induce motor adverse effects.

Clozapine aside, all available atypical antipsychotics have proved ineffective for psychosis in PD patients, and most caused significant motor worsening.³ Although quetiapine does not cause motor effects, it has been shown to be ineffective for psychosis in PD patients in multiple trials.⁴

The effect size for clozapine response is large (0.80) in PD patients with psychosis, but tolerability issues and administrative burdens regarding patient and prescriber registration and routine hematological monitoring pose significant clinical barriers. Clozapine also lacks an FDA indication for this purpose, which may pose a hurdle to its use in certain treatment settings.

Why Rx? The reasons to prescribe pimavanserin for PD patients with psychosis likely include:

• absence of tolerability issues seen with the only other effective agent, clozapine
• lack of motor effects
• lack of administrative and monitoring burden related to clozapine prescribing
• only agent with FDA approval for hallucinations and delusions in PD patients with psychosis.

Dosing

The recommended dosage of pimavanserin is 34 mg/d administered as a single dose with or without food. There is no need for titration, and none was performed in the pivotal clinical trial. Given the long half-life (57 hours), steady state is not achieved until day 12, therefore initiation with a lower dosage might prolong the time to efficacy. There is no dosage adjustment required in patients with mild or moderate renal impairment, but pimavanserin treatment is not recommended in patients with severe renal impairment. Pimavanserin has not been evaluated in patients with hepatic impairment (using Child-Pugh criteria), and is not recommended for these patients.

Other key aspects of dosing to keep in mind.

• Because pimavanserin is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a strong CYP3A4 inhibitor; the recommended dosage is 17 mg/d when administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of pimavanserin with CYP3A4 inducers, patients should be monitored for lack of efficacy during concomitant use with a CYP3A4 inducer, and consideration given to a dosage increase.

Use in pregnancy and lactation. There are no data on the use of pimavanserin in pregnant women, but no developmental effects were seen when the drug was administered orally at 10 or 12 times the maximum recommended human dosage to rats or rabbits during organogenesis. Pimavanserin was not teratogenic in pregnant rats and rabbits. There is no information regarding the presence of pimavanserin in human breast milk.

Geriatric patients. No dosage adjustment is required for older patients. The study population in the pivotal trial was mean age 72.4 years.

Summing up

Before development of pimavanserin, clozapine was the only effective treatment for psychosis in PD patients. Despite clozapine’s robust effects across several trials, patients often were given ineffective medications, such as quetiapine, because of the administrative and tolerability barriers posed by clozapine use. Because psychosis is the most common cause of nursing home placement in non-demented PD patients, an agent with demonstrated efficacy and without the adverse effect profile of clozapine or monitoring requirements represents an enormous advance in the treatment of psychosis in PD patients.

Pimavanserin is a potent 5-HT2A inverse agonist and 5-HT2C inverse agonist, with 5-fold greater affinity for the 5-HT2A receptor.¹ Although antagonists block agonist actions at the receptor site, inverse agonists reduce the level of baseline constitutive activity seen in many G protein-coupled receptors. This medication is FDA approved for treating hallucinations and delusions associated with Parkinson’s disease (PD) psychosis (Table 1).¹

In the pivotal 6-week clinical trial, pimavanserin significantly reduced positive symptoms seen in PD patients with psychosis (effect size = 0.50), with no evident impairment of motor function.² Only 2 adverse effects occurred in ≥5% of pimavanserin-treated patients and at ≥2 times the rate of placebo: peripheral edema (7% vs 3% for placebo) and confusion (6% vs 3% for placebo). There was a mean increase in the QTc of 7.3 milliseconds compared with placebo in the pivotal phase III study.

Clinical implications

Despite numerous developments in the pharmacotherapeutics of psychotic disorders, patients with psychosis related to PD previously responded in a robust manner to only 1 antipsychotic, low-dosage clozapine (mean effect size, 0.80),² with numerous failed trials for other atypical antipsychotics, including quetiapine.^3,4 The pathophysiology of psychosis in PD patients is not related to dopamine agonist treatment, but is caused by the accumulation of cortical Lewy body burden, which results in loss of serotonergic signaling from dorsal raphe neurons. The net effect is up-regulation of postsynaptic 5-HT2A receptors.⁵ Psychosis is the most common cause of nursing home placement among PD patients without dementia.⁶

Receptor blocking. Based on the finding that clozapine in low dosages acts at 5-HT2A receptors,⁷ pimavanserin was designed to be a potent 5-HT2A inverse agonist, with more than 5-fold higher selectivity over 5-HT2C receptors, and no appreciable affinity for other serotonergic, adrenergic, dopaminergic, muscarinic, or histaminergic receptors⁸ (Table 2). The concept that 5-HT2A receptor stimulation can cause psychosis with prominent visual hallucinations is known from studies of LSD and other hallucinogenic compounds whose activity is blocked by 5-HT2A antagonists.

As an agent devoid of dopamine D2 antagonism, pimavanserin carries no risk of exacerbating motor symptoms, which was commonly seen with most atypical antipsychotics studied for psychosis in PD patients, except for clozapine and quetiapine.³ Although quetiapine did not cause motor effects, it proved ineffective in multiple studies (n = 153), likely because of the near absence of potent 5-HT2A binding.⁴

Pimavanserin also lacks:

• the hematologic monitoring requirement of clozapine
• clozapine’s risks of sedation, orthostasis, and anticholinergic and metabolic adverse effects.

Pimavanserin is significantly more potent than other non-antipsychotic psychotropics at the 5-HT2Areceptor, including doxepin (26 nM), trazodone (36 nM), and mirtazapine (60 nM).

Use in psychosis associated with PD. Recommended dosage is 34 mg once daily without titration (with or without food), based on results from a phase III clinical trial² (because of the FDA breakthrough therapy designation for this compound, only 1 phase III trial was required). Pimavanserin produced significant improvement on the PD-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD), a 9-item instrument extracted from the larger SAPS used in schizophrenia research. Specifically, pimavanserin was effective for both the hallucinations and delusions components of the SAPS-PD.

Pharmacologic profile, adverse effects. Pimavanserin lacks affinity for receptors other than 5-HT2A and 5-HT2C, leading to an absence of significant anticholinergic effects, orthostasis, or sedation in clinical trials.² In all short-term clinical trials, the only common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were peripheral edema (7% vs 2% placebo) and confusional state (6% vs 3% placebo).² More than 300 patients have been treated for >6 months, >270 have been treated for at least 12 months, and >150 have been treated for at least 24 months with no adverse effects other than those seen in the short-term trials.¹

There is a measurable impact on cardiac conduction seen in phase III data and in the thorough QT study. In the thorough QT study, 252 healthy participants received multiple dosages in a randomized, double-blind manner with positive controls.¹ The maximum mean change from baseline was 13.5 milliseconds at dosages twice the recommended dosage, and the upper limit of the 90% CI was only slightly greater at 16.6 milliseconds. Subsequent kinetic analyses suggested concentration-dependent QTc interval prolongation in the therapeutic range, with a recommendation to halve the daily dosage in patients taking potent cytochrome P450 (CYP) 3A4 inhibitors.

In the 6-week, placebo-controlled effectiveness studies, mean increases in QTc interval were in the range of 5 to 8 milliseconds. There were sporadic reports of QTcF values ≥500 milliseconds, or changes from baseline QTc values ≥60 milliseconds in pimavanserin-treated participants, although the incidence generally was the same for pimavanserin and placebo groups. There were no reports of torsades de pointes or any differences from placebo in the incidence of adverse reactions associated with delayed ventricular repolarization.

How it works

The theory behind development of pimavanserin rests in the finding that low-dosage clozapine (6.25 to 50 mg/d) was effective for PD patients with psychosis (effect size 0.80).⁸ Although clozapine has high affinity for multiple sites, including histamine H1 receptors (Ki = 1.13 nM), α-1A and a α-2C adrenergic receptors (Ki = 1.62 nM and 6 nM, respectively), 5-HT2A receptors (Ki = 5.35 nM), and muscarinic M1 receptors (Ki = 6 nM), the hypothesized primary mechanism of clozapine’s effectiveness for PD psychosis at low dosages focused on the 5-HT2Areceptor. This idea was based on the knowledge that hallucinogens such as mescaline, psilocybin, and LSD are 5-HT2A agonists.⁹ This hallucinogenic activity can be blocked with 5-HT2A antagonists. Because of pimavanserin’s binding profile, the compound was studied as a treatment for psychosis in PD patients.

Pharmacokinetics

Pimavanserin demonstrates dose-proportional pharmacokinetics after a single oral dose as much as 7.5 times the recommended dosage. The pharmacokinetics of pimavanserin were similar in study participants (mean age, 72.4) and healthy controls, and a high-fat meal had no impact on the maximum blood levels (Cmax) or total drug exposure (area under the curve [AUC]).

The mean plasma half-lives for pimavanserin and its metabolite N-desmethyl-pimavanserin (AC-279) are 57 hours and 200 hours, respectively. Although the metabolite appears active in in vitro assays, it does not cross the blood-brain barrier to any appreciable extent, therefore contributing little to the clinical effect. The median time to maximum concentration (Tmax) of pimavanserin is 6 hours with a range of 4 to 24 hours, while the median Tmax of the primary metabolite AC-279 is 6 hours. The bioavailability of pimavanserin in an oral tablet or solution essentially is identical.

Pimavanserin is primarily metabolized via CYP3A4 to AC-279, and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, indinavir) increase pimavanserin Cmax by 1.5-fold, and AUC by 3-fold. In patients taking strong CYP3A4 inhibitors, the dosage of pimavanserin should be reduced by 50% to 17 mg/d. Conversely, patients on CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin) should be monitored for lack of efficacy; consider a dosage increase as necessary. Neither pimavanserin nor its metabolite, AC-279, are inhibitors or inducers of major CYP enzymes or drug transporters.

Efficacy in PD psychosis

Study 1. This 6-week, fixed dosage, double-blind, placebo-controlled trial was performed in adult PD patients age ≥40 with PD psychosis.² Participants had to have (1) a PD diagnosis for at least 1 year and (2) psychotic symptoms that developed after diagnosis. Psychotic symptoms had to be present for at least 1 month, occurring at least weekly in the month before screening, and severe enough to warrant antipsychotic treatment. Baseline Mini-Mental State Examination score had to be ≥21 out of 30, with no evidence of delirium. Patients with dementia preceding or concurrent with the PD diagnosis were excluded. Antipsychotic treatments were not permitted during the trial.

After a 2-week nonpharmacotherapeutic lead-in phase that included a brief, daily psychosocial intervention by a caregiver, 199 patients who still met severity criteria were randomly allocated in a 1:1 manner to pimavanserin (34 mg of active drug, reported in the paper as 40 mg of pimavanserin tartrate) or matched placebo. Based on kinetic modeling and earlier clinical data, lower dosages (ie, 17 mg) were not explored, because they achieved only 50% of the steady state plasma levels thought to be required for efficacy.

The primary outcome was assessed by central, independent raters using the PD-adapted SAPS-PD. The efficacy analysis included 95 pimavanserin-treated individuals and 90 taking placebo. Baseline SAPS-PD scores were 14.7 ± 5.55 in the placebo group, and 15.9 ± 6.12 in the pimavanserin arm. Participants had a mean age of 72.4 and 94% white ethnicity across both cohorts; 42% of the placebo group and 33% of the pimavanserin group were female. Antipsychotic exposure in the 21 days prior to study entry were reported in 17% (n = 15) and 19% (n = 18) of the placebo and pimavanserin groups, respectively, with the most common agent being quetiapine (13 of 15, placebo, 16 of 18, pimavanserin). Approximately one-third of all participants were taking a cholinesterase inhibitor throughout the study.

Efficacy outcome. Pimavanserin was associated with a 5.79-point decrease in SAPS-PD scores compared with 2.73-point decrease for placebo (difference −3.06, 95% CI −4.91 to −1.20; P = .001). The effect size for this difference (Cohen’s d) was 0.50. The significant effect of pimavanserin vs placebo also was seen in separate analyses of the SAPS-PD subscore for hallucinations and delusions (effect size 0.50), and individually for hallucinations (effect size 0.45) and delusions (effect size 0.33). Separation from placebo appeared after the second week of pimavanserin treatment, and continued through the end of the study. There is unpublished data showing efficacy through week 10, and longer term, uncontrolled data consistent with sustained response. An exploratory analysis of caregiver burden demonstrated an effect size of 0.50.

Tolerability

The discontinuation rate because of adverse events for pimavanserin and placebo-treated patients was 10 patients in the pimavanserin group (4 due to psychotic symptoms within 10 days of starting the study drug) compared with 2 in the placebo group. There was no evidence of motor worsening in either group, demonstrated by the score on part II of the Unified Parkinson’s Disease Rating Scale (UPDRS) that captures self-reported activities of daily living, or on UPDRS part III (motor examination). Pimavanserin has no contraindications.

Unique clinical issues

Binding properties. Pimavanserin possesses potent 5-HT2A inverse agonist properties required to manage psychosis in PD patients, but lacks clozapine’s affinities for α-1 adrenergic, muscarinic, or histaminergic receptors that contribute to clozapine’s poor tolerability. Moreover, pimavanserin has no appreciable affinity for dopaminergic receptors, and therefore does not induce motor adverse effects.

Clozapine aside, all available atypical antipsychotics have proved ineffective for psychosis in PD patients, and most caused significant motor worsening.³ Although quetiapine does not cause motor effects, it has been shown to be ineffective for psychosis in PD patients in multiple trials.⁴

The effect size for clozapine response is large (0.80) in PD patients with psychosis, but tolerability issues and administrative burdens regarding patient and prescriber registration and routine hematological monitoring pose significant clinical barriers. Clozapine also lacks an FDA indication for this purpose, which may pose a hurdle to its use in certain treatment settings.

Why Rx? The reasons to prescribe pimavanserin for PD patients with psychosis likely include:

• absence of tolerability issues seen with the only other effective agent, clozapine
• lack of motor effects
• lack of administrative and monitoring burden related to clozapine prescribing
• only agent with FDA approval for hallucinations and delusions in PD patients with psychosis.

Dosing

The recommended dosage of pimavanserin is 34 mg/d administered as a single dose with or without food. There is no need for titration, and none was performed in the pivotal clinical trial. Given the long half-life (57 hours), steady state is not achieved until day 12, therefore initiation with a lower dosage might prolong the time to efficacy. There is no dosage adjustment required in patients with mild or moderate renal impairment, but pimavanserin treatment is not recommended in patients with severe renal impairment. Pimavanserin has not been evaluated in patients with hepatic impairment (using Child-Pugh criteria), and is not recommended for these patients.

Other key aspects of dosing to keep in mind.

• Because pimavanserin is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a strong CYP3A4 inhibitor; the recommended dosage is 17 mg/d when administered concomitantly with a strong CYP3A4 inhibitor.
• Because data are not available regarding concomitant use of pimavanserin with CYP3A4 inducers, patients should be monitored for lack of efficacy during concomitant use with a CYP3A4 inducer, and consideration given to a dosage increase.

Use in pregnancy and lactation. There are no data on the use of pimavanserin in pregnant women, but no developmental effects were seen when the drug was administered orally at 10 or 12 times the maximum recommended human dosage to rats or rabbits during organogenesis. Pimavanserin was not teratogenic in pregnant rats and rabbits. There is no information regarding the presence of pimavanserin in human breast milk.

Geriatric patients. No dosage adjustment is required for older patients. The study population in the pivotal trial was mean age 72.4 years.

Summing up

Before development of pimavanserin, clozapine was the only effective treatment for psychosis in PD patients. Despite clozapine’s robust effects across several trials, patients often were given ineffective medications, such as quetiapine, because of the administrative and tolerability barriers posed by clozapine use. Because psychosis is the most common cause of nursing home placement in non-demented PD patients, an agent with demonstrated efficacy and without the adverse effect profile of clozapine or monitoring requirements represents an enormous advance in the treatment of psychosis in PD patients.

Although there has been success in defining the minimum therapeu­tic response threshold for certain antipsychotics—for example, clozap­ine (350 to 450 ng/mL), haloperidol (3 to 5 ng/mL), and fluphenazine (0.8 ng/mL)—one aspect of antipsychotic plasma levels not widely discussed is their value as a marker of adherence.

Many schizophrenia patients achieve an optimal response to agents for which there is no depot formulation. For them, maintenance of symptom con­trol depends wholly on oral medication adherence.¹ Regrettably, nonadherence with oral antipsychotic treatment is prevalent among patients with schizo­phrenia; yet, in routine clinical practice, the extent of nonadherence rarely is measured.

Studies have been able to quantify oral medication nonadherence using moni­toring devices, such as the Medication Event Monitoring System (MEMS) that electronically records opening of the medication container and strongly cor­relates with pill count. Although patients knew they were participating in a trial using MEMS technology, only 48% were able to take their medication at least 80% of the time in a 4-week study,² and only 43% met the 70% adherence threshold in a 6-month trial.³

Clinicians, patients: Unreliable indicators of adherence
Neither clinician rating nor patient self-reporting is a reliable predictor of adherence with an oral medication regimen. In the 6-month adherence trial,³ clinicians estimated that 95% of their patients met the 70% adherence threshold (the actual percentage was 43%); in a 12-week study, clinician rat­ings correlated weakly with adherence (r = 0.32; P = .001), but patient self-reporting showed no significant correla­tion (r = 0.18; P = .08) with pill count.⁴

Clinicians underestimate not only the extent of nonadherence but also the impact that even a brief period of modest nonadherence has on the risk of relapse. In an 18-month prospec­tive study of patients who recently had been given a diagnosis of schizo­phrenia, and in whom clinician and patient reports were supplemented with a pill count every 1 to 2 weeks and plasma antipsychotic levels every 4 weeks, any period of at least mild nonadherence was significantly pre­dictive of symptom exacerbation or relapse (hazard ratio [HR], 3.4; 95% CI, 1.4–8.4; P < .002).¹ Moreover, 50% to 75% adherence for ≥ 2 consecutive weeks increased the HR to 5.8, and moderate nonadherence (<50% for 2.0 to 3.9 weeks) to an HR of 28.5.

There might be a better method already available
Given the poor correlation between a cli­nician’s judgment and a patient’s actual pill-taking, it is clear that more accurate methods of tracking adherence must be devised. Because MEMS technology is not widely available, and because pill counts require a home visit or a coop­erative patient who brings medications to office visits, plasma antipsychotic monitoring potentially is an appealing method of tracking adherence.

Correlation between the plasma antipsychotic level and relapse is not consistently seen in the literature,⁴ but plasma levels obtained during periods of clinical stability offer the opportunity to define, for the individual patient, a range of drug exposure that is associated with clinical response. The ideal plasma level baseline is obtained at steady state during a presumed period of observed adherence, such as during a hospital stay. Although patients can be nonadherent in the hospital, this setting offers the best proxy for an acute clinical response to a given plasma level. The alternative is to obtain several plasma levels during a period of outpatient clinical stability.

Clinicians must be mindful that changes in the plasma antipsychotic level after hospital discharge might not reflect poor adherence; environmental factors (eg, exposure to cytochrome P450 or P-glycoprotein inducers) can have a sig­nificant impact on results. Resumption of smoking is a classic example, and rou­tinely is associated with a 50% reduction in plasma clozapine levels.5

There also is expected variability in plasma antipsychotic levels based on (1) the timing of prior doses with regard to trough levels, and (2) the effects of an occasional missed dose. Nevertheless, in a sample of adherent clozapine-treated patients, investigators found that 98% of patients had a coefficient of variability (CV) of 30% for sequential plasma con­centrations (mean CV, 14%).⁶

Clinicians should inform patients that the plasma antipsychotic level is a tool for helping track treatment engagement before relapse—the same way metabolic monitoring helps track abnormalities that can be associated with future cardiovascular events. (Clinicians also must be charitable with their patients when discussing a significant drop in the plasma antipsychotic level [eg, >30%], acknowledging that many patients often miss doses.)

Using the patient’s input about specific difficulties with a medication regimen, clinicians should strive to find ways to improve oral medication adherence. In many cases, the clinician can assist through medication simplifi­cation, consolidation of multiple daily doses, provision of pill boxes, and dis­cussions about long-acting injectable (LAI) antipsychotics.

In short, plasma antipsychotic levels offer an opportunity to have a richer, evidence-based discussion about adherence, beyond the trite, ineffective question “Did you take your medica­tion?” Use of an objective measure can (1) serve as a benchmark for the patient (eg, “You seemed to do better when your clozapine level was above 400 ng/mL”), and (2) remind clinicians of the variable adherence inherent with oral medication regimens.

A note about long-acting injectable antipsychotics
Because nonadherence is seen through­out the course of schizophrenia, dis­cussion of LAI therapy should not be limited to patients with chronic ill­ness. Results of recent naturalistic⁷ and randomized studies8 show significant reduction in the rate of psychotic relapse and improved symptom control⁸ among first-episode patients who are taking an LAI. Moreover, compelling data show that most first-episode patients who are taking an oral antipsychotic will accept a recommendation for treatment with an LAI.⁹

Summing up: 2 Tools for achieving therapeutic success
Monitoring plasma levels of antipsy­chotics offers a method for quantifying the problem of nonadherence. For many patients, an LAI antipsychotic provides a solution to nonadherence, and the increasing variety of LAI preparations means more options with which to match individual patients.

Clinicians have a limited amount of time to spend with patients in the office, but time spent discussing LAIs is an investment in the patient’s stability and functional outcome. Minutes once spent managing nonadherence can be devoted to understanding the patient’s aspirations and to developing strategies to achieve those goals.

In the end, isn’t that what we’d rather be talking about with our patients?

Although there has been success in defining the minimum therapeu­tic response threshold for certain antipsychotics—for example, clozap­ine (350 to 450 ng/mL), haloperidol (3 to 5 ng/mL), and fluphenazine (0.8 ng/mL)—one aspect of antipsychotic plasma levels not widely discussed is their value as a marker of adherence.

Many schizophrenia patients achieve an optimal response to agents for which there is no depot formulation. For them, maintenance of symptom con­trol depends wholly on oral medication adherence.¹ Regrettably, nonadherence with oral antipsychotic treatment is prevalent among patients with schizo­phrenia; yet, in routine clinical practice, the extent of nonadherence rarely is measured.

Studies have been able to quantify oral medication nonadherence using moni­toring devices, such as the Medication Event Monitoring System (MEMS) that electronically records opening of the medication container and strongly cor­relates with pill count. Although patients knew they were participating in a trial using MEMS technology, only 48% were able to take their medication at least 80% of the time in a 4-week study,² and only 43% met the 70% adherence threshold in a 6-month trial.³

Clinicians, patients: Unreliable indicators of adherence
Neither clinician rating nor patient self-reporting is a reliable predictor of adherence with an oral medication regimen. In the 6-month adherence trial,³ clinicians estimated that 95% of their patients met the 70% adherence threshold (the actual percentage was 43%); in a 12-week study, clinician rat­ings correlated weakly with adherence (r = 0.32; P = .001), but patient self-reporting showed no significant correla­tion (r = 0.18; P = .08) with pill count.⁴

Clinicians underestimate not only the extent of nonadherence but also the impact that even a brief period of modest nonadherence has on the risk of relapse. In an 18-month prospec­tive study of patients who recently had been given a diagnosis of schizo­phrenia, and in whom clinician and patient reports were supplemented with a pill count every 1 to 2 weeks and plasma antipsychotic levels every 4 weeks, any period of at least mild nonadherence was significantly pre­dictive of symptom exacerbation or relapse (hazard ratio [HR], 3.4; 95% CI, 1.4–8.4; P < .002).¹ Moreover, 50% to 75% adherence for ≥ 2 consecutive weeks increased the HR to 5.8, and moderate nonadherence (<50% for 2.0 to 3.9 weeks) to an HR of 28.5.

There might be a better method already available
Given the poor correlation between a cli­nician’s judgment and a patient’s actual pill-taking, it is clear that more accurate methods of tracking adherence must be devised. Because MEMS technology is not widely available, and because pill counts require a home visit or a coop­erative patient who brings medications to office visits, plasma antipsychotic monitoring potentially is an appealing method of tracking adherence.

Correlation between the plasma antipsychotic level and relapse is not consistently seen in the literature,⁴ but plasma levels obtained during periods of clinical stability offer the opportunity to define, for the individual patient, a range of drug exposure that is associated with clinical response. The ideal plasma level baseline is obtained at steady state during a presumed period of observed adherence, such as during a hospital stay. Although patients can be nonadherent in the hospital, this setting offers the best proxy for an acute clinical response to a given plasma level. The alternative is to obtain several plasma levels during a period of outpatient clinical stability.

Clinicians must be mindful that changes in the plasma antipsychotic level after hospital discharge might not reflect poor adherence; environmental factors (eg, exposure to cytochrome P450 or P-glycoprotein inducers) can have a sig­nificant impact on results. Resumption of smoking is a classic example, and rou­tinely is associated with a 50% reduction in plasma clozapine levels.5

There also is expected variability in plasma antipsychotic levels based on (1) the timing of prior doses with regard to trough levels, and (2) the effects of an occasional missed dose. Nevertheless, in a sample of adherent clozapine-treated patients, investigators found that 98% of patients had a coefficient of variability (CV) of 30% for sequential plasma con­centrations (mean CV, 14%).⁶

Clinicians should inform patients that the plasma antipsychotic level is a tool for helping track treatment engagement before relapse—the same way metabolic monitoring helps track abnormalities that can be associated with future cardiovascular events. (Clinicians also must be charitable with their patients when discussing a significant drop in the plasma antipsychotic level [eg, >30%], acknowledging that many patients often miss doses.)

Using the patient’s input about specific difficulties with a medication regimen, clinicians should strive to find ways to improve oral medication adherence. In many cases, the clinician can assist through medication simplifi­cation, consolidation of multiple daily doses, provision of pill boxes, and dis­cussions about long-acting injectable (LAI) antipsychotics.

In short, plasma antipsychotic levels offer an opportunity to have a richer, evidence-based discussion about adherence, beyond the trite, ineffective question “Did you take your medica­tion?” Use of an objective measure can (1) serve as a benchmark for the patient (eg, “You seemed to do better when your clozapine level was above 400 ng/mL”), and (2) remind clinicians of the variable adherence inherent with oral medication regimens.

A note about long-acting injectable antipsychotics
Because nonadherence is seen through­out the course of schizophrenia, dis­cussion of LAI therapy should not be limited to patients with chronic ill­ness. Results of recent naturalistic⁷ and randomized studies8 show significant reduction in the rate of psychotic relapse and improved symptom control⁸ among first-episode patients who are taking an LAI. Moreover, compelling data show that most first-episode patients who are taking an oral antipsychotic will accept a recommendation for treatment with an LAI.⁹

Summing up: 2 Tools for achieving therapeutic success
Monitoring plasma levels of antipsy­chotics offers a method for quantifying the problem of nonadherence. For many patients, an LAI antipsychotic provides a solution to nonadherence, and the increasing variety of LAI preparations means more options with which to match individual patients.

Clinicians have a limited amount of time to spend with patients in the office, but time spent discussing LAIs is an investment in the patient’s stability and functional outcome. Minutes once spent managing nonadherence can be devoted to understanding the patient’s aspirations and to developing strategies to achieve those goals.

In the end, isn’t that what we’d rather be talking about with our patients?

Although there has been success in defining the minimum therapeu­tic response threshold for certain antipsychotics—for example, clozap­ine (350 to 450 ng/mL), haloperidol (3 to 5 ng/mL), and fluphenazine (0.8 ng/mL)—one aspect of antipsychotic plasma levels not widely discussed is their value as a marker of adherence.

Many schizophrenia patients achieve an optimal response to agents for which there is no depot formulation. For them, maintenance of symptom con­trol depends wholly on oral medication adherence.¹ Regrettably, nonadherence with oral antipsychotic treatment is prevalent among patients with schizo­phrenia; yet, in routine clinical practice, the extent of nonadherence rarely is measured.

Studies have been able to quantify oral medication nonadherence using moni­toring devices, such as the Medication Event Monitoring System (MEMS) that electronically records opening of the medication container and strongly cor­relates with pill count. Although patients knew they were participating in a trial using MEMS technology, only 48% were able to take their medication at least 80% of the time in a 4-week study,² and only 43% met the 70% adherence threshold in a 6-month trial.³

Clinicians, patients: Unreliable indicators of adherence
Neither clinician rating nor patient self-reporting is a reliable predictor of adherence with an oral medication regimen. In the 6-month adherence trial,³ clinicians estimated that 95% of their patients met the 70% adherence threshold (the actual percentage was 43%); in a 12-week study, clinician rat­ings correlated weakly with adherence (r = 0.32; P = .001), but patient self-reporting showed no significant correla­tion (r = 0.18; P = .08) with pill count.⁴

Clinicians underestimate not only the extent of nonadherence but also the impact that even a brief period of modest nonadherence has on the risk of relapse. In an 18-month prospec­tive study of patients who recently had been given a diagnosis of schizo­phrenia, and in whom clinician and patient reports were supplemented with a pill count every 1 to 2 weeks and plasma antipsychotic levels every 4 weeks, any period of at least mild nonadherence was significantly pre­dictive of symptom exacerbation or relapse (hazard ratio [HR], 3.4; 95% CI, 1.4–8.4; P < .002).¹ Moreover, 50% to 75% adherence for ≥ 2 consecutive weeks increased the HR to 5.8, and moderate nonadherence (<50% for 2.0 to 3.9 weeks) to an HR of 28.5.

There might be a better method already available
Given the poor correlation between a cli­nician’s judgment and a patient’s actual pill-taking, it is clear that more accurate methods of tracking adherence must be devised. Because MEMS technology is not widely available, and because pill counts require a home visit or a coop­erative patient who brings medications to office visits, plasma antipsychotic monitoring potentially is an appealing method of tracking adherence.

Correlation between the plasma antipsychotic level and relapse is not consistently seen in the literature,⁴ but plasma levels obtained during periods of clinical stability offer the opportunity to define, for the individual patient, a range of drug exposure that is associated with clinical response. The ideal plasma level baseline is obtained at steady state during a presumed period of observed adherence, such as during a hospital stay. Although patients can be nonadherent in the hospital, this setting offers the best proxy for an acute clinical response to a given plasma level. The alternative is to obtain several plasma levels during a period of outpatient clinical stability.

Clinicians must be mindful that changes in the plasma antipsychotic level after hospital discharge might not reflect poor adherence; environmental factors (eg, exposure to cytochrome P450 or P-glycoprotein inducers) can have a sig­nificant impact on results. Resumption of smoking is a classic example, and rou­tinely is associated with a 50% reduction in plasma clozapine levels.5

There also is expected variability in plasma antipsychotic levels based on (1) the timing of prior doses with regard to trough levels, and (2) the effects of an occasional missed dose. Nevertheless, in a sample of adherent clozapine-treated patients, investigators found that 98% of patients had a coefficient of variability (CV) of 30% for sequential plasma con­centrations (mean CV, 14%).⁶

Clinicians should inform patients that the plasma antipsychotic level is a tool for helping track treatment engagement before relapse—the same way metabolic monitoring helps track abnormalities that can be associated with future cardiovascular events. (Clinicians also must be charitable with their patients when discussing a significant drop in the plasma antipsychotic level [eg, >30%], acknowledging that many patients often miss doses.)

Using the patient’s input about specific difficulties with a medication regimen, clinicians should strive to find ways to improve oral medication adherence. In many cases, the clinician can assist through medication simplifi­cation, consolidation of multiple daily doses, provision of pill boxes, and dis­cussions about long-acting injectable (LAI) antipsychotics.

In short, plasma antipsychotic levels offer an opportunity to have a richer, evidence-based discussion about adherence, beyond the trite, ineffective question “Did you take your medica­tion?” Use of an objective measure can (1) serve as a benchmark for the patient (eg, “You seemed to do better when your clozapine level was above 400 ng/mL”), and (2) remind clinicians of the variable adherence inherent with oral medication regimens.

A note about long-acting injectable antipsychotics
Because nonadherence is seen through­out the course of schizophrenia, dis­cussion of LAI therapy should not be limited to patients with chronic ill­ness. Results of recent naturalistic⁷ and randomized studies8 show significant reduction in the rate of psychotic relapse and improved symptom control⁸ among first-episode patients who are taking an LAI. Moreover, compelling data show that most first-episode patients who are taking an oral antipsychotic will accept a recommendation for treatment with an LAI.⁹

Summing up: 2 Tools for achieving therapeutic success
Monitoring plasma levels of antipsy­chotics offers a method for quantifying the problem of nonadherence. For many patients, an LAI antipsychotic provides a solution to nonadherence, and the increasing variety of LAI preparations means more options with which to match individual patients.

Clinicians have a limited amount of time to spend with patients in the office, but time spent discussing LAIs is an investment in the patient’s stability and functional outcome. Minutes once spent managing nonadherence can be devoted to understanding the patient’s aspirations and to developing strategies to achieve those goals.

In the end, isn’t that what we’d rather be talking about with our patients?

To recap what I discussed in Part 1 of this article (December 2014): As part of a trend across all medical specialty boards, the American Board of Psychiatry and Neurology (ABPN) instituted a recertification pro­cess for all new general psychiatry certifications, starting October 1, 1994.¹ In 2000, the specialties that comprise the American Board of Medical Specialties (ABMS) agreed to develop a comprehensive maintenance of certification (MOC) process to demonstrate ongoing learning and com­petency beyond what can be captured by a recertification examination. All ABMS member boards now use a 4-part process for recertification.

A great deal of professional and personal importance has been attached to maintaining one’s general and sub­specialty certifications. To that end, the 2 parts of this article highlight current ABPN MOC requirements and provide resources for understanding, tracking, and completing the self-assessment (SA) and performance-in-practice (PIP) components.

In this installment, I examine 3 components of MOC:
   • continuing medical education (CME), including SA requirements
   • improvement in medical practice (PIP)
   • continuous maintenance of certification (C-MOC)

In addition to this review, all physicians who are subject to MOC should download and read the 20-page revised MOC Program booklet v. 2.1 (May 2014).²

Continuing medical education
The CME requirement is clear: All diplo­mate physicians must accrue, on average, 30 Category-1 CME credits a year; the CME must be relevant to the specialty or subspecialty in which the diplomate prac­tices.³ For physicians who hold >1 ABPN certificates, the total CME requirement is the same; CME credits can be applied across each specialty and subspecialty.

The May 2014 MOC revision states that, for physicians who certified or recertified between 2005 and 2011 and who applied for the 2015 examination in 2014, the required CME credit total is 270.2 For all subsequent years of certification or recertification, including 2012, diplomates are enrolled in C-MOC, which is described below.²

To even out the accrual of CME credits across the prior 10 years, ABPN mandates that, for diplomates who certified or recer­tified between 2005 and 2011, one hundred fifty of the CME credits be accrued in the 5 years before they apply for the examina­tion. Diplomates in C-MOC should accrue, on average, 30 CME credits a year in each of the 3-year blocks (ie, 90 units in each block).²

Self-assessment
SA is a specific form of CME that is designed to provide comprehensive test-based feedback on knowledge acquired, to enhance the learning process.⁴ SA CME feedback must include:
   • the correct answer to each test question
   • recommended literature resources for each question
   • performance compared to peers on each question.

Given the structured nature of SA activi­ties, beginning January 1, 2014, one must use only ABPN-approved SA products (see Related Resources for a list of APBN-approved SA products).⁵

Table 1 and Table 2 outline SA require­ments for, respectively, physicians who certified or recertified from 2005 through 2011, and those who certified or recertified in 2012 (and later). The SA requirement increases after 2011 to 24 credits in each 3-year block (8 credits a year, on average).² Multiple SA activities can be used to fulfill the credit requirement of each 3-year block.

Improvement in medical practice, or PIP
Physicians who are active clinically must complete PIP modules. Each module comprises peer or patient feedback plus a clinical aspect. The May 2014 MOC revi­sion simplified the feedback process to mandate peer or patient feedback—but not both, as required previously.² For the feedback PIP module, the physician selects 5 peers or patients to complete review forms, examines the results, and creates a plan of improvement. An exception to this “rule of 5” applies to diplomates who have a supervisor capable of evaluating all gen­eral competencies, defined below.

Related Resources provides a link to ABPN-created forms.

Within 24 months, but not sooner than 1 month, 5 peers or patients (or 1 appli­cable supervisor) are selected to complete review forms; changes in practice are noted. The same peers or patients might be selected for a second review. As noted in Table 1 and Table 2, the number of PIP modules is fewer for physicians who certi­fied or recertified between 2005 and 2011; from 2012 onward, 1 PIP clinical module is required in each 3-year block.²

There are 6 ABPN-approved feedback module options, of which the diplomate must choose 1 in any given block²:
   • 5 patient surveys
   • 5 peer evaluations of general competencies^a
   • 5 resident evaluations of general competencies^a  
   • 360° evaluation of general competencies,a with 5 respondents
   • institutional peer review of general competencies,^a with 5 respondents
   • 1 supervisor evaluation of general competencies.^a

^aGeneral competencies include patient care; practice-based learning and improvement; professionalism; medical knowledge; interpersonal and communication skills; and system-based practices.

Although many institutions have a quality improvement (QI) program, that program must be approved by the Multi-Specialty MOC Portfolio Approval Program sponsored by ABMS for a clinician to receive credit for 1 PIP clinical module. If the approved QI program includes patient or peer feedback (eg, a survey), the diplo­ mate can receive credit for 1 PIP feedback module.²

For the clinical PIP module, the physician selects 5 charts for review and examines them based on criteria found in an ABPN-approved (starting in 2014) PIP product. (Related Resources provides a link to this list.) After reviewing the initial 5 charts, a plan for improvement is created. Within 24 months, but no sooner than 1 month, 5 charts are again selected and reviewed, and changes in practice are noted. The same charts can be selected for the second review.

As noted in Table 1 and Table 2, the number of PIP modules is fewer for those who initially certified or recertified between 2005 and 2011; from 2012 onward, 1 PIP clinical module is required in each 3-year block.²


The C-MOC process
Physicians who certified or recertified in 2012, or who will certify or recertify after that year, are enrolled automatically in C-MOC.^6,7 The purpose of C-MOC is to keep diplomates on track to fulfill the higher level of SA requirements that began with this group; this is done by mandating use of the ABPN Physician Folios system. As shown in Table 2, there is no longer a 10-year cycle; instead, there are continuous 3-year stages, within which each diplomate must accrue 90 CME cred­its (on average, 30 credits a year), 24 SA credits (on average, 8 a year), 1 PIP clinical module, and 1 PIP feedback module.^6,7

The first 3-year block of C-MOC require­ments will be waived for physicians who complete Accreditation Council on Graduate Medical Education–accredited or ABPN-approved subspecialty training in 2012 or later—if they pass the corre­sponding ABPN subspecialty examination during the first 3-year block of enrollment in C-MOC.2 For diplomates enrolled in C-MOC, failure to track progress of each 3-year block, via the ABPN Physician Folios system, has significant consequences: Those who do not complete the first stage of the program by the end of 3 years will be listed on the ABPN Web site as “certified— not meeting MOC requirements.” Those who do not complete 2 stages by the end of 6 years will be listed as “not certified.”²

Cognitive exam still in place. The only remnant of the old 10-year cycle is the requirement to pass the cognitive examina­tion every 10 years, although the exam can be taken earlier if the diplomate wishes. If all requirements are met and one does not sit for, or fails, the exam, the ABPN Web site will report the diplomate as “not meet­ing MOC requirements.” One can retake the exam within 1 year of the failed or missed exam, but a subsequent failure or missed exam will result in being listed as “not certified.”²

Fee structure. Instead of a single fee paid at the time of the exam(s), physicians in the C-MOC program pay an annual fee that covers participation in ABPN Physician Folios and 1 exam in a 10-year period. Fewer than 10 years of participation, or applying for a combined examination (for diplomates who hold multiple certifica­tions), requires an additional fee.⁷ 

Bottom Line
Maintenance of certification (MOC) is manageable, although it requires you to be familiar with its various elements. Those elements include continuing medical education (CME requirements); the additional self-assessment component of CME; performance-in-practice modules; and continuous maintenance of certification. The MOC program booklet of the American Board of Psychiatry and Neurology provides all necessary details.

Disclosure
Dr. Meyer reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

To recap what I discussed in Part 1 of this article (December 2014): As part of a trend across all medical specialty boards, the American Board of Psychiatry and Neurology (ABPN) instituted a recertification pro­cess for all new general psychiatry certifications, starting October 1, 1994.¹ In 2000, the specialties that comprise the American Board of Medical Specialties (ABMS) agreed to develop a comprehensive maintenance of certification (MOC) process to demonstrate ongoing learning and com­petency beyond what can be captured by a recertification examination. All ABMS member boards now use a 4-part process for recertification.

A great deal of professional and personal importance has been attached to maintaining one’s general and sub­specialty certifications. To that end, the 2 parts of this article highlight current ABPN MOC requirements and provide resources for understanding, tracking, and completing the self-assessment (SA) and performance-in-practice (PIP) components.

In this installment, I examine 3 components of MOC:
   • continuing medical education (CME), including SA requirements
   • improvement in medical practice (PIP)
   • continuous maintenance of certification (C-MOC)

In addition to this review, all physicians who are subject to MOC should download and read the 20-page revised MOC Program booklet v. 2.1 (May 2014).²

Continuing medical education
The CME requirement is clear: All diplo­mate physicians must accrue, on average, 30 Category-1 CME credits a year; the CME must be relevant to the specialty or subspecialty in which the diplomate prac­tices.³ For physicians who hold >1 ABPN certificates, the total CME requirement is the same; CME credits can be applied across each specialty and subspecialty.

The May 2014 MOC revision states that, for physicians who certified or recertified between 2005 and 2011 and who applied for the 2015 examination in 2014, the required CME credit total is 270.2 For all subsequent years of certification or recertification, including 2012, diplomates are enrolled in C-MOC, which is described below.²

To even out the accrual of CME credits across the prior 10 years, ABPN mandates that, for diplomates who certified or recer­tified between 2005 and 2011, one hundred fifty of the CME credits be accrued in the 5 years before they apply for the examina­tion. Diplomates in C-MOC should accrue, on average, 30 CME credits a year in each of the 3-year blocks (ie, 90 units in each block).²

Self-assessment
SA is a specific form of CME that is designed to provide comprehensive test-based feedback on knowledge acquired, to enhance the learning process.⁴ SA CME feedback must include:
   • the correct answer to each test question
   • recommended literature resources for each question
   • performance compared to peers on each question.

Given the structured nature of SA activi­ties, beginning January 1, 2014, one must use only ABPN-approved SA products (see Related Resources for a list of APBN-approved SA products).⁵

Table 1 and Table 2 outline SA require­ments for, respectively, physicians who certified or recertified from 2005 through 2011, and those who certified or recertified in 2012 (and later). The SA requirement increases after 2011 to 24 credits in each 3-year block (8 credits a year, on average).² Multiple SA activities can be used to fulfill the credit requirement of each 3-year block.

Improvement in medical practice, or PIP
Physicians who are active clinically must complete PIP modules. Each module comprises peer or patient feedback plus a clinical aspect. The May 2014 MOC revi­sion simplified the feedback process to mandate peer or patient feedback—but not both, as required previously.² For the feedback PIP module, the physician selects 5 peers or patients to complete review forms, examines the results, and creates a plan of improvement. An exception to this “rule of 5” applies to diplomates who have a supervisor capable of evaluating all gen­eral competencies, defined below.

Related Resources provides a link to ABPN-created forms.

Within 24 months, but not sooner than 1 month, 5 peers or patients (or 1 appli­cable supervisor) are selected to complete review forms; changes in practice are noted. The same peers or patients might be selected for a second review. As noted in Table 1 and Table 2, the number of PIP modules is fewer for physicians who certi­fied or recertified between 2005 and 2011; from 2012 onward, 1 PIP clinical module is required in each 3-year block.²

There are 6 ABPN-approved feedback module options, of which the diplomate must choose 1 in any given block²:
   • 5 patient surveys
   • 5 peer evaluations of general competencies^a
   • 5 resident evaluations of general competencies^a  
   • 360° evaluation of general competencies,a with 5 respondents
   • institutional peer review of general competencies,^a with 5 respondents
   • 1 supervisor evaluation of general competencies.^a

^aGeneral competencies include patient care; practice-based learning and improvement; professionalism; medical knowledge; interpersonal and communication skills; and system-based practices.

Although many institutions have a quality improvement (QI) program, that program must be approved by the Multi-Specialty MOC Portfolio Approval Program sponsored by ABMS for a clinician to receive credit for 1 PIP clinical module. If the approved QI program includes patient or peer feedback (eg, a survey), the diplo­ mate can receive credit for 1 PIP feedback module.²

For the clinical PIP module, the physician selects 5 charts for review and examines them based on criteria found in an ABPN-approved (starting in 2014) PIP product. (Related Resources provides a link to this list.) After reviewing the initial 5 charts, a plan for improvement is created. Within 24 months, but no sooner than 1 month, 5 charts are again selected and reviewed, and changes in practice are noted. The same charts can be selected for the second review.

As noted in Table 1 and Table 2, the number of PIP modules is fewer for those who initially certified or recertified between 2005 and 2011; from 2012 onward, 1 PIP clinical module is required in each 3-year block.²


The C-MOC process
Physicians who certified or recertified in 2012, or who will certify or recertify after that year, are enrolled automatically in C-MOC.^6,7 The purpose of C-MOC is to keep diplomates on track to fulfill the higher level of SA requirements that began with this group; this is done by mandating use of the ABPN Physician Folios system. As shown in Table 2, there is no longer a 10-year cycle; instead, there are continuous 3-year stages, within which each diplomate must accrue 90 CME cred­its (on average, 30 credits a year), 24 SA credits (on average, 8 a year), 1 PIP clinical module, and 1 PIP feedback module.^6,7

The first 3-year block of C-MOC require­ments will be waived for physicians who complete Accreditation Council on Graduate Medical Education–accredited or ABPN-approved subspecialty training in 2012 or later—if they pass the corre­sponding ABPN subspecialty examination during the first 3-year block of enrollment in C-MOC.2 For diplomates enrolled in C-MOC, failure to track progress of each 3-year block, via the ABPN Physician Folios system, has significant consequences: Those who do not complete the first stage of the program by the end of 3 years will be listed on the ABPN Web site as “certified— not meeting MOC requirements.” Those who do not complete 2 stages by the end of 6 years will be listed as “not certified.”²

Cognitive exam still in place. The only remnant of the old 10-year cycle is the requirement to pass the cognitive examina­tion every 10 years, although the exam can be taken earlier if the diplomate wishes. If all requirements are met and one does not sit for, or fails, the exam, the ABPN Web site will report the diplomate as “not meet­ing MOC requirements.” One can retake the exam within 1 year of the failed or missed exam, but a subsequent failure or missed exam will result in being listed as “not certified.”²

Fee structure. Instead of a single fee paid at the time of the exam(s), physicians in the C-MOC program pay an annual fee that covers participation in ABPN Physician Folios and 1 exam in a 10-year period. Fewer than 10 years of participation, or applying for a combined examination (for diplomates who hold multiple certifica­tions), requires an additional fee.⁷ 

Bottom Line
Maintenance of certification (MOC) is manageable, although it requires you to be familiar with its various elements. Those elements include continuing medical education (CME requirements); the additional self-assessment component of CME; performance-in-practice modules; and continuous maintenance of certification. The MOC program booklet of the American Board of Psychiatry and Neurology provides all necessary details.

Disclosure
Dr. Meyer reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

To recap what I discussed in Part 1 of this article (December 2014): As part of a trend across all medical specialty boards, the American Board of Psychiatry and Neurology (ABPN) instituted a recertification pro­cess for all new general psychiatry certifications, starting October 1, 1994.¹ In 2000, the specialties that comprise the American Board of Medical Specialties (ABMS) agreed to develop a comprehensive maintenance of certification (MOC) process to demonstrate ongoing learning and com­petency beyond what can be captured by a recertification examination. All ABMS member boards now use a 4-part process for recertification.

A great deal of professional and personal importance has been attached to maintaining one’s general and sub­specialty certifications. To that end, the 2 parts of this article highlight current ABPN MOC requirements and provide resources for understanding, tracking, and completing the self-assessment (SA) and performance-in-practice (PIP) components.

In this installment, I examine 3 components of MOC:
   • continuing medical education (CME), including SA requirements
   • improvement in medical practice (PIP)
   • continuous maintenance of certification (C-MOC)

In addition to this review, all physicians who are subject to MOC should download and read the 20-page revised MOC Program booklet v. 2.1 (May 2014).²

Continuing medical education
The CME requirement is clear: All diplo­mate physicians must accrue, on average, 30 Category-1 CME credits a year; the CME must be relevant to the specialty or subspecialty in which the diplomate prac­tices.³ For physicians who hold >1 ABPN certificates, the total CME requirement is the same; CME credits can be applied across each specialty and subspecialty.

The May 2014 MOC revision states that, for physicians who certified or recertified between 2005 and 2011 and who applied for the 2015 examination in 2014, the required CME credit total is 270.2 For all subsequent years of certification or recertification, including 2012, diplomates are enrolled in C-MOC, which is described below.²

To even out the accrual of CME credits across the prior 10 years, ABPN mandates that, for diplomates who certified or recer­tified between 2005 and 2011, one hundred fifty of the CME credits be accrued in the 5 years before they apply for the examina­tion. Diplomates in C-MOC should accrue, on average, 30 CME credits a year in each of the 3-year blocks (ie, 90 units in each block).²

Self-assessment
SA is a specific form of CME that is designed to provide comprehensive test-based feedback on knowledge acquired, to enhance the learning process.⁴ SA CME feedback must include:
   • the correct answer to each test question
   • recommended literature resources for each question
   • performance compared to peers on each question.

Given the structured nature of SA activi­ties, beginning January 1, 2014, one must use only ABPN-approved SA products (see Related Resources for a list of APBN-approved SA products).⁵

Table 1 and Table 2 outline SA require­ments for, respectively, physicians who certified or recertified from 2005 through 2011, and those who certified or recertified in 2012 (and later). The SA requirement increases after 2011 to 24 credits in each 3-year block (8 credits a year, on average).² Multiple SA activities can be used to fulfill the credit requirement of each 3-year block.

Improvement in medical practice, or PIP
Physicians who are active clinically must complete PIP modules. Each module comprises peer or patient feedback plus a clinical aspect. The May 2014 MOC revi­sion simplified the feedback process to mandate peer or patient feedback—but not both, as required previously.² For the feedback PIP module, the physician selects 5 peers or patients to complete review forms, examines the results, and creates a plan of improvement. An exception to this “rule of 5” applies to diplomates who have a supervisor capable of evaluating all gen­eral competencies, defined below.

Related Resources provides a link to ABPN-created forms.

Within 24 months, but not sooner than 1 month, 5 peers or patients (or 1 appli­cable supervisor) are selected to complete review forms; changes in practice are noted. The same peers or patients might be selected for a second review. As noted in Table 1 and Table 2, the number of PIP modules is fewer for physicians who certi­fied or recertified between 2005 and 2011; from 2012 onward, 1 PIP clinical module is required in each 3-year block.²

There are 6 ABPN-approved feedback module options, of which the diplomate must choose 1 in any given block²:
   • 5 patient surveys
   • 5 peer evaluations of general competencies^a
   • 5 resident evaluations of general competencies^a  
   • 360° evaluation of general competencies,a with 5 respondents
   • institutional peer review of general competencies,^a with 5 respondents
   • 1 supervisor evaluation of general competencies.^a

^aGeneral competencies include patient care; practice-based learning and improvement; professionalism; medical knowledge; interpersonal and communication skills; and system-based practices.

Although many institutions have a quality improvement (QI) program, that program must be approved by the Multi-Specialty MOC Portfolio Approval Program sponsored by ABMS for a clinician to receive credit for 1 PIP clinical module. If the approved QI program includes patient or peer feedback (eg, a survey), the diplo­ mate can receive credit for 1 PIP feedback module.²

For the clinical PIP module, the physician selects 5 charts for review and examines them based on criteria found in an ABPN-approved (starting in 2014) PIP product. (Related Resources provides a link to this list.) After reviewing the initial 5 charts, a plan for improvement is created. Within 24 months, but no sooner than 1 month, 5 charts are again selected and reviewed, and changes in practice are noted. The same charts can be selected for the second review.

As noted in Table 1 and Table 2, the number of PIP modules is fewer for those who initially certified or recertified between 2005 and 2011; from 2012 onward, 1 PIP clinical module is required in each 3-year block.²


The C-MOC process
Physicians who certified or recertified in 2012, or who will certify or recertify after that year, are enrolled automatically in C-MOC.^6,7 The purpose of C-MOC is to keep diplomates on track to fulfill the higher level of SA requirements that began with this group; this is done by mandating use of the ABPN Physician Folios system. As shown in Table 2, there is no longer a 10-year cycle; instead, there are continuous 3-year stages, within which each diplomate must accrue 90 CME cred­its (on average, 30 credits a year), 24 SA credits (on average, 8 a year), 1 PIP clinical module, and 1 PIP feedback module.^6,7

The first 3-year block of C-MOC require­ments will be waived for physicians who complete Accreditation Council on Graduate Medical Education–accredited or ABPN-approved subspecialty training in 2012 or later—if they pass the corre­sponding ABPN subspecialty examination during the first 3-year block of enrollment in C-MOC.2 For diplomates enrolled in C-MOC, failure to track progress of each 3-year block, via the ABPN Physician Folios system, has significant consequences: Those who do not complete the first stage of the program by the end of 3 years will be listed on the ABPN Web site as “certified— not meeting MOC requirements.” Those who do not complete 2 stages by the end of 6 years will be listed as “not certified.”²

Cognitive exam still in place. The only remnant of the old 10-year cycle is the requirement to pass the cognitive examina­tion every 10 years, although the exam can be taken earlier if the diplomate wishes. If all requirements are met and one does not sit for, or fails, the exam, the ABPN Web site will report the diplomate as “not meet­ing MOC requirements.” One can retake the exam within 1 year of the failed or missed exam, but a subsequent failure or missed exam will result in being listed as “not certified.”²

Fee structure. Instead of a single fee paid at the time of the exam(s), physicians in the C-MOC program pay an annual fee that covers participation in ABPN Physician Folios and 1 exam in a 10-year period. Fewer than 10 years of participation, or applying for a combined examination (for diplomates who hold multiple certifica­tions), requires an additional fee.⁷ 

Bottom Line
Maintenance of certification (MOC) is manageable, although it requires you to be familiar with its various elements. Those elements include continuing medical education (CME requirements); the additional self-assessment component of CME; performance-in-practice modules; and continuous maintenance of certification. The MOC program booklet of the American Board of Psychiatry and Neurology provides all necessary details.

Disclosure
Dr. Meyer reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.