A once-daily regimen of two investigational, direct-acting anti-HCV agents, ABT-493 and ABT-530, was well tolerated and achieved sustained viral response at 12 weeks (SVR12) for nearly all patients with compensated cirrhosis and chronic genotype (GT) 1 or 3 hepatitis C virus infection, according to open-label phase II studies.

“The unique potency of these agents against all genotypes, even in the presence of common NS3 and/or NS5A baseline substitutions that confer resistance to most contemporary NS3/4A protease inhibitors and NS5A inhibitors, offers the potential for pangenotypic [HCV] therapy without ribavirin,” Edward J. Gane, MD, of the University of Auckland, New Zealand, and his associates wrote in the October issue of Gastroenterology. Phase III trials are now testing this hypothesis by focusing on cohorts of treatment-experienced, genotype 3–infected patients, on patients with renal impairment, and on patients who failed earlier-generation direct-acting antiviral regimens, they said.

The prevalence of HCV-related cirrhosis has yet to peak, and gold standard therapies for GT3 and GT1a infections can take weeks of treatment and the use of ribavirin, which causes undesirable side effects, the investigators noted. Attempts to surmount these residual barriers led to the development of ABT-493, an HCV nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530, an HCV NS5A inhibitor. During in vitro studies, both agents showed “potent” activity against all major HCV genotypes, including variants with mutations that confer resistance to earlier, direct-acting antivirals, the researchers said (Gastroenterology. 2016 Jul 22. doi: 10.1053/j.gastro.2016.07.020). Their two open-label phase II studies enrolled adults with compensated cirrhosis and chronic GT3 (55 patients) or GT1 (27 patients) infection. Among GT1 patients, 41% had baseline NS3 substitutions conferring resistance to earlier-generation drugs, 19% had NS5A substitutions, and 11% had both mutations. The GT1-infected patients received 200 mg ABT-493 and 120 mg of ABT-530. The GT3-infected patients received 300 mg ABT-493 and 120 mg ABT-530, and half (27 patients) also received ribavirin. Most patients were treatment-naive, male, and white, with Child-Pugh scores of 5 and HCV RNA levels averaging about 6.2-6.6 log10 IU/mL.

In all, 26 patients with GT1 infection (96%) achieved SVR12 (95% confidence interval, 82% to 99%). The remaining patient relapsed after completing treatment. All treatment-naive GT3 patients achieved SVR12 whether or not they received ribavirin. However, one treatment-experienced GT3 patient who did not receive ribavirin relapsed after 16 weeks of treatment. Thus, rates of SVR12 were 96% (95% confidence interval, 82%-99%) for GT3 patients who did not receive ribavirin and 100% (95% CI, 88%-100%) for those who did. Notably, 94% of patients with baseline substitutions in NS3 and NS5A achieved SVR12, and there was no apparent link between treatment failure and any demographic or clinical characteristics, the investigators wrote.

Adverse events affected about 74% of patients and were usually mild or moderate in severity. Patients who did not receive ribavirin were most likely to report headache (15%), diarrhea (13%), and fatigue (11%). Only 4% of GT1 patients and 7% of the GT3 cohorts developed serious adverse events, and the only serious adverse event considered possibly treatment related involved a delusional disorder in a 57-year-old male who was receiving ribavirin and admitted amphetamine and alcohol use on the day it occurred. Treatment-related laboratory abnormalities were uncommon, no patients stopped treatment because of adverse events, and there were no deaths. “The rates of some adverse events were numerically higher with the higher ABT-493 dose, though the sample sizes are small and this was a cross-study comparison,” the investigators added. “Though not included in this study, patients with severe or end-stage kidney disease are predicted to be able to be treated with ABT-493 and ABT-530 because both agents have negligible renal excretion. These drugs were well tolerated in HCV-uninfected patients with renal impairment and can be administered without dose adjustment.”AbbVie funded the study and makes ABT-493 and ABT-530. Dr. Gane disclosed ties to AbbVie, Achillion Pharmaceuticals, Alnylam, Janssen, Merck, Novartis, and Novira.

A once-daily regimen of two investigational, direct-acting anti-HCV agents, ABT-493 and ABT-530, was well tolerated and achieved sustained viral response at 12 weeks (SVR12) for nearly all patients with compensated cirrhosis and chronic genotype (GT) 1 or 3 hepatitis C virus infection, according to open-label phase II studies.

“The unique potency of these agents against all genotypes, even in the presence of common NS3 and/or NS5A baseline substitutions that confer resistance to most contemporary NS3/4A protease inhibitors and NS5A inhibitors, offers the potential for pangenotypic [HCV] therapy without ribavirin,” Edward J. Gane, MD, of the University of Auckland, New Zealand, and his associates wrote in the October issue of Gastroenterology. Phase III trials are now testing this hypothesis by focusing on cohorts of treatment-experienced, genotype 3–infected patients, on patients with renal impairment, and on patients who failed earlier-generation direct-acting antiviral regimens, they said.

The prevalence of HCV-related cirrhosis has yet to peak, and gold standard therapies for GT3 and GT1a infections can take weeks of treatment and the use of ribavirin, which causes undesirable side effects, the investigators noted. Attempts to surmount these residual barriers led to the development of ABT-493, an HCV nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530, an HCV NS5A inhibitor. During in vitro studies, both agents showed “potent” activity against all major HCV genotypes, including variants with mutations that confer resistance to earlier, direct-acting antivirals, the researchers said (Gastroenterology. 2016 Jul 22. doi: 10.1053/j.gastro.2016.07.020). Their two open-label phase II studies enrolled adults with compensated cirrhosis and chronic GT3 (55 patients) or GT1 (27 patients) infection. Among GT1 patients, 41% had baseline NS3 substitutions conferring resistance to earlier-generation drugs, 19% had NS5A substitutions, and 11% had both mutations. The GT1-infected patients received 200 mg ABT-493 and 120 mg of ABT-530. The GT3-infected patients received 300 mg ABT-493 and 120 mg ABT-530, and half (27 patients) also received ribavirin. Most patients were treatment-naive, male, and white, with Child-Pugh scores of 5 and HCV RNA levels averaging about 6.2-6.6 log10 IU/mL.

In all, 26 patients with GT1 infection (96%) achieved SVR12 (95% confidence interval, 82% to 99%). The remaining patient relapsed after completing treatment. All treatment-naive GT3 patients achieved SVR12 whether or not they received ribavirin. However, one treatment-experienced GT3 patient who did not receive ribavirin relapsed after 16 weeks of treatment. Thus, rates of SVR12 were 96% (95% confidence interval, 82%-99%) for GT3 patients who did not receive ribavirin and 100% (95% CI, 88%-100%) for those who did. Notably, 94% of patients with baseline substitutions in NS3 and NS5A achieved SVR12, and there was no apparent link between treatment failure and any demographic or clinical characteristics, the investigators wrote.

Adverse events affected about 74% of patients and were usually mild or moderate in severity. Patients who did not receive ribavirin were most likely to report headache (15%), diarrhea (13%), and fatigue (11%). Only 4% of GT1 patients and 7% of the GT3 cohorts developed serious adverse events, and the only serious adverse event considered possibly treatment related involved a delusional disorder in a 57-year-old male who was receiving ribavirin and admitted amphetamine and alcohol use on the day it occurred. Treatment-related laboratory abnormalities were uncommon, no patients stopped treatment because of adverse events, and there were no deaths. “The rates of some adverse events were numerically higher with the higher ABT-493 dose, though the sample sizes are small and this was a cross-study comparison,” the investigators added. “Though not included in this study, patients with severe or end-stage kidney disease are predicted to be able to be treated with ABT-493 and ABT-530 because both agents have negligible renal excretion. These drugs were well tolerated in HCV-uninfected patients with renal impairment and can be administered without dose adjustment.”AbbVie funded the study and makes ABT-493 and ABT-530. Dr. Gane disclosed ties to AbbVie, Achillion Pharmaceuticals, Alnylam, Janssen, Merck, Novartis, and Novira.

A once-daily regimen of two investigational, direct-acting anti-HCV agents, ABT-493 and ABT-530, was well tolerated and achieved sustained viral response at 12 weeks (SVR12) for nearly all patients with compensated cirrhosis and chronic genotype (GT) 1 or 3 hepatitis C virus infection, according to open-label phase II studies.

“The unique potency of these agents against all genotypes, even in the presence of common NS3 and/or NS5A baseline substitutions that confer resistance to most contemporary NS3/4A protease inhibitors and NS5A inhibitors, offers the potential for pangenotypic [HCV] therapy without ribavirin,” Edward J. Gane, MD, of the University of Auckland, New Zealand, and his associates wrote in the October issue of Gastroenterology. Phase III trials are now testing this hypothesis by focusing on cohorts of treatment-experienced, genotype 3–infected patients, on patients with renal impairment, and on patients who failed earlier-generation direct-acting antiviral regimens, they said.

The prevalence of HCV-related cirrhosis has yet to peak, and gold standard therapies for GT3 and GT1a infections can take weeks of treatment and the use of ribavirin, which causes undesirable side effects, the investigators noted. Attempts to surmount these residual barriers led to the development of ABT-493, an HCV nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530, an HCV NS5A inhibitor. During in vitro studies, both agents showed “potent” activity against all major HCV genotypes, including variants with mutations that confer resistance to earlier, direct-acting antivirals, the researchers said (Gastroenterology. 2016 Jul 22. doi: 10.1053/j.gastro.2016.07.020). Their two open-label phase II studies enrolled adults with compensated cirrhosis and chronic GT3 (55 patients) or GT1 (27 patients) infection. Among GT1 patients, 41% had baseline NS3 substitutions conferring resistance to earlier-generation drugs, 19% had NS5A substitutions, and 11% had both mutations. The GT1-infected patients received 200 mg ABT-493 and 120 mg of ABT-530. The GT3-infected patients received 300 mg ABT-493 and 120 mg ABT-530, and half (27 patients) also received ribavirin. Most patients were treatment-naive, male, and white, with Child-Pugh scores of 5 and HCV RNA levels averaging about 6.2-6.6 log10 IU/mL.

In all, 26 patients with GT1 infection (96%) achieved SVR12 (95% confidence interval, 82% to 99%). The remaining patient relapsed after completing treatment. All treatment-naive GT3 patients achieved SVR12 whether or not they received ribavirin. However, one treatment-experienced GT3 patient who did not receive ribavirin relapsed after 16 weeks of treatment. Thus, rates of SVR12 were 96% (95% confidence interval, 82%-99%) for GT3 patients who did not receive ribavirin and 100% (95% CI, 88%-100%) for those who did. Notably, 94% of patients with baseline substitutions in NS3 and NS5A achieved SVR12, and there was no apparent link between treatment failure and any demographic or clinical characteristics, the investigators wrote.

Adverse events affected about 74% of patients and were usually mild or moderate in severity. Patients who did not receive ribavirin were most likely to report headache (15%), diarrhea (13%), and fatigue (11%). Only 4% of GT1 patients and 7% of the GT3 cohorts developed serious adverse events, and the only serious adverse event considered possibly treatment related involved a delusional disorder in a 57-year-old male who was receiving ribavirin and admitted amphetamine and alcohol use on the day it occurred. Treatment-related laboratory abnormalities were uncommon, no patients stopped treatment because of adverse events, and there were no deaths. “The rates of some adverse events were numerically higher with the higher ABT-493 dose, though the sample sizes are small and this was a cross-study comparison,” the investigators added. “Though not included in this study, patients with severe or end-stage kidney disease are predicted to be able to be treated with ABT-493 and ABT-530 because both agents have negligible renal excretion. These drugs were well tolerated in HCV-uninfected patients with renal impairment and can be administered without dose adjustment.”AbbVie funded the study and makes ABT-493 and ABT-530. Dr. Gane disclosed ties to AbbVie, Achillion Pharmaceuticals, Alnylam, Janssen, Merck, Novartis, and Novira.

Neuropsychiatric disorders are associated with high rates of impaired work capacity despite the best efforts of treating clinicians to help their patients stay employed or resume working after symptoms improve.¹

In the past, a note from the psychiatrist stating that the patient was unable to work because of a neuropsychiatric condition often was sufficient to approve a disability claim. This is no longer the case in today’s more restrictive climate, and what constitutes prima facie evidence of a patient’s inability to sustain competitive employment secondary to neuropsychiatric illness has significantly changed.

The following practices can help facilitate approval of your patient’s disability claim.

Document as you go. Progress notes should include the type, frequency, context, duration, and severity of symptoms supporting ≥1 psychiatric diagnoses which prevent your patient from holding a job. It also is important to document the parameters of treatment and the patient’s response, including compliance with treatment recommendations. Preferably, progress notes should include quantitative ratings over time that pertain to everyday functioning, highlighting how your patient is coping with the psychosocial, cognitive, and executive functioning demands of his (her) job.

When documented over time, ratings based on the Global Assessment of Functioning scale or a comparable scale are useful in quantifying the nature and degree of impaired functioning related to work capacity. Consider administering rating scales at periodic intervals to show changes over time. When feasible, scales should be based on a patient’s and informant’s report of symptomatic status and everyday functioning, and could include use of instruments such as the World Health Organization’s Disability Assessment Schedule.^2,3

Include documentation specific to work capacity. Disability claims often are denied, in part, because the treating psychiatrist’s judgment regarding work capacity seems to “come out of the blue,” appears premature, or lacks discussion of the functional implications of the patient’s clinical status in regards to recent or current job expectations. Therefore, progress notes should include reference to long-standing, emerging, or worsening behaviors or symptoms that have clear implications for your patient’s ability to work.

Outline the functional implications of the patient’s preserved and impaired abilities and skills as they relate to work capacity, vocational history, and recent or current job situation. For example, work requirements that are highly dependent on interaction with the public, supervisors, or coworkers would be significantly affected by recurrent or persistent psychosis, even if the patient adheres to treatment and symptoms are relatively mild. Problems with working memory or anterograde memory could impair work that routinely involves learning and retention of new instructions and procedures.

Provide psychoeducation and support. Educate your patient and their family about the disability claims process, including the high rate that claims are initially denied. Consider retaining an advocate—clinical case manager, family member, or non-family third party—to assist your patient in navigating the disability application process, such as help completing paperwork, setting up appointments, and providing transportation.

Remain responsive to inquiries from disability examiners. Return forms and phone calls from disability examiners, psychiatrists, and other health care professionals reviewing your patient’s claim for long-term disability in a timely manner. Failure to do so can be used to support denial of the claim.

Consider referral for consultations and diagnostics to support the claim of impaired work capacity. Depending on the nature of the case, this could involve additional medical workup (including neuroimaging), a consultation from a vocational rehabilitation specialist, or referral for psychological or neuropsychological testing.

Psychometric assessment is becoming the preferred method for garnering support for impaired work capacity caused by neuropsychiatric factors. Findings from psychometric assessment hold up to scrutiny better if the evaluation includes symptom validity testing to rule out factitious disorder, malingering, or somatization, and results from self-report and informant-based measures of adaptive behavior and functioning.⁴

Neuropsychiatric disorders are associated with high rates of impaired work capacity despite the best efforts of treating clinicians to help their patients stay employed or resume working after symptoms improve.¹

In the past, a note from the psychiatrist stating that the patient was unable to work because of a neuropsychiatric condition often was sufficient to approve a disability claim. This is no longer the case in today’s more restrictive climate, and what constitutes prima facie evidence of a patient’s inability to sustain competitive employment secondary to neuropsychiatric illness has significantly changed.

The following practices can help facilitate approval of your patient’s disability claim.

Document as you go. Progress notes should include the type, frequency, context, duration, and severity of symptoms supporting ≥1 psychiatric diagnoses which prevent your patient from holding a job. It also is important to document the parameters of treatment and the patient’s response, including compliance with treatment recommendations. Preferably, progress notes should include quantitative ratings over time that pertain to everyday functioning, highlighting how your patient is coping with the psychosocial, cognitive, and executive functioning demands of his (her) job.

When documented over time, ratings based on the Global Assessment of Functioning scale or a comparable scale are useful in quantifying the nature and degree of impaired functioning related to work capacity. Consider administering rating scales at periodic intervals to show changes over time. When feasible, scales should be based on a patient’s and informant’s report of symptomatic status and everyday functioning, and could include use of instruments such as the World Health Organization’s Disability Assessment Schedule.^2,3

Include documentation specific to work capacity. Disability claims often are denied, in part, because the treating psychiatrist’s judgment regarding work capacity seems to “come out of the blue,” appears premature, or lacks discussion of the functional implications of the patient’s clinical status in regards to recent or current job expectations. Therefore, progress notes should include reference to long-standing, emerging, or worsening behaviors or symptoms that have clear implications for your patient’s ability to work.

Outline the functional implications of the patient’s preserved and impaired abilities and skills as they relate to work capacity, vocational history, and recent or current job situation. For example, work requirements that are highly dependent on interaction with the public, supervisors, or coworkers would be significantly affected by recurrent or persistent psychosis, even if the patient adheres to treatment and symptoms are relatively mild. Problems with working memory or anterograde memory could impair work that routinely involves learning and retention of new instructions and procedures.

Provide psychoeducation and support. Educate your patient and their family about the disability claims process, including the high rate that claims are initially denied. Consider retaining an advocate—clinical case manager, family member, or non-family third party—to assist your patient in navigating the disability application process, such as help completing paperwork, setting up appointments, and providing transportation.

Remain responsive to inquiries from disability examiners. Return forms and phone calls from disability examiners, psychiatrists, and other health care professionals reviewing your patient’s claim for long-term disability in a timely manner. Failure to do so can be used to support denial of the claim.

Consider referral for consultations and diagnostics to support the claim of impaired work capacity. Depending on the nature of the case, this could involve additional medical workup (including neuroimaging), a consultation from a vocational rehabilitation specialist, or referral for psychological or neuropsychological testing.

Psychometric assessment is becoming the preferred method for garnering support for impaired work capacity caused by neuropsychiatric factors. Findings from psychometric assessment hold up to scrutiny better if the evaluation includes symptom validity testing to rule out factitious disorder, malingering, or somatization, and results from self-report and informant-based measures of adaptive behavior and functioning.⁴

Neuropsychiatric disorders are associated with high rates of impaired work capacity despite the best efforts of treating clinicians to help their patients stay employed or resume working after symptoms improve.¹

In the past, a note from the psychiatrist stating that the patient was unable to work because of a neuropsychiatric condition often was sufficient to approve a disability claim. This is no longer the case in today’s more restrictive climate, and what constitutes prima facie evidence of a patient’s inability to sustain competitive employment secondary to neuropsychiatric illness has significantly changed.

The following practices can help facilitate approval of your patient’s disability claim.

Document as you go. Progress notes should include the type, frequency, context, duration, and severity of symptoms supporting ≥1 psychiatric diagnoses which prevent your patient from holding a job. It also is important to document the parameters of treatment and the patient’s response, including compliance with treatment recommendations. Preferably, progress notes should include quantitative ratings over time that pertain to everyday functioning, highlighting how your patient is coping with the psychosocial, cognitive, and executive functioning demands of his (her) job.

When documented over time, ratings based on the Global Assessment of Functioning scale or a comparable scale are useful in quantifying the nature and degree of impaired functioning related to work capacity. Consider administering rating scales at periodic intervals to show changes over time. When feasible, scales should be based on a patient’s and informant’s report of symptomatic status and everyday functioning, and could include use of instruments such as the World Health Organization’s Disability Assessment Schedule.^2,3

Include documentation specific to work capacity. Disability claims often are denied, in part, because the treating psychiatrist’s judgment regarding work capacity seems to “come out of the blue,” appears premature, or lacks discussion of the functional implications of the patient’s clinical status in regards to recent or current job expectations. Therefore, progress notes should include reference to long-standing, emerging, or worsening behaviors or symptoms that have clear implications for your patient’s ability to work.

Outline the functional implications of the patient’s preserved and impaired abilities and skills as they relate to work capacity, vocational history, and recent or current job situation. For example, work requirements that are highly dependent on interaction with the public, supervisors, or coworkers would be significantly affected by recurrent or persistent psychosis, even if the patient adheres to treatment and symptoms are relatively mild. Problems with working memory or anterograde memory could impair work that routinely involves learning and retention of new instructions and procedures.

Provide psychoeducation and support. Educate your patient and their family about the disability claims process, including the high rate that claims are initially denied. Consider retaining an advocate—clinical case manager, family member, or non-family third party—to assist your patient in navigating the disability application process, such as help completing paperwork, setting up appointments, and providing transportation.

Remain responsive to inquiries from disability examiners. Return forms and phone calls from disability examiners, psychiatrists, and other health care professionals reviewing your patient’s claim for long-term disability in a timely manner. Failure to do so can be used to support denial of the claim.

Consider referral for consultations and diagnostics to support the claim of impaired work capacity. Depending on the nature of the case, this could involve additional medical workup (including neuroimaging), a consultation from a vocational rehabilitation specialist, or referral for psychological or neuropsychological testing.

Psychometric assessment is becoming the preferred method for garnering support for impaired work capacity caused by neuropsychiatric factors. Findings from psychometric assessment hold up to scrutiny better if the evaluation includes symptom validity testing to rule out factitious disorder, malingering, or somatization, and results from self-report and informant-based measures of adaptive behavior and functioning.⁴

CASE
Disoriented and confused

Mr. D, age 42, presents to our emergency department (ED) accompanied by his family with recent onset of disorientation, confusion, depressive mood with labile affect, sleep disturbances, purposeless movements, and grossly reduced kinetics/verbal output. He has a history of schizoaffective disorder, bipolar type, and recurrent admissions for psychotic mood instability.

A few months earlier, Mr. D was treated at our facility for acute exacerbation of his schizoaffective disorder. He was stabilized and discharged with aripiprazole, 30 mg/d, and mirtazapine, 15 mg/d—he had been taking both medications for some time—and newly started extended-release divalproex, 500 mg in the morning/1000 mg nightly (13.2 mg/kg). His trough valproic acid serum level was 70 µg/mL at discharge. He continued on this medication regimen until he returns to our ED with his family.

Mr. D has several medical problems, such as type 2 diabetes mellitus and hypertension, for which he has been receiving metformin, 1,000 mg/d, lisinopril, 10 mg/d, and simvastatin, 20 mg/d. He has no history of alcohol or substance abuse and does not smoke.

Serum and urine analyses are unremarkable and include finger-stick blood glucose, complete blood count, urinalysis, urine drug screen, comprehensive metabolic panel, magnesium, γ-glutamyl transpeptidase (GGTP), amylase, thyroid-stimulating hormone, and blood alcohol level. Random valproic acid serum level taken in the ED is 64 µg/mL. Non-contrast head CT is interpreted as non-acute. There are no documented abnormal findings during the physical exam.

What could be causing Mr. D’s altered mental status?

a) symptoms of a medical illness
b) medication, undetected substance intoxication, or withdrawal-related symptoms
c) acute exacerbation of schizoaffective disorder
d) delirium
e) catatonia of undetected and/or multiple causes

The authors’ observations

The differential diagnosis was broad at the time of Mr. D’s presentation to the ED because his symptoms overlapped across clinical considerations. The initial medical evaluation was negative, which suggested an active primary mental illness. However, Mr. D’s presenting symptoms warranted continued vigilance for concurrent or emergent delirium or catatonia, especially because of the potential morbidity if these conditions are not detected and managed.

EVALUATION
Fluctuating status

Mr. D is admitted to the mental health unit for treatment of presumptive bipolar depression with catatonic features. The initial admitting team continues aripiprazole, increased divalproex extended release to 1,000 mg in the morning/1,500 mg at night, held mirtazapine, and started lorazepam, 2 mg, 3 times daily, for catatonia. Metformin, lisinopril, and simvastatin are continued. Mr. D’s mental status and behavior fluctuates over the next 48 hours prompting the treatment team to consider an emergent delirious process.

On day 3, the primary team assumes care and observes fluctuations in level of arousal with disorientation, inattention, labile affect, disorganized speech and behavior, and responsiveness to internal (visual) stimuli. Finger-stick blood glucose level remains stable. Review of physical symptoms is notable for nausea and examination reveals unsteady gait and asterixis. His family denies that Mr. D used alcohol or drugs before admission. Collateral information from the family and review of Mr. D’s outpatient records is consistent with an acutely fluctuating confusional state that began 10 days before admission.

At this point, what is your differential diagnosis for Mr. D’s altered mental status?

a) symptoms of a medical illness

b) medication, undetected substance intoxication, or withdrawal-related symptoms

c) acute exacerbation of schizoaffective disorder
d) delirium
e) catatonia of undetected or multiple causes

TREATMENT
Valproate stopped

Mr. D’s ammonia level is 119 µg/dL (reference range, 15 to 45 μg/dL) on hospital day 3. Divalproex and lorazepam are discontinued, and standing lactulose is started because it is evident that he has active valproate-related hyperammonemic encephalopathy (VHE), also known as delirium due to valproate-related hyperammonemia.

Awake and drowsy EEG within 24 hours reveals “diffuse irregular slow activity” without epileptogenic features. HIV, syphilis, and vitamin B₁₂ and red blood cell folate screening are negative. We confirm that Mr. D is not a vegetarian (dietary carnitine deficiency is a risk factor for VHE). He is not screened for a urea cycle disorder.

The authors’ observations

Divalproex is a commonly used FDA-approved treatment for a variety of neurologic and psychiatric conditions including acute bipolar mania.^1-3 It also is used for off-label control of various psychiatric symptoms. It is a stable coordination compound composed of sodium valproate and valproic acid that dissipates into the valproate ion in the gastrointestinal tract.¹ (In this article, references to valproate [VPA] include valproic acid and divalproex.) The drug is relatively well-tolerated; however, use may carry teratogenic risk and can adversely impact a variety of body systems, especially hematopoietic, gastrointestinal, and neurologic systems.^1-3 Adverse effects can be idiosyncratic or in part related to VPA serum levels.^1,4 VPA toxicity increases the likelihood of some adverse health outcomes, such as nausea, diarrhea, and tremors.¹

Identifying and treating VHE

Asymptomatic elevations in ammonia without evidence of hepatic injury are common, might be related to valproic serum levels, and may occur in up to one-half of psychiatric patients receiving VPA.^2-4 In contrast, VHE is a rare and potentially lethal idiosyncratic event unrelated to duration of VPA treatment, dosage, or valproic serum level.^2-4 In addition, prior safe use might not protect against future VHE.^3,4

VHE presents as delirium with characteristic acute changes in mental status, including alterations in cognition or level of consciousness ranging from lethargy to coma, along with possible focal neurological findings or vomiting.^1,3,4 Although more common among patients with a seizure disorder, VHE also might be associated with new seizure activity in patients who do not have a seizure disorder.⁵

Although symptomatically acute in onset, emergence is unpredictable and can occur within days or up to years of use with therapeutic VPA dosing and valproic serum levels.^2,4 Complicating identification, laboratory transaminase or ammonia elevations may or may not be present^2-4; however, VHE typically occurs in the setting of hyperammonemia and normal transaminase levels.² Reversible EEG findings are nonspecific² and could show generalized slowing with occasional bursts of frontal intermittent rhythmic delta activity and triphasic waves.^2,4

Pathophysiological descriptions of emergent VHE have been hypothesized,^2-4 but the definitive causal mechanism remains unclear.⁶ Published VHE risk factors^2-6 include:

• polypharmacy (especially anti-­convulsants)
• inherited or dietary-based carnitine deficiency
• urea cycle disorders
• mental retardation.

How would you treat VHE?

a) cholinesterase inhibitors
b) antipsychotic therapy
c) supportive care

d) ammonia-reducing agents such as lactulose, carnitine, and neomycin

e) discontinue valproate

Outcome Normalized ammonia

Four days after discontinuing divalproex and starting lactulose, Mr. D’s fluctuating level of arousal, orientation, attention, and perceptual disturbances resolve along with restoration of environmental relatedness in setting of normalized ammonia level to 39 µg/dL. He is euthymic, non-psychotic, and without cognitive impairment at time of discharge. An “allergy” to divalproex is entered in his electronic medical record in an effort to discourage future retrial.

The authors’ observations

Once identified, management of VHE invariably includes consideration for discontinuation of valproate^1,2,4,19; other adjunctive, expediting, ammonia-reducing strategies, including lactulose and carnitine, have also been described.^2,4,5,20 Although lactulose is more commonly used, carnitine supplementation might be associated with a preferable dosing schedule and drug interaction and side-effect profile.²⁰ Rapidly deteriorating clinical status could indicate hemodialysis.⁴

Of critical importance, these management strategies rely on awareness of and prompt identification of the condition, which includes an ability to distinguish emergent VHE from the mental illness VPA is used to treat.

Stopping the offending agent generally results in complete recovery in VHE patients with psychiatric illness.⁴ Most (>90%, n = 31) psychiatric patients in our and prior⁵ case series reviews recovered within 2 weeks of intervention.⁵ Cautious resumption of divalproex could be considered if there is a compelling clinical indication and you suspect that a putative polypharmacy agent such as topiramate has been removed; otherwise future retrial of VPA should be avoided.¹⁴

Mr. D’s case was consistent with a valproate-related hyperammonemic delirious event. He had preadmission acute onset, intra-daily fluctuating confusion, and visual perceptual disturbances with nausea, asterixis, gait disturbance, elevated ammonia, and a supportive EEG months after starting divalproex. Similar to our case, some challenging aspects of identifying emergent VHE include:

• earlier safe use of divalproex over extended periods
• lack of elevated VPA serum level
• lack of transaminase elevation
• lack of apparent risk factors
• presence of background serious mental illness, which can distract from VHE detection via misattribution to uncontrolled primary mental illness.

This last point is critical because it can delay VHE identification and treatment or worse, result in misdiagnosis with accompanying continuation or escalation of VPA dosing as has initially occurred in Mr. D’s case. Similar concerns have been raised^2,5 and occurred,^5,19 which is not surprising given the frequency of VPA use for psychiatric conditions and symptoms.

Providers should have a low threshold for checking an ammonia level in clinical scenarios that involve any alteration in mental status that may resemble delirium in psychiatric patients treated with valproate. From a preventative perspective, it may be prudent to avoid valproate in psychiatric patients with known VHE risk factors. Either way, promotion of VHE awareness and detection across medical disciplines is paramount.

CASE
Disoriented and confused

Mr. D, age 42, presents to our emergency department (ED) accompanied by his family with recent onset of disorientation, confusion, depressive mood with labile affect, sleep disturbances, purposeless movements, and grossly reduced kinetics/verbal output. He has a history of schizoaffective disorder, bipolar type, and recurrent admissions for psychotic mood instability.

A few months earlier, Mr. D was treated at our facility for acute exacerbation of his schizoaffective disorder. He was stabilized and discharged with aripiprazole, 30 mg/d, and mirtazapine, 15 mg/d—he had been taking both medications for some time—and newly started extended-release divalproex, 500 mg in the morning/1000 mg nightly (13.2 mg/kg). His trough valproic acid serum level was 70 µg/mL at discharge. He continued on this medication regimen until he returns to our ED with his family.

Mr. D has several medical problems, such as type 2 diabetes mellitus and hypertension, for which he has been receiving metformin, 1,000 mg/d, lisinopril, 10 mg/d, and simvastatin, 20 mg/d. He has no history of alcohol or substance abuse and does not smoke.

Serum and urine analyses are unremarkable and include finger-stick blood glucose, complete blood count, urinalysis, urine drug screen, comprehensive metabolic panel, magnesium, γ-glutamyl transpeptidase (GGTP), amylase, thyroid-stimulating hormone, and blood alcohol level. Random valproic acid serum level taken in the ED is 64 µg/mL. Non-contrast head CT is interpreted as non-acute. There are no documented abnormal findings during the physical exam.

What could be causing Mr. D’s altered mental status?

a) symptoms of a medical illness
b) medication, undetected substance intoxication, or withdrawal-related symptoms
c) acute exacerbation of schizoaffective disorder
d) delirium
e) catatonia of undetected and/or multiple causes

The authors’ observations

The differential diagnosis was broad at the time of Mr. D’s presentation to the ED because his symptoms overlapped across clinical considerations. The initial medical evaluation was negative, which suggested an active primary mental illness. However, Mr. D’s presenting symptoms warranted continued vigilance for concurrent or emergent delirium or catatonia, especially because of the potential morbidity if these conditions are not detected and managed.

EVALUATION
Fluctuating status

Mr. D is admitted to the mental health unit for treatment of presumptive bipolar depression with catatonic features. The initial admitting team continues aripiprazole, increased divalproex extended release to 1,000 mg in the morning/1,500 mg at night, held mirtazapine, and started lorazepam, 2 mg, 3 times daily, for catatonia. Metformin, lisinopril, and simvastatin are continued. Mr. D’s mental status and behavior fluctuates over the next 48 hours prompting the treatment team to consider an emergent delirious process.

On day 3, the primary team assumes care and observes fluctuations in level of arousal with disorientation, inattention, labile affect, disorganized speech and behavior, and responsiveness to internal (visual) stimuli. Finger-stick blood glucose level remains stable. Review of physical symptoms is notable for nausea and examination reveals unsteady gait and asterixis. His family denies that Mr. D used alcohol or drugs before admission. Collateral information from the family and review of Mr. D’s outpatient records is consistent with an acutely fluctuating confusional state that began 10 days before admission.

At this point, what is your differential diagnosis for Mr. D’s altered mental status?

a) symptoms of a medical illness

b) medication, undetected substance intoxication, or withdrawal-related symptoms

c) acute exacerbation of schizoaffective disorder
d) delirium
e) catatonia of undetected or multiple causes

TREATMENT
Valproate stopped

Mr. D’s ammonia level is 119 µg/dL (reference range, 15 to 45 μg/dL) on hospital day 3. Divalproex and lorazepam are discontinued, and standing lactulose is started because it is evident that he has active valproate-related hyperammonemic encephalopathy (VHE), also known as delirium due to valproate-related hyperammonemia.

Awake and drowsy EEG within 24 hours reveals “diffuse irregular slow activity” without epileptogenic features. HIV, syphilis, and vitamin B₁₂ and red blood cell folate screening are negative. We confirm that Mr. D is not a vegetarian (dietary carnitine deficiency is a risk factor for VHE). He is not screened for a urea cycle disorder.

The authors’ observations

Divalproex is a commonly used FDA-approved treatment for a variety of neurologic and psychiatric conditions including acute bipolar mania.^1-3 It also is used for off-label control of various psychiatric symptoms. It is a stable coordination compound composed of sodium valproate and valproic acid that dissipates into the valproate ion in the gastrointestinal tract.¹ (In this article, references to valproate [VPA] include valproic acid and divalproex.) The drug is relatively well-tolerated; however, use may carry teratogenic risk and can adversely impact a variety of body systems, especially hematopoietic, gastrointestinal, and neurologic systems.^1-3 Adverse effects can be idiosyncratic or in part related to VPA serum levels.^1,4 VPA toxicity increases the likelihood of some adverse health outcomes, such as nausea, diarrhea, and tremors.¹

Identifying and treating VHE

Asymptomatic elevations in ammonia without evidence of hepatic injury are common, might be related to valproic serum levels, and may occur in up to one-half of psychiatric patients receiving VPA.^2-4 In contrast, VHE is a rare and potentially lethal idiosyncratic event unrelated to duration of VPA treatment, dosage, or valproic serum level.^2-4 In addition, prior safe use might not protect against future VHE.^3,4

VHE presents as delirium with characteristic acute changes in mental status, including alterations in cognition or level of consciousness ranging from lethargy to coma, along with possible focal neurological findings or vomiting.^1,3,4 Although more common among patients with a seizure disorder, VHE also might be associated with new seizure activity in patients who do not have a seizure disorder.⁵

Although symptomatically acute in onset, emergence is unpredictable and can occur within days or up to years of use with therapeutic VPA dosing and valproic serum levels.^2,4 Complicating identification, laboratory transaminase or ammonia elevations may or may not be present^2-4; however, VHE typically occurs in the setting of hyperammonemia and normal transaminase levels.² Reversible EEG findings are nonspecific² and could show generalized slowing with occasional bursts of frontal intermittent rhythmic delta activity and triphasic waves.^2,4

Pathophysiological descriptions of emergent VHE have been hypothesized,^2-4 but the definitive causal mechanism remains unclear.⁶ Published VHE risk factors^2-6 include:

• polypharmacy (especially anti-­convulsants)
• inherited or dietary-based carnitine deficiency
• urea cycle disorders
• mental retardation.

How would you treat VHE?

a) cholinesterase inhibitors
b) antipsychotic therapy
c) supportive care

d) ammonia-reducing agents such as lactulose, carnitine, and neomycin

e) discontinue valproate

Outcome Normalized ammonia

Four days after discontinuing divalproex and starting lactulose, Mr. D’s fluctuating level of arousal, orientation, attention, and perceptual disturbances resolve along with restoration of environmental relatedness in setting of normalized ammonia level to 39 µg/dL. He is euthymic, non-psychotic, and without cognitive impairment at time of discharge. An “allergy” to divalproex is entered in his electronic medical record in an effort to discourage future retrial.

The authors’ observations

Once identified, management of VHE invariably includes consideration for discontinuation of valproate^1,2,4,19; other adjunctive, expediting, ammonia-reducing strategies, including lactulose and carnitine, have also been described.^2,4,5,20 Although lactulose is more commonly used, carnitine supplementation might be associated with a preferable dosing schedule and drug interaction and side-effect profile.²⁰ Rapidly deteriorating clinical status could indicate hemodialysis.⁴

Of critical importance, these management strategies rely on awareness of and prompt identification of the condition, which includes an ability to distinguish emergent VHE from the mental illness VPA is used to treat.

Stopping the offending agent generally results in complete recovery in VHE patients with psychiatric illness.⁴ Most (>90%, n = 31) psychiatric patients in our and prior⁵ case series reviews recovered within 2 weeks of intervention.⁵ Cautious resumption of divalproex could be considered if there is a compelling clinical indication and you suspect that a putative polypharmacy agent such as topiramate has been removed; otherwise future retrial of VPA should be avoided.¹⁴

Mr. D’s case was consistent with a valproate-related hyperammonemic delirious event. He had preadmission acute onset, intra-daily fluctuating confusion, and visual perceptual disturbances with nausea, asterixis, gait disturbance, elevated ammonia, and a supportive EEG months after starting divalproex. Similar to our case, some challenging aspects of identifying emergent VHE include:

• earlier safe use of divalproex over extended periods
• lack of elevated VPA serum level
• lack of transaminase elevation
• lack of apparent risk factors
• presence of background serious mental illness, which can distract from VHE detection via misattribution to uncontrolled primary mental illness.

This last point is critical because it can delay VHE identification and treatment or worse, result in misdiagnosis with accompanying continuation or escalation of VPA dosing as has initially occurred in Mr. D’s case. Similar concerns have been raised^2,5 and occurred,^5,19 which is not surprising given the frequency of VPA use for psychiatric conditions and symptoms.

Providers should have a low threshold for checking an ammonia level in clinical scenarios that involve any alteration in mental status that may resemble delirium in psychiatric patients treated with valproate. From a preventative perspective, it may be prudent to avoid valproate in psychiatric patients with known VHE risk factors. Either way, promotion of VHE awareness and detection across medical disciplines is paramount.

CASE
Disoriented and confused

Mr. D, age 42, presents to our emergency department (ED) accompanied by his family with recent onset of disorientation, confusion, depressive mood with labile affect, sleep disturbances, purposeless movements, and grossly reduced kinetics/verbal output. He has a history of schizoaffective disorder, bipolar type, and recurrent admissions for psychotic mood instability.

A few months earlier, Mr. D was treated at our facility for acute exacerbation of his schizoaffective disorder. He was stabilized and discharged with aripiprazole, 30 mg/d, and mirtazapine, 15 mg/d—he had been taking both medications for some time—and newly started extended-release divalproex, 500 mg in the morning/1000 mg nightly (13.2 mg/kg). His trough valproic acid serum level was 70 µg/mL at discharge. He continued on this medication regimen until he returns to our ED with his family.

Mr. D has several medical problems, such as type 2 diabetes mellitus and hypertension, for which he has been receiving metformin, 1,000 mg/d, lisinopril, 10 mg/d, and simvastatin, 20 mg/d. He has no history of alcohol or substance abuse and does not smoke.

Serum and urine analyses are unremarkable and include finger-stick blood glucose, complete blood count, urinalysis, urine drug screen, comprehensive metabolic panel, magnesium, γ-glutamyl transpeptidase (GGTP), amylase, thyroid-stimulating hormone, and blood alcohol level. Random valproic acid serum level taken in the ED is 64 µg/mL. Non-contrast head CT is interpreted as non-acute. There are no documented abnormal findings during the physical exam.

What could be causing Mr. D’s altered mental status?

a) symptoms of a medical illness
b) medication, undetected substance intoxication, or withdrawal-related symptoms
c) acute exacerbation of schizoaffective disorder
d) delirium
e) catatonia of undetected and/or multiple causes

The authors’ observations

The differential diagnosis was broad at the time of Mr. D’s presentation to the ED because his symptoms overlapped across clinical considerations. The initial medical evaluation was negative, which suggested an active primary mental illness. However, Mr. D’s presenting symptoms warranted continued vigilance for concurrent or emergent delirium or catatonia, especially because of the potential morbidity if these conditions are not detected and managed.

EVALUATION
Fluctuating status

Mr. D is admitted to the mental health unit for treatment of presumptive bipolar depression with catatonic features. The initial admitting team continues aripiprazole, increased divalproex extended release to 1,000 mg in the morning/1,500 mg at night, held mirtazapine, and started lorazepam, 2 mg, 3 times daily, for catatonia. Metformin, lisinopril, and simvastatin are continued. Mr. D’s mental status and behavior fluctuates over the next 48 hours prompting the treatment team to consider an emergent delirious process.

On day 3, the primary team assumes care and observes fluctuations in level of arousal with disorientation, inattention, labile affect, disorganized speech and behavior, and responsiveness to internal (visual) stimuli. Finger-stick blood glucose level remains stable. Review of physical symptoms is notable for nausea and examination reveals unsteady gait and asterixis. His family denies that Mr. D used alcohol or drugs before admission. Collateral information from the family and review of Mr. D’s outpatient records is consistent with an acutely fluctuating confusional state that began 10 days before admission.

At this point, what is your differential diagnosis for Mr. D’s altered mental status?

a) symptoms of a medical illness

b) medication, undetected substance intoxication, or withdrawal-related symptoms

c) acute exacerbation of schizoaffective disorder
d) delirium
e) catatonia of undetected or multiple causes

TREATMENT
Valproate stopped

Mr. D’s ammonia level is 119 µg/dL (reference range, 15 to 45 μg/dL) on hospital day 3. Divalproex and lorazepam are discontinued, and standing lactulose is started because it is evident that he has active valproate-related hyperammonemic encephalopathy (VHE), also known as delirium due to valproate-related hyperammonemia.

Awake and drowsy EEG within 24 hours reveals “diffuse irregular slow activity” without epileptogenic features. HIV, syphilis, and vitamin B₁₂ and red blood cell folate screening are negative. We confirm that Mr. D is not a vegetarian (dietary carnitine deficiency is a risk factor for VHE). He is not screened for a urea cycle disorder.

The authors’ observations

Divalproex is a commonly used FDA-approved treatment for a variety of neurologic and psychiatric conditions including acute bipolar mania.^1-3 It also is used for off-label control of various psychiatric symptoms. It is a stable coordination compound composed of sodium valproate and valproic acid that dissipates into the valproate ion in the gastrointestinal tract.¹ (In this article, references to valproate [VPA] include valproic acid and divalproex.) The drug is relatively well-tolerated; however, use may carry teratogenic risk and can adversely impact a variety of body systems, especially hematopoietic, gastrointestinal, and neurologic systems.^1-3 Adverse effects can be idiosyncratic or in part related to VPA serum levels.^1,4 VPA toxicity increases the likelihood of some adverse health outcomes, such as nausea, diarrhea, and tremors.¹

Identifying and treating VHE

Asymptomatic elevations in ammonia without evidence of hepatic injury are common, might be related to valproic serum levels, and may occur in up to one-half of psychiatric patients receiving VPA.^2-4 In contrast, VHE is a rare and potentially lethal idiosyncratic event unrelated to duration of VPA treatment, dosage, or valproic serum level.^2-4 In addition, prior safe use might not protect against future VHE.^3,4

VHE presents as delirium with characteristic acute changes in mental status, including alterations in cognition or level of consciousness ranging from lethargy to coma, along with possible focal neurological findings or vomiting.^1,3,4 Although more common among patients with a seizure disorder, VHE also might be associated with new seizure activity in patients who do not have a seizure disorder.⁵

Although symptomatically acute in onset, emergence is unpredictable and can occur within days or up to years of use with therapeutic VPA dosing and valproic serum levels.^2,4 Complicating identification, laboratory transaminase or ammonia elevations may or may not be present^2-4; however, VHE typically occurs in the setting of hyperammonemia and normal transaminase levels.² Reversible EEG findings are nonspecific² and could show generalized slowing with occasional bursts of frontal intermittent rhythmic delta activity and triphasic waves.^2,4

Pathophysiological descriptions of emergent VHE have been hypothesized,^2-4 but the definitive causal mechanism remains unclear.⁶ Published VHE risk factors^2-6 include:

• polypharmacy (especially anti-­convulsants)
• inherited or dietary-based carnitine deficiency
• urea cycle disorders
• mental retardation.

How would you treat VHE?

a) cholinesterase inhibitors
b) antipsychotic therapy
c) supportive care

d) ammonia-reducing agents such as lactulose, carnitine, and neomycin

e) discontinue valproate

Outcome Normalized ammonia

Four days after discontinuing divalproex and starting lactulose, Mr. D’s fluctuating level of arousal, orientation, attention, and perceptual disturbances resolve along with restoration of environmental relatedness in setting of normalized ammonia level to 39 µg/dL. He is euthymic, non-psychotic, and without cognitive impairment at time of discharge. An “allergy” to divalproex is entered in his electronic medical record in an effort to discourage future retrial.

The authors’ observations

Once identified, management of VHE invariably includes consideration for discontinuation of valproate^1,2,4,19; other adjunctive, expediting, ammonia-reducing strategies, including lactulose and carnitine, have also been described.^2,4,5,20 Although lactulose is more commonly used, carnitine supplementation might be associated with a preferable dosing schedule and drug interaction and side-effect profile.²⁰ Rapidly deteriorating clinical status could indicate hemodialysis.⁴

Of critical importance, these management strategies rely on awareness of and prompt identification of the condition, which includes an ability to distinguish emergent VHE from the mental illness VPA is used to treat.

Stopping the offending agent generally results in complete recovery in VHE patients with psychiatric illness.⁴ Most (>90%, n = 31) psychiatric patients in our and prior⁵ case series reviews recovered within 2 weeks of intervention.⁵ Cautious resumption of divalproex could be considered if there is a compelling clinical indication and you suspect that a putative polypharmacy agent such as topiramate has been removed; otherwise future retrial of VPA should be avoided.¹⁴

Mr. D’s case was consistent with a valproate-related hyperammonemic delirious event. He had preadmission acute onset, intra-daily fluctuating confusion, and visual perceptual disturbances with nausea, asterixis, gait disturbance, elevated ammonia, and a supportive EEG months after starting divalproex. Similar to our case, some challenging aspects of identifying emergent VHE include:

• earlier safe use of divalproex over extended periods
• lack of elevated VPA serum level
• lack of transaminase elevation
• lack of apparent risk factors
• presence of background serious mental illness, which can distract from VHE detection via misattribution to uncontrolled primary mental illness.

This last point is critical because it can delay VHE identification and treatment or worse, result in misdiagnosis with accompanying continuation or escalation of VPA dosing as has initially occurred in Mr. D’s case. Similar concerns have been raised^2,5 and occurred,^5,19 which is not surprising given the frequency of VPA use for psychiatric conditions and symptoms.

Providers should have a low threshold for checking an ammonia level in clinical scenarios that involve any alteration in mental status that may resemble delirium in psychiatric patients treated with valproate. From a preventative perspective, it may be prudent to avoid valproate in psychiatric patients with known VHE risk factors. Either way, promotion of VHE awareness and detection across medical disciplines is paramount.

Clozapine has been available for decades, but relatively little has been published regarding its off-label uses. This data shortage likely is due in part to clozapine’s strict monitoring requirements, and we suspect off-label use is more commonplace than the literature reflects.

Refractory schizophrenia and reduction in suicidal behavior in schizophrenia or schizoaffective disorder are clozapine’s 2 FDA-approved indications. Clozapine also may be prescribed for other indications, and off-label uses have varying degrees of scientific support.

Our goal in “Rediscovering clozapine” has been to deepen clinicians’ appreciation for this unique medication and provide practical clinical guidance for its safe and effective use.^1,2 This final segment reviews representative literature regarding clozapine’s off-label use for bipolar disorder and other indications (Table).

7 Steps define off-label use

Seven steps are useful to consider when prescribing a medication off-label (Figure).³ Off-label prescribing is common in medicine and remains an important component of clinical practice. Sixty percent of antipsychotic prescriptions are written off-label,⁴ and physicians can prescribe any available medication to any patient for any purpose.

The FDA endorses off-label prescribing: “Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment.”⁵ Published case reports and case series provide guidance about the scientific support behind specific off-label indications.

Prescribing off-label based on clinical experience alone is legal, and 1 study reported that 73% of off-label prescriptions written by office-based physicians had little or no scientific support.⁶ From a medico­legal perspective, prescribing off-label with scientific support is preferred.

Bipolar disorder

Clozapine clearly is established as the most effective antipsychotic for treating refractory schizophrenia. A growing body of evidence supports the off-label use of clozapine for patients with bipolar disorder as well. This literature includes:

• a randomized, open-label trial of maintenance treatment of refractory bipolar disorder⁷
• 2 studies of treatment of acute mania^8,9
• a case series of 3 patients with refractory bipolar disorder and psychotic features who were effectively treated during acute manic episodes with ultra-rapid dose titrations of clozapine.¹⁰

In China, clozapine commonly is used to treat bipolar disorder. Results have been positive, and some clinicians there consider clozapine a first-line treatment for this indication.¹¹

In the largest published study of clozapine’s benefits for bipolar disorder, a Danish group presented a retrospective analysis of 326 patients with bipolar disorder (and no history of a schizophrenia-spectrum disorder) treated with clozapine between 1996 and 2007. The study group displayed a significant and clinically relevant reduction in psychiatric hospitalizations, polypharmacy, and self-harm. The authors concluded that clozapine appeared to be an appropriate choice for refractory bipolar disorder and encouraged future investigators to consider randomized controlled studies.¹²

Major depressive disorder

Published evidence supporting clozapine’s use for refractory unipolar depression is less robust than the evidence for refractory bipolar disorder. One retrospective analysis comparing clozapine treatment for bipolar disorder and unipolar depression concluded that patients with bipolar disorder responded better overall.¹³

Most case reports involve psychotic depression. One case series discussed clozapine treatment of 3 patients with psychotic depression and reported significant improvement in both depressive and psychotic symptoms.¹⁴ Other case reports also described patients with refractory psychotic depression.^15,16

We located only 1 case report about using clozapine for depressive symptoms absent psychosis. This case involved a patient who developed recurrent depression, hypersomnia, and behavioral disturbances at age 13 after a viral febrile infection. At age 27, she was hospitalized during an episode and started on low-dose clozapine. After discharge, she remained symptom-free for 30 months on clozapine, 50 to 100 mg/d. Although her symptoms included recurrent depression, her overall clinical picture seemed most consistent with Kleine-Levin syndrome (also known as “Sleeping Beauty” syndrome) rather than a primary mood disorder.¹⁷

Borderline personality disorder

Psychotherapy is the mainstay for treating borderline personality disorder (BPD), with pharmacotherapy often added to target symptoms such as anger and impulsivity.¹⁸ Some small studies and case series have examined clozapine use for BPD.

An open-label study of 15 inpatients with BPD and psychotic disorder not otherwise specified showed improvement on multiple rating scales with clozapine dosages averaging 250 mg/d.¹⁹ In a case series of 22 female inpatients with a primary diagnosis of BPD, clozapine showed beneficial effects in several clinical domains, including symptom severity and frequency of aggressive incidents. The greatest improvement occurred within the first 6 months of treatment.²⁰

Eight patients who continued clozapine after hospital discharge had fewer and shorter subsequent hospitalizations than others with BPD who were not prescribed clozapine at discharge.²¹ Individual case reports have discussed benefits of clozapine in challenging BPD cases.^22-24

Substance use treatment

A growing body of literature suggests that clozapine may reduce cravings for alcohol and illicit drugs because of its unique receptor profile. Much of the data has been collected in dual diagnosis patients taking clozapine primarily to treat schizophrenia or schizoaffective disorder. Patients in 1 study showed a comparable response to clozapine therapy whether they had a history of substance abuse or not. The authors opined that their results demonstrated a more generalizable decrease in cravings and recommended further study.²⁵

In a naturalistic study of 151 dual diagnosis patients with schizophrenia, alcohol use rates decreased significantly among those who received clozapine for psychiatric symptoms. After 3 years, 79% of patients treated with clozapine were in remission from alcohol use, compared with 33.7% of patients treated with other antipsychotics.²⁶

Other studies have reported decreased alcohol and illicit drug use in patients with schizophrenia and concomitant substance use.^27,28 Animal studies have displayed similar results, showing decreased alcohol intake with clozapine.^29,30

Compelling results have been shown in patients with schizophrenia and Cannabis use disorder. A small randomized trial compared clozapine with other anti­psychotics in individuals with schizophrenia and Cannabis use disorder. Clozapine was associated with significantly decreased Cannabis use, independent of overall symptom response or level of functioning.³¹ An animal study demonstrated an attenuated development of conditioned place preference (classical conditioning) to cocaine. The authors suggested that clozapine should be considered as a future pharmacotherapy to treat cocaine use.³²

The literature does not support prescribing clozapine solely for alcohol or illicit drug use, but clozapine merits consideration in patients with schizophrenia and comorbid substance use. This approach may be most beneficial in controlled environments, such as inpatient or residential facilities.

Suicidality

The 2-year International Suicide Prevention Trial (InterSePT) was the first to support clozapine’s efficacy in reducing the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder.³³ InterSePT data were in line with earlier observations, including improvement in reported depression and hopelessness in patients with primary psychotic disorders.^34,35 Clozapine’s action at serotonin receptors (in addition to dopamine receptors) may explain the benefits, based on the suspected link between suicide risk and serotonin.^34,36

Most published reports regarding clozapine for suicidality involve patients with schizophrenia or schizoaffective disorder. We found only 1 published case report describing clozapine’s use for recurrent suicidality in a patient with bipolar disorder. The authors described a dramatic reduction in suicidal ideation, suicide attempts, and hospitalizations after other attempted interventions—including electroconvulsive therapy—had been ineffective.³⁷

Aggression

In the absence of FDA-approved treatments for long-term management of aggression, many clinicians prescribe atypical antipsychotics. With the exception of clozapine, the demonstrated benefits of these medications for reducing aggression are equivocal. Clozapine is thought to be superior among atypical antipsychotics for addressing aggression because of its unique and broad combination of dopaminergic and serotonergic activity. Its effects on the D1-dopamine receptor likely target aggression, and its effects on the serotonin 2A receptor (5-HT2A) likely target the impulsivity commonly associated with aggression.^38,39

Clozapine has been shown to reduce long-term aggression in patients with psychotic disorders.^40-44 Most reports involve individuals with schizophrenia or schizo­affective disorder because this population is most commonly treated with clozapine. However, clozapine’s anti-aggressive benefits appear not to be solely related to sedation or improvement in psychosis.^42,45

What is known about clozapine’s mechanism suggests that its anti-aggressive benefits would extend beyond patients with schizophrenia and schizoaffective disorder. In a case series of 7 nonpsychotic patients with antisocial personality disorder and psychopathic traits, all displayed benefits with clozapine—particularly in domains of impulsive behavioral dyscontrol and anger.⁴⁶

Self-injurious behaviors (SIB) and aggression in 2 patients with profound mental retardation were reduced significantly after treatment was switched from risperidone to clozapine.⁴⁷ In a similar case, SIB and aggression improved in a man with cognitive impairment.⁴⁸ The case of Mr. C recounts our experience with using clozapine in a patient with cognitive impairment.

CASE REPORT
Daily assaults keep patient hospitalized

Mr. C, age 19 at the end of treatment, had moderate intellectual disability and an extensive history of violence. He grew up in group homes and long-term psychiatric facilities. Immediately after turning 18, he was transferred from an adolescent facility to an adult psychiatric hospital.

Our treatment team tried various combinations of benzodiazepines, mood stabilizers, and antipsychotics, but Mr. C consistently assaulted 1 or 2 peers daily without clear provocation. Eventually we started him on clozapine, which we titrated to an effective dose (based on a therapeutic serum level). We also added a therapeutic dosage of lithium to address his residual aggression. With the regimen of clozapine and lithium, Mr. C’s assaultive behavior improved dramatically. After going more than 1 year without assaulting a peer, he was placed in the community.

Movement disorders

Parkinson’s disease. The most extensive evidence for treating movement disorders with clozapine involves patients with Parkinson’s disease (PD). Geriatric psychiatrists commonly use clozapine, particularly at low doses, to treat psychotic symptoms in patients with PD. Because of a relatively low likelihood of extrapyramidal side effects, clozapine and quetiapine are the 2 antipsychotics most often used to treat dopamimetic psychosis in PD.⁴⁹ In a randomized, placebo-controlled study, low-dose clozapine showed benefits in treating dopamimetic psychosis in PD, without worsening overall motor function.⁵⁰ (The recent approval of pimavanserin for PD psychosis likely will impact off-label use of clozapine for this condition.)

A retrospective review of patients with PD and Lewy body dementia described benefits of treating psychosis with clozapine.⁵¹ Benefits also have been reported in using clozapine to address levodopa-induced dyskinesia (LID) absent psychotic symptoms. In an evidence-based review, the Movement Disorder Society described clozapine for LID as “efficacious and possibly useful.”⁵²

Tardive syndromes. In a retrospective review of clozapine use for tardive dyskinesia, 43% of the 30 patients showed improvement, particularly those with concomitant dystonia.⁵³ Another retrospective analysis reported similar outcomes for 48 patients with tardive dyskinesia treated with clozapine.⁵⁴ Case series and case reports show support for clozapine as monotherapy for tardive dystonia.⁵⁵

Huntington’s disease. A randomized, double-blind study found little benefit in using clozapine for patients with Huntington’s disease. The authors concluded that, although individual patients may be able to tolerate sufficiently high dosages to improve chorea, clinicians should use restraint when considering clozapine for this population.⁵⁶

Precautions in older patients. Caution is advised when using clozapine for movement disorders in older individuals, particularly those with concurrent dementia. All antipsychotics, including clozapine,⁵⁷ carry a “black-box” warning of increased mortality in older adults with dementia.

We hope that this series, “Rediscovering clozapine,” has helped you get reacquainted with this effective medication, employ appropriate caution, and explore off-label uses.

Clozapine has been available for decades, but relatively little has been published regarding its off-label uses. This data shortage likely is due in part to clozapine’s strict monitoring requirements, and we suspect off-label use is more commonplace than the literature reflects.

Refractory schizophrenia and reduction in suicidal behavior in schizophrenia or schizoaffective disorder are clozapine’s 2 FDA-approved indications. Clozapine also may be prescribed for other indications, and off-label uses have varying degrees of scientific support.

Our goal in “Rediscovering clozapine” has been to deepen clinicians’ appreciation for this unique medication and provide practical clinical guidance for its safe and effective use.^1,2 This final segment reviews representative literature regarding clozapine’s off-label use for bipolar disorder and other indications (Table).

7 Steps define off-label use

Seven steps are useful to consider when prescribing a medication off-label (Figure).³ Off-label prescribing is common in medicine and remains an important component of clinical practice. Sixty percent of antipsychotic prescriptions are written off-label,⁴ and physicians can prescribe any available medication to any patient for any purpose.

The FDA endorses off-label prescribing: “Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment.”⁵ Published case reports and case series provide guidance about the scientific support behind specific off-label indications.

Prescribing off-label based on clinical experience alone is legal, and 1 study reported that 73% of off-label prescriptions written by office-based physicians had little or no scientific support.⁶ From a medico­legal perspective, prescribing off-label with scientific support is preferred.

Bipolar disorder

Clozapine clearly is established as the most effective antipsychotic for treating refractory schizophrenia. A growing body of evidence supports the off-label use of clozapine for patients with bipolar disorder as well. This literature includes:

• a randomized, open-label trial of maintenance treatment of refractory bipolar disorder⁷
• 2 studies of treatment of acute mania^8,9
• a case series of 3 patients with refractory bipolar disorder and psychotic features who were effectively treated during acute manic episodes with ultra-rapid dose titrations of clozapine.¹⁰

In China, clozapine commonly is used to treat bipolar disorder. Results have been positive, and some clinicians there consider clozapine a first-line treatment for this indication.¹¹

In the largest published study of clozapine’s benefits for bipolar disorder, a Danish group presented a retrospective analysis of 326 patients with bipolar disorder (and no history of a schizophrenia-spectrum disorder) treated with clozapine between 1996 and 2007. The study group displayed a significant and clinically relevant reduction in psychiatric hospitalizations, polypharmacy, and self-harm. The authors concluded that clozapine appeared to be an appropriate choice for refractory bipolar disorder and encouraged future investigators to consider randomized controlled studies.¹²

Major depressive disorder

Published evidence supporting clozapine’s use for refractory unipolar depression is less robust than the evidence for refractory bipolar disorder. One retrospective analysis comparing clozapine treatment for bipolar disorder and unipolar depression concluded that patients with bipolar disorder responded better overall.¹³

Most case reports involve psychotic depression. One case series discussed clozapine treatment of 3 patients with psychotic depression and reported significant improvement in both depressive and psychotic symptoms.¹⁴ Other case reports also described patients with refractory psychotic depression.^15,16

We located only 1 case report about using clozapine for depressive symptoms absent psychosis. This case involved a patient who developed recurrent depression, hypersomnia, and behavioral disturbances at age 13 after a viral febrile infection. At age 27, she was hospitalized during an episode and started on low-dose clozapine. After discharge, she remained symptom-free for 30 months on clozapine, 50 to 100 mg/d. Although her symptoms included recurrent depression, her overall clinical picture seemed most consistent with Kleine-Levin syndrome (also known as “Sleeping Beauty” syndrome) rather than a primary mood disorder.¹⁷

Borderline personality disorder

Psychotherapy is the mainstay for treating borderline personality disorder (BPD), with pharmacotherapy often added to target symptoms such as anger and impulsivity.¹⁸ Some small studies and case series have examined clozapine use for BPD.

An open-label study of 15 inpatients with BPD and psychotic disorder not otherwise specified showed improvement on multiple rating scales with clozapine dosages averaging 250 mg/d.¹⁹ In a case series of 22 female inpatients with a primary diagnosis of BPD, clozapine showed beneficial effects in several clinical domains, including symptom severity and frequency of aggressive incidents. The greatest improvement occurred within the first 6 months of treatment.²⁰

Eight patients who continued clozapine after hospital discharge had fewer and shorter subsequent hospitalizations than others with BPD who were not prescribed clozapine at discharge.²¹ Individual case reports have discussed benefits of clozapine in challenging BPD cases.^22-24

Substance use treatment

A growing body of literature suggests that clozapine may reduce cravings for alcohol and illicit drugs because of its unique receptor profile. Much of the data has been collected in dual diagnosis patients taking clozapine primarily to treat schizophrenia or schizoaffective disorder. Patients in 1 study showed a comparable response to clozapine therapy whether they had a history of substance abuse or not. The authors opined that their results demonstrated a more generalizable decrease in cravings and recommended further study.²⁵

In a naturalistic study of 151 dual diagnosis patients with schizophrenia, alcohol use rates decreased significantly among those who received clozapine for psychiatric symptoms. After 3 years, 79% of patients treated with clozapine were in remission from alcohol use, compared with 33.7% of patients treated with other antipsychotics.²⁶

Other studies have reported decreased alcohol and illicit drug use in patients with schizophrenia and concomitant substance use.^27,28 Animal studies have displayed similar results, showing decreased alcohol intake with clozapine.^29,30

Compelling results have been shown in patients with schizophrenia and Cannabis use disorder. A small randomized trial compared clozapine with other anti­psychotics in individuals with schizophrenia and Cannabis use disorder. Clozapine was associated with significantly decreased Cannabis use, independent of overall symptom response or level of functioning.³¹ An animal study demonstrated an attenuated development of conditioned place preference (classical conditioning) to cocaine. The authors suggested that clozapine should be considered as a future pharmacotherapy to treat cocaine use.³²

The literature does not support prescribing clozapine solely for alcohol or illicit drug use, but clozapine merits consideration in patients with schizophrenia and comorbid substance use. This approach may be most beneficial in controlled environments, such as inpatient or residential facilities.

Suicidality

The 2-year International Suicide Prevention Trial (InterSePT) was the first to support clozapine’s efficacy in reducing the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder.³³ InterSePT data were in line with earlier observations, including improvement in reported depression and hopelessness in patients with primary psychotic disorders.^34,35 Clozapine’s action at serotonin receptors (in addition to dopamine receptors) may explain the benefits, based on the suspected link between suicide risk and serotonin.^34,36

Most published reports regarding clozapine for suicidality involve patients with schizophrenia or schizoaffective disorder. We found only 1 published case report describing clozapine’s use for recurrent suicidality in a patient with bipolar disorder. The authors described a dramatic reduction in suicidal ideation, suicide attempts, and hospitalizations after other attempted interventions—including electroconvulsive therapy—had been ineffective.³⁷

Aggression

In the absence of FDA-approved treatments for long-term management of aggression, many clinicians prescribe atypical antipsychotics. With the exception of clozapine, the demonstrated benefits of these medications for reducing aggression are equivocal. Clozapine is thought to be superior among atypical antipsychotics for addressing aggression because of its unique and broad combination of dopaminergic and serotonergic activity. Its effects on the D1-dopamine receptor likely target aggression, and its effects on the serotonin 2A receptor (5-HT2A) likely target the impulsivity commonly associated with aggression.^38,39

Clozapine has been shown to reduce long-term aggression in patients with psychotic disorders.^40-44 Most reports involve individuals with schizophrenia or schizo­affective disorder because this population is most commonly treated with clozapine. However, clozapine’s anti-aggressive benefits appear not to be solely related to sedation or improvement in psychosis.^42,45

What is known about clozapine’s mechanism suggests that its anti-aggressive benefits would extend beyond patients with schizophrenia and schizoaffective disorder. In a case series of 7 nonpsychotic patients with antisocial personality disorder and psychopathic traits, all displayed benefits with clozapine—particularly in domains of impulsive behavioral dyscontrol and anger.⁴⁶

Self-injurious behaviors (SIB) and aggression in 2 patients with profound mental retardation were reduced significantly after treatment was switched from risperidone to clozapine.⁴⁷ In a similar case, SIB and aggression improved in a man with cognitive impairment.⁴⁸ The case of Mr. C recounts our experience with using clozapine in a patient with cognitive impairment.

CASE REPORT
Daily assaults keep patient hospitalized

Mr. C, age 19 at the end of treatment, had moderate intellectual disability and an extensive history of violence. He grew up in group homes and long-term psychiatric facilities. Immediately after turning 18, he was transferred from an adolescent facility to an adult psychiatric hospital.

Our treatment team tried various combinations of benzodiazepines, mood stabilizers, and antipsychotics, but Mr. C consistently assaulted 1 or 2 peers daily without clear provocation. Eventually we started him on clozapine, which we titrated to an effective dose (based on a therapeutic serum level). We also added a therapeutic dosage of lithium to address his residual aggression. With the regimen of clozapine and lithium, Mr. C’s assaultive behavior improved dramatically. After going more than 1 year without assaulting a peer, he was placed in the community.

Movement disorders

Parkinson’s disease. The most extensive evidence for treating movement disorders with clozapine involves patients with Parkinson’s disease (PD). Geriatric psychiatrists commonly use clozapine, particularly at low doses, to treat psychotic symptoms in patients with PD. Because of a relatively low likelihood of extrapyramidal side effects, clozapine and quetiapine are the 2 antipsychotics most often used to treat dopamimetic psychosis in PD.⁴⁹ In a randomized, placebo-controlled study, low-dose clozapine showed benefits in treating dopamimetic psychosis in PD, without worsening overall motor function.⁵⁰ (The recent approval of pimavanserin for PD psychosis likely will impact off-label use of clozapine for this condition.)

A retrospective review of patients with PD and Lewy body dementia described benefits of treating psychosis with clozapine.⁵¹ Benefits also have been reported in using clozapine to address levodopa-induced dyskinesia (LID) absent psychotic symptoms. In an evidence-based review, the Movement Disorder Society described clozapine for LID as “efficacious and possibly useful.”⁵²

Tardive syndromes. In a retrospective review of clozapine use for tardive dyskinesia, 43% of the 30 patients showed improvement, particularly those with concomitant dystonia.⁵³ Another retrospective analysis reported similar outcomes for 48 patients with tardive dyskinesia treated with clozapine.⁵⁴ Case series and case reports show support for clozapine as monotherapy for tardive dystonia.⁵⁵

Huntington’s disease. A randomized, double-blind study found little benefit in using clozapine for patients with Huntington’s disease. The authors concluded that, although individual patients may be able to tolerate sufficiently high dosages to improve chorea, clinicians should use restraint when considering clozapine for this population.⁵⁶

Precautions in older patients. Caution is advised when using clozapine for movement disorders in older individuals, particularly those with concurrent dementia. All antipsychotics, including clozapine,⁵⁷ carry a “black-box” warning of increased mortality in older adults with dementia.

We hope that this series, “Rediscovering clozapine,” has helped you get reacquainted with this effective medication, employ appropriate caution, and explore off-label uses.

Clozapine has been available for decades, but relatively little has been published regarding its off-label uses. This data shortage likely is due in part to clozapine’s strict monitoring requirements, and we suspect off-label use is more commonplace than the literature reflects.

Refractory schizophrenia and reduction in suicidal behavior in schizophrenia or schizoaffective disorder are clozapine’s 2 FDA-approved indications. Clozapine also may be prescribed for other indications, and off-label uses have varying degrees of scientific support.

Our goal in “Rediscovering clozapine” has been to deepen clinicians’ appreciation for this unique medication and provide practical clinical guidance for its safe and effective use.^1,2 This final segment reviews representative literature regarding clozapine’s off-label use for bipolar disorder and other indications (Table).

7 Steps define off-label use

Seven steps are useful to consider when prescribing a medication off-label (Figure).³ Off-label prescribing is common in medicine and remains an important component of clinical practice. Sixty percent of antipsychotic prescriptions are written off-label,⁴ and physicians can prescribe any available medication to any patient for any purpose.

The FDA endorses off-label prescribing: “Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment.”⁵ Published case reports and case series provide guidance about the scientific support behind specific off-label indications.

Prescribing off-label based on clinical experience alone is legal, and 1 study reported that 73% of off-label prescriptions written by office-based physicians had little or no scientific support.⁶ From a medico­legal perspective, prescribing off-label with scientific support is preferred.

Bipolar disorder

Clozapine clearly is established as the most effective antipsychotic for treating refractory schizophrenia. A growing body of evidence supports the off-label use of clozapine for patients with bipolar disorder as well. This literature includes:

• a randomized, open-label trial of maintenance treatment of refractory bipolar disorder⁷
• 2 studies of treatment of acute mania^8,9
• a case series of 3 patients with refractory bipolar disorder and psychotic features who were effectively treated during acute manic episodes with ultra-rapid dose titrations of clozapine.¹⁰

In China, clozapine commonly is used to treat bipolar disorder. Results have been positive, and some clinicians there consider clozapine a first-line treatment for this indication.¹¹

In the largest published study of clozapine’s benefits for bipolar disorder, a Danish group presented a retrospective analysis of 326 patients with bipolar disorder (and no history of a schizophrenia-spectrum disorder) treated with clozapine between 1996 and 2007. The study group displayed a significant and clinically relevant reduction in psychiatric hospitalizations, polypharmacy, and self-harm. The authors concluded that clozapine appeared to be an appropriate choice for refractory bipolar disorder and encouraged future investigators to consider randomized controlled studies.¹²

Major depressive disorder

Published evidence supporting clozapine’s use for refractory unipolar depression is less robust than the evidence for refractory bipolar disorder. One retrospective analysis comparing clozapine treatment for bipolar disorder and unipolar depression concluded that patients with bipolar disorder responded better overall.¹³

Most case reports involve psychotic depression. One case series discussed clozapine treatment of 3 patients with psychotic depression and reported significant improvement in both depressive and psychotic symptoms.¹⁴ Other case reports also described patients with refractory psychotic depression.^15,16

We located only 1 case report about using clozapine for depressive symptoms absent psychosis. This case involved a patient who developed recurrent depression, hypersomnia, and behavioral disturbances at age 13 after a viral febrile infection. At age 27, she was hospitalized during an episode and started on low-dose clozapine. After discharge, she remained symptom-free for 30 months on clozapine, 50 to 100 mg/d. Although her symptoms included recurrent depression, her overall clinical picture seemed most consistent with Kleine-Levin syndrome (also known as “Sleeping Beauty” syndrome) rather than a primary mood disorder.¹⁷

Borderline personality disorder

Psychotherapy is the mainstay for treating borderline personality disorder (BPD), with pharmacotherapy often added to target symptoms such as anger and impulsivity.¹⁸ Some small studies and case series have examined clozapine use for BPD.

An open-label study of 15 inpatients with BPD and psychotic disorder not otherwise specified showed improvement on multiple rating scales with clozapine dosages averaging 250 mg/d.¹⁹ In a case series of 22 female inpatients with a primary diagnosis of BPD, clozapine showed beneficial effects in several clinical domains, including symptom severity and frequency of aggressive incidents. The greatest improvement occurred within the first 6 months of treatment.²⁰

Eight patients who continued clozapine after hospital discharge had fewer and shorter subsequent hospitalizations than others with BPD who were not prescribed clozapine at discharge.²¹ Individual case reports have discussed benefits of clozapine in challenging BPD cases.^22-24

Substance use treatment

A growing body of literature suggests that clozapine may reduce cravings for alcohol and illicit drugs because of its unique receptor profile. Much of the data has been collected in dual diagnosis patients taking clozapine primarily to treat schizophrenia or schizoaffective disorder. Patients in 1 study showed a comparable response to clozapine therapy whether they had a history of substance abuse or not. The authors opined that their results demonstrated a more generalizable decrease in cravings and recommended further study.²⁵

In a naturalistic study of 151 dual diagnosis patients with schizophrenia, alcohol use rates decreased significantly among those who received clozapine for psychiatric symptoms. After 3 years, 79% of patients treated with clozapine were in remission from alcohol use, compared with 33.7% of patients treated with other antipsychotics.²⁶

Other studies have reported decreased alcohol and illicit drug use in patients with schizophrenia and concomitant substance use.^27,28 Animal studies have displayed similar results, showing decreased alcohol intake with clozapine.^29,30

Compelling results have been shown in patients with schizophrenia and Cannabis use disorder. A small randomized trial compared clozapine with other anti­psychotics in individuals with schizophrenia and Cannabis use disorder. Clozapine was associated with significantly decreased Cannabis use, independent of overall symptom response or level of functioning.³¹ An animal study demonstrated an attenuated development of conditioned place preference (classical conditioning) to cocaine. The authors suggested that clozapine should be considered as a future pharmacotherapy to treat cocaine use.³²

The literature does not support prescribing clozapine solely for alcohol or illicit drug use, but clozapine merits consideration in patients with schizophrenia and comorbid substance use. This approach may be most beneficial in controlled environments, such as inpatient or residential facilities.

Suicidality

The 2-year International Suicide Prevention Trial (InterSePT) was the first to support clozapine’s efficacy in reducing the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder.³³ InterSePT data were in line with earlier observations, including improvement in reported depression and hopelessness in patients with primary psychotic disorders.^34,35 Clozapine’s action at serotonin receptors (in addition to dopamine receptors) may explain the benefits, based on the suspected link between suicide risk and serotonin.^34,36

Most published reports regarding clozapine for suicidality involve patients with schizophrenia or schizoaffective disorder. We found only 1 published case report describing clozapine’s use for recurrent suicidality in a patient with bipolar disorder. The authors described a dramatic reduction in suicidal ideation, suicide attempts, and hospitalizations after other attempted interventions—including electroconvulsive therapy—had been ineffective.³⁷

Aggression

In the absence of FDA-approved treatments for long-term management of aggression, many clinicians prescribe atypical antipsychotics. With the exception of clozapine, the demonstrated benefits of these medications for reducing aggression are equivocal. Clozapine is thought to be superior among atypical antipsychotics for addressing aggression because of its unique and broad combination of dopaminergic and serotonergic activity. Its effects on the D1-dopamine receptor likely target aggression, and its effects on the serotonin 2A receptor (5-HT2A) likely target the impulsivity commonly associated with aggression.^38,39

Clozapine has been shown to reduce long-term aggression in patients with psychotic disorders.^40-44 Most reports involve individuals with schizophrenia or schizo­affective disorder because this population is most commonly treated with clozapine. However, clozapine’s anti-aggressive benefits appear not to be solely related to sedation or improvement in psychosis.^42,45

What is known about clozapine’s mechanism suggests that its anti-aggressive benefits would extend beyond patients with schizophrenia and schizoaffective disorder. In a case series of 7 nonpsychotic patients with antisocial personality disorder and psychopathic traits, all displayed benefits with clozapine—particularly in domains of impulsive behavioral dyscontrol and anger.⁴⁶

Self-injurious behaviors (SIB) and aggression in 2 patients with profound mental retardation were reduced significantly after treatment was switched from risperidone to clozapine.⁴⁷ In a similar case, SIB and aggression improved in a man with cognitive impairment.⁴⁸ The case of Mr. C recounts our experience with using clozapine in a patient with cognitive impairment.

CASE REPORT
Daily assaults keep patient hospitalized

Mr. C, age 19 at the end of treatment, had moderate intellectual disability and an extensive history of violence. He grew up in group homes and long-term psychiatric facilities. Immediately after turning 18, he was transferred from an adolescent facility to an adult psychiatric hospital.

Our treatment team tried various combinations of benzodiazepines, mood stabilizers, and antipsychotics, but Mr. C consistently assaulted 1 or 2 peers daily without clear provocation. Eventually we started him on clozapine, which we titrated to an effective dose (based on a therapeutic serum level). We also added a therapeutic dosage of lithium to address his residual aggression. With the regimen of clozapine and lithium, Mr. C’s assaultive behavior improved dramatically. After going more than 1 year without assaulting a peer, he was placed in the community.

Movement disorders

Parkinson’s disease. The most extensive evidence for treating movement disorders with clozapine involves patients with Parkinson’s disease (PD). Geriatric psychiatrists commonly use clozapine, particularly at low doses, to treat psychotic symptoms in patients with PD. Because of a relatively low likelihood of extrapyramidal side effects, clozapine and quetiapine are the 2 antipsychotics most often used to treat dopamimetic psychosis in PD.⁴⁹ In a randomized, placebo-controlled study, low-dose clozapine showed benefits in treating dopamimetic psychosis in PD, without worsening overall motor function.⁵⁰ (The recent approval of pimavanserin for PD psychosis likely will impact off-label use of clozapine for this condition.)

A retrospective review of patients with PD and Lewy body dementia described benefits of treating psychosis with clozapine.⁵¹ Benefits also have been reported in using clozapine to address levodopa-induced dyskinesia (LID) absent psychotic symptoms. In an evidence-based review, the Movement Disorder Society described clozapine for LID as “efficacious and possibly useful.”⁵²

Tardive syndromes. In a retrospective review of clozapine use for tardive dyskinesia, 43% of the 30 patients showed improvement, particularly those with concomitant dystonia.⁵³ Another retrospective analysis reported similar outcomes for 48 patients with tardive dyskinesia treated with clozapine.⁵⁴ Case series and case reports show support for clozapine as monotherapy for tardive dystonia.⁵⁵

Huntington’s disease. A randomized, double-blind study found little benefit in using clozapine for patients with Huntington’s disease. The authors concluded that, although individual patients may be able to tolerate sufficiently high dosages to improve chorea, clinicians should use restraint when considering clozapine for this population.⁵⁶

Precautions in older patients. Caution is advised when using clozapine for movement disorders in older individuals, particularly those with concurrent dementia. All antipsychotics, including clozapine,⁵⁷ carry a “black-box” warning of increased mortality in older adults with dementia.

We hope that this series, “Rediscovering clozapine,” has helped you get reacquainted with this effective medication, employ appropriate caution, and explore off-label uses.

CASE
Sudden deterioration

R, age 11, has attention-deficit/hyperactivity disorder (ADHD), combined type, and oppositional defiant disorder, which has been stable for more than a year on extended-release (ER) methylphenidate (brand name: Concerta), 54 mg/d (1.2 mg/kg). With combined pharma­cotherapy and behavioral management, his symptoms of hyperactivity, inattention, and impulsivity improved at school and at home. He shows some academic gains as evidenced by improved achievement at school.

Over 2 months, R experiences a substantial deterioration in behavioral and academic performance. Along with core symptoms of ADHD, he begins to exhibit physical and verbal aggression. A report from school states that R has been using obscene language and destroying property, and has had episodes of provoked aggression toward his peers. His grades drop and he receives 2 school suspensions because of aggressive behavior.

What could be causing R’s ADHD symptoms to reemerge?

a) nonadherence to treatment
b) substance abuse
c) medication change
d) all of the above

The authors’ observations

Worsening of psychiatric symptoms in a stable patient is relatively common. Many factors can contribute to patient destabilization. Treatment nonadherence is a leading cause, along with psychosocial stressors and substance use (Table).

EVALUATION
Adherence confirmed

R is hyperactive and distracted during his visit, a clear deterioration from his baseline status. R is oppositional and defiant toward his mother during the session, but shows good social skills when communicating with the physician.

R’s mother reports that her son seldom forgets to take his medication, and she ensures that he is swallowing the pill, rather than chewing it. Data from the prescription drug-monitoring program show that the family is filling the prescriptions regularly. The ER methylphenidate dosage is raised to 72 mg/d. The clinicians provide psychoeducation about adherence to a medication regimen to R and his family. Also, his parents and teachers receive Vanderbilt Assessment Scales for ADHD to assess the symptoms in different settings.

At a follow-up visit a week later, R’s mother reports that her son continues to have problems in school and at home. The Vanderbilt scales reveal that R is having clinically significant problems with attention, hyperactivity, impulse control, and oppositional behavior.

A urine drug screen is ordered to rule out the possibility of a sudden deterioration of ADHD symptoms secondary to substance use disorder. To ensure compliance, we recommend that R take his medication at the school nurse’s office in the morning.

A week later

Although R takes his medication at school, he continues to show core symptoms of ADHD without improvement. The urine drug screen is negative. A physical examination does not reveal any medical illness. The treatment team calls the pharmacist to obtain a complete list of medications R is taking, who confirms that he is only receiving ER methylphenidate, 72 mg/d. The pharmacist also notes that R’s medication was switched from the brand-name drug to a generic 3 months ago because of a change in insurance coverage. This change coincided with the reemergence of his ADHD symptoms.

R’s mother reports that the new pills do not look like the old ones even before the dosage was raised. A new brand-necessary prescription is sent to the pharmacy. With the brand-name medication, R’s symptoms quickly improve, and remain improved when the dosage is decreased to the previous dosage of 54 mg/d.

With osmotic-controlled release oral delivery system (OROS) and outer coating of ER methylphenidate, how much drug is released immediately vs slow release?

a) 22% immediate release and 78% slow release
b) 78% immediate release and 22% slow release
c) 50% immediate release and 50% slow release

The authors’ observations

Generic substitution of a brand medication can result in worsening of symptoms and increased adverse effects. Possible bioequivalence issues can lead to failure of drug therapy.¹

In 2013, the FDA determined that 2 specific generic formulations of ER methylphenidate do not have therapeutic equivalency to the brand-name medication, Concerta. The FDA stated, “Based on an analysis of data, FDA has concerns about whether or not two approved generic versions of Concerta tablets (methylphenidate hydrochloride extended-release tablets), used to treat attention-deficit hyperactivity disorder in adults and children, are therapeutically equiv

In an apparent confirmation of the FDA’s concerns, a case series of children and adolescents with ADHD observed that almost all of the patients showed symptom improvement when they switched from a non-OROS formulation to an OROS preparation at the same dosage.³

The OROS preparation is thought to provide more predictable medication delivery over an extended period of time (Figure). A patient taking an ER formulation without OROS might lose this benefit, which could lead to symptom destabilization, even if the patient is taking the medication as instructed.

Brand vs generic

Under FDA regulations, companies seeking approval for generic formulations of approved drugs must demonstrate that their products are the same as the brand-name drug in terms of:  

• active ingredients
• strength
• dosage form
• route of administration  
• packaging label.

In addition, the pharmaceutical company must demonstrate that the generic form is absorbed and distributed to the part of the body at which it has its effect at acceptably similar levels to the brand-name drug. All medications—new or generic, in clinical trials or approved, prescription or over-the-counter—must be manufactured under controlled conditions that assure product quality.

However, some studies have disputed this equivalency. In 1 study, patients with schizophrenia receiving generic olanz­apine had lower serum concentration than patients with schizophrenia taking equivalent dosages of brand-name olanzapine.⁴ Similarly, studies comparing generic and brand-name venlafaxine showed significant differences in peak plasma concentration (Cmax)between generic and brand-name compounds.⁵

The FDA has considered upgrading the manufacturers’ warnings about the risk of generic medications, but has delayed the decision to 2017.⁶

FDA’s approval process for generic drugs

To receive approval of a generic formulation in the United States, the FDA requires that the generic drug should be compared with the corresponding brand-name drug in small crossover trials involving at least 24 to 36 healthy volunteers.

Bioequivalence is then established based on assessments of the rate of absorption (Cmax and area under the plasma concentration-time curve [AUC]). The FDA’s criteria are designed to achieve 90% confidence that the ratios of the test-to-reference log-transformed mean values for AUC and Cmax are within the interval of 80% to 125%. The FDA accepts −20% to 25% variation in Cmax and AUC in products that are considered bioequivalent. This is much less stringent than its −5% to 5% standard used for brand-name products. The FDA publishes a list of generic drugs that have been certified as bioequivalent, known as the “Orange Book.”⁵

Considerations when substituting generic medication

Because of the growing number of generic formulations of the same medication, generic–generic switches are becoming more commonplace. Theoretically, any 2 generic versions of the same medication can have a variation of up to 40% in AUC and Cmax. Generic medications are tested in healthy human controls through single-dose studies, which raises concerns about their applicability to the entire patient population.

Bioequivalence. It is a matter of debate whether bioequivalence translates to therapeutic equivalency. For medications with a narrow therapeutic index, the FDA has accepted that these 2 phenomena are not necessarily linked. With the exception of a few medications, including lithium and some anticonvulsants such as divalproex sodium and carbamazepine, serum level of the medications usually does not predict clinical response.

Inert ingredients. Generic medications can include inert ingredients (excipients) that are different from those in their branded counterparts. Some of these inactive ingredients can cause adverse effects. A study comparing paroxetine mesylate and paroxetine hydrochloride showed differences in bioequivalence and clinical efficacy.⁷

In some cases, brand-to-generic substitution can thwart clinical progress in a stable patient. This small change in the medication could destabilize the patient’s condition, which, in turn, may lead to unnecessary and significant social and financial burdens on the patient’s family, school, community, and the health care system.

Recommendations

In the event of a change in clinical response, clinicians first should evaluate adherence and explore other factors, such as biological, psychological, medical, and social issues. Adherence can be adversely affected by a change in the physical characteristics of the pill. Prescribers should remain cognizant of brand–generic and generic–generic switches. It may be reasonable to adjust the dosage of the new generic medication to address changes in clinical effectiveness.

If these strategies are ineffective, consider switching to a brand-name medication. Write “Dispense As Written” on the prescription to ensure delivery of the branded medication or a specific generic version of the medication.

An insurance company might require prior authorization to approve payment for the brand medication. To save time, use electronic forms or fax for communicating with the insurance company. Adding references to FDA statements and research papers, along with the patient’s history and presentations, would be prudent to demonstrate doubts about efficacy of the generic medication.

CASE
Sudden deterioration

R, age 11, has attention-deficit/hyperactivity disorder (ADHD), combined type, and oppositional defiant disorder, which has been stable for more than a year on extended-release (ER) methylphenidate (brand name: Concerta), 54 mg/d (1.2 mg/kg). With combined pharma­cotherapy and behavioral management, his symptoms of hyperactivity, inattention, and impulsivity improved at school and at home. He shows some academic gains as evidenced by improved achievement at school.

Over 2 months, R experiences a substantial deterioration in behavioral and academic performance. Along with core symptoms of ADHD, he begins to exhibit physical and verbal aggression. A report from school states that R has been using obscene language and destroying property, and has had episodes of provoked aggression toward his peers. His grades drop and he receives 2 school suspensions because of aggressive behavior.

What could be causing R’s ADHD symptoms to reemerge?

a) nonadherence to treatment
b) substance abuse
c) medication change
d) all of the above

The authors’ observations

Worsening of psychiatric symptoms in a stable patient is relatively common. Many factors can contribute to patient destabilization. Treatment nonadherence is a leading cause, along with psychosocial stressors and substance use (Table).

EVALUATION
Adherence confirmed

R is hyperactive and distracted during his visit, a clear deterioration from his baseline status. R is oppositional and defiant toward his mother during the session, but shows good social skills when communicating with the physician.

R’s mother reports that her son seldom forgets to take his medication, and she ensures that he is swallowing the pill, rather than chewing it. Data from the prescription drug-monitoring program show that the family is filling the prescriptions regularly. The ER methylphenidate dosage is raised to 72 mg/d. The clinicians provide psychoeducation about adherence to a medication regimen to R and his family. Also, his parents and teachers receive Vanderbilt Assessment Scales for ADHD to assess the symptoms in different settings.

At a follow-up visit a week later, R’s mother reports that her son continues to have problems in school and at home. The Vanderbilt scales reveal that R is having clinically significant problems with attention, hyperactivity, impulse control, and oppositional behavior.

A urine drug screen is ordered to rule out the possibility of a sudden deterioration of ADHD symptoms secondary to substance use disorder. To ensure compliance, we recommend that R take his medication at the school nurse’s office in the morning.

A week later

Although R takes his medication at school, he continues to show core symptoms of ADHD without improvement. The urine drug screen is negative. A physical examination does not reveal any medical illness. The treatment team calls the pharmacist to obtain a complete list of medications R is taking, who confirms that he is only receiving ER methylphenidate, 72 mg/d. The pharmacist also notes that R’s medication was switched from the brand-name drug to a generic 3 months ago because of a change in insurance coverage. This change coincided with the reemergence of his ADHD symptoms.

R’s mother reports that the new pills do not look like the old ones even before the dosage was raised. A new brand-necessary prescription is sent to the pharmacy. With the brand-name medication, R’s symptoms quickly improve, and remain improved when the dosage is decreased to the previous dosage of 54 mg/d.

With osmotic-controlled release oral delivery system (OROS) and outer coating of ER methylphenidate, how much drug is released immediately vs slow release?

a) 22% immediate release and 78% slow release
b) 78% immediate release and 22% slow release
c) 50% immediate release and 50% slow release

The authors’ observations

Generic substitution of a brand medication can result in worsening of symptoms and increased adverse effects. Possible bioequivalence issues can lead to failure of drug therapy.¹

In 2013, the FDA determined that 2 specific generic formulations of ER methylphenidate do not have therapeutic equivalency to the brand-name medication, Concerta. The FDA stated, “Based on an analysis of data, FDA has concerns about whether or not two approved generic versions of Concerta tablets (methylphenidate hydrochloride extended-release tablets), used to treat attention-deficit hyperactivity disorder in adults and children, are therapeutically equiv

In an apparent confirmation of the FDA’s concerns, a case series of children and adolescents with ADHD observed that almost all of the patients showed symptom improvement when they switched from a non-OROS formulation to an OROS preparation at the same dosage.³

The OROS preparation is thought to provide more predictable medication delivery over an extended period of time (Figure). A patient taking an ER formulation without OROS might lose this benefit, which could lead to symptom destabilization, even if the patient is taking the medication as instructed.

Brand vs generic

Under FDA regulations, companies seeking approval for generic formulations of approved drugs must demonstrate that their products are the same as the brand-name drug in terms of:  

• active ingredients
• strength
• dosage form
• route of administration  
• packaging label.

In addition, the pharmaceutical company must demonstrate that the generic form is absorbed and distributed to the part of the body at which it has its effect at acceptably similar levels to the brand-name drug. All medications—new or generic, in clinical trials or approved, prescription or over-the-counter—must be manufactured under controlled conditions that assure product quality.

However, some studies have disputed this equivalency. In 1 study, patients with schizophrenia receiving generic olanz­apine had lower serum concentration than patients with schizophrenia taking equivalent dosages of brand-name olanzapine.⁴ Similarly, studies comparing generic and brand-name venlafaxine showed significant differences in peak plasma concentration (Cmax)between generic and brand-name compounds.⁵

The FDA has considered upgrading the manufacturers’ warnings about the risk of generic medications, but has delayed the decision to 2017.⁶

FDA’s approval process for generic drugs

To receive approval of a generic formulation in the United States, the FDA requires that the generic drug should be compared with the corresponding brand-name drug in small crossover trials involving at least 24 to 36 healthy volunteers.

Bioequivalence is then established based on assessments of the rate of absorption (Cmax and area under the plasma concentration-time curve [AUC]). The FDA’s criteria are designed to achieve 90% confidence that the ratios of the test-to-reference log-transformed mean values for AUC and Cmax are within the interval of 80% to 125%. The FDA accepts −20% to 25% variation in Cmax and AUC in products that are considered bioequivalent. This is much less stringent than its −5% to 5% standard used for brand-name products. The FDA publishes a list of generic drugs that have been certified as bioequivalent, known as the “Orange Book.”⁵

Considerations when substituting generic medication

Because of the growing number of generic formulations of the same medication, generic–generic switches are becoming more commonplace. Theoretically, any 2 generic versions of the same medication can have a variation of up to 40% in AUC and Cmax. Generic medications are tested in healthy human controls through single-dose studies, which raises concerns about their applicability to the entire patient population.

Bioequivalence. It is a matter of debate whether bioequivalence translates to therapeutic equivalency. For medications with a narrow therapeutic index, the FDA has accepted that these 2 phenomena are not necessarily linked. With the exception of a few medications, including lithium and some anticonvulsants such as divalproex sodium and carbamazepine, serum level of the medications usually does not predict clinical response.

Inert ingredients. Generic medications can include inert ingredients (excipients) that are different from those in their branded counterparts. Some of these inactive ingredients can cause adverse effects. A study comparing paroxetine mesylate and paroxetine hydrochloride showed differences in bioequivalence and clinical efficacy.⁷

In some cases, brand-to-generic substitution can thwart clinical progress in a stable patient. This small change in the medication could destabilize the patient’s condition, which, in turn, may lead to unnecessary and significant social and financial burdens on the patient’s family, school, community, and the health care system.

Recommendations

In the event of a change in clinical response, clinicians first should evaluate adherence and explore other factors, such as biological, psychological, medical, and social issues. Adherence can be adversely affected by a change in the physical characteristics of the pill. Prescribers should remain cognizant of brand–generic and generic–generic switches. It may be reasonable to adjust the dosage of the new generic medication to address changes in clinical effectiveness.

If these strategies are ineffective, consider switching to a brand-name medication. Write “Dispense As Written” on the prescription to ensure delivery of the branded medication or a specific generic version of the medication.

An insurance company might require prior authorization to approve payment for the brand medication. To save time, use electronic forms or fax for communicating with the insurance company. Adding references to FDA statements and research papers, along with the patient’s history and presentations, would be prudent to demonstrate doubts about efficacy of the generic medication.

CASE
Sudden deterioration

R, age 11, has attention-deficit/hyperactivity disorder (ADHD), combined type, and oppositional defiant disorder, which has been stable for more than a year on extended-release (ER) methylphenidate (brand name: Concerta), 54 mg/d (1.2 mg/kg). With combined pharma­cotherapy and behavioral management, his symptoms of hyperactivity, inattention, and impulsivity improved at school and at home. He shows some academic gains as evidenced by improved achievement at school.

Over 2 months, R experiences a substantial deterioration in behavioral and academic performance. Along with core symptoms of ADHD, he begins to exhibit physical and verbal aggression. A report from school states that R has been using obscene language and destroying property, and has had episodes of provoked aggression toward his peers. His grades drop and he receives 2 school suspensions because of aggressive behavior.

What could be causing R’s ADHD symptoms to reemerge?

a) nonadherence to treatment
b) substance abuse
c) medication change
d) all of the above

The authors’ observations

Worsening of psychiatric symptoms in a stable patient is relatively common. Many factors can contribute to patient destabilization. Treatment nonadherence is a leading cause, along with psychosocial stressors and substance use (Table).

EVALUATION
Adherence confirmed

R is hyperactive and distracted during his visit, a clear deterioration from his baseline status. R is oppositional and defiant toward his mother during the session, but shows good social skills when communicating with the physician.

R’s mother reports that her son seldom forgets to take his medication, and she ensures that he is swallowing the pill, rather than chewing it. Data from the prescription drug-monitoring program show that the family is filling the prescriptions regularly. The ER methylphenidate dosage is raised to 72 mg/d. The clinicians provide psychoeducation about adherence to a medication regimen to R and his family. Also, his parents and teachers receive Vanderbilt Assessment Scales for ADHD to assess the symptoms in different settings.

At a follow-up visit a week later, R’s mother reports that her son continues to have problems in school and at home. The Vanderbilt scales reveal that R is having clinically significant problems with attention, hyperactivity, impulse control, and oppositional behavior.

A urine drug screen is ordered to rule out the possibility of a sudden deterioration of ADHD symptoms secondary to substance use disorder. To ensure compliance, we recommend that R take his medication at the school nurse’s office in the morning.

A week later

Although R takes his medication at school, he continues to show core symptoms of ADHD without improvement. The urine drug screen is negative. A physical examination does not reveal any medical illness. The treatment team calls the pharmacist to obtain a complete list of medications R is taking, who confirms that he is only receiving ER methylphenidate, 72 mg/d. The pharmacist also notes that R’s medication was switched from the brand-name drug to a generic 3 months ago because of a change in insurance coverage. This change coincided with the reemergence of his ADHD symptoms.

R’s mother reports that the new pills do not look like the old ones even before the dosage was raised. A new brand-necessary prescription is sent to the pharmacy. With the brand-name medication, R’s symptoms quickly improve, and remain improved when the dosage is decreased to the previous dosage of 54 mg/d.

With osmotic-controlled release oral delivery system (OROS) and outer coating of ER methylphenidate, how much drug is released immediately vs slow release?

a) 22% immediate release and 78% slow release
b) 78% immediate release and 22% slow release
c) 50% immediate release and 50% slow release

The authors’ observations

Generic substitution of a brand medication can result in worsening of symptoms and increased adverse effects. Possible bioequivalence issues can lead to failure of drug therapy.¹

In 2013, the FDA determined that 2 specific generic formulations of ER methylphenidate do not have therapeutic equivalency to the brand-name medication, Concerta. The FDA stated, “Based on an analysis of data, FDA has concerns about whether or not two approved generic versions of Concerta tablets (methylphenidate hydrochloride extended-release tablets), used to treat attention-deficit hyperactivity disorder in adults and children, are therapeutically equiv

In an apparent confirmation of the FDA’s concerns, a case series of children and adolescents with ADHD observed that almost all of the patients showed symptom improvement when they switched from a non-OROS formulation to an OROS preparation at the same dosage.³

The OROS preparation is thought to provide more predictable medication delivery over an extended period of time (Figure). A patient taking an ER formulation without OROS might lose this benefit, which could lead to symptom destabilization, even if the patient is taking the medication as instructed.

Brand vs generic

Under FDA regulations, companies seeking approval for generic formulations of approved drugs must demonstrate that their products are the same as the brand-name drug in terms of:  

• active ingredients
• strength
• dosage form
• route of administration  
• packaging label.

In addition, the pharmaceutical company must demonstrate that the generic form is absorbed and distributed to the part of the body at which it has its effect at acceptably similar levels to the brand-name drug. All medications—new or generic, in clinical trials or approved, prescription or over-the-counter—must be manufactured under controlled conditions that assure product quality.

However, some studies have disputed this equivalency. In 1 study, patients with schizophrenia receiving generic olanz­apine had lower serum concentration than patients with schizophrenia taking equivalent dosages of brand-name olanzapine.⁴ Similarly, studies comparing generic and brand-name venlafaxine showed significant differences in peak plasma concentration (Cmax)between generic and brand-name compounds.⁵

The FDA has considered upgrading the manufacturers’ warnings about the risk of generic medications, but has delayed the decision to 2017.⁶

FDA’s approval process for generic drugs

To receive approval of a generic formulation in the United States, the FDA requires that the generic drug should be compared with the corresponding brand-name drug in small crossover trials involving at least 24 to 36 healthy volunteers.

Bioequivalence is then established based on assessments of the rate of absorption (Cmax and area under the plasma concentration-time curve [AUC]). The FDA’s criteria are designed to achieve 90% confidence that the ratios of the test-to-reference log-transformed mean values for AUC and Cmax are within the interval of 80% to 125%. The FDA accepts −20% to 25% variation in Cmax and AUC in products that are considered bioequivalent. This is much less stringent than its −5% to 5% standard used for brand-name products. The FDA publishes a list of generic drugs that have been certified as bioequivalent, known as the “Orange Book.”⁵

Considerations when substituting generic medication

Because of the growing number of generic formulations of the same medication, generic–generic switches are becoming more commonplace. Theoretically, any 2 generic versions of the same medication can have a variation of up to 40% in AUC and Cmax. Generic medications are tested in healthy human controls through single-dose studies, which raises concerns about their applicability to the entire patient population.

Bioequivalence. It is a matter of debate whether bioequivalence translates to therapeutic equivalency. For medications with a narrow therapeutic index, the FDA has accepted that these 2 phenomena are not necessarily linked. With the exception of a few medications, including lithium and some anticonvulsants such as divalproex sodium and carbamazepine, serum level of the medications usually does not predict clinical response.

Inert ingredients. Generic medications can include inert ingredients (excipients) that are different from those in their branded counterparts. Some of these inactive ingredients can cause adverse effects. A study comparing paroxetine mesylate and paroxetine hydrochloride showed differences in bioequivalence and clinical efficacy.⁷

In some cases, brand-to-generic substitution can thwart clinical progress in a stable patient. This small change in the medication could destabilize the patient’s condition, which, in turn, may lead to unnecessary and significant social and financial burdens on the patient’s family, school, community, and the health care system.

Recommendations

In the event of a change in clinical response, clinicians first should evaluate adherence and explore other factors, such as biological, psychological, medical, and social issues. Adherence can be adversely affected by a change in the physical characteristics of the pill. Prescribers should remain cognizant of brand–generic and generic–generic switches. It may be reasonable to adjust the dosage of the new generic medication to address changes in clinical effectiveness.

If these strategies are ineffective, consider switching to a brand-name medication. Write “Dispense As Written” on the prescription to ensure delivery of the branded medication or a specific generic version of the medication.

An insurance company might require prior authorization to approve payment for the brand medication. To save time, use electronic forms or fax for communicating with the insurance company. Adding references to FDA statements and research papers, along with the patient’s history and presentations, would be prudent to demonstrate doubts about efficacy of the generic medication.

Cancer screening is an important example of secondary prevention—the aim being to detect disease at an early stage, when treatment can prevent symptomatic disease. Over the years, screening tests for breast cancer, colorectal cancer (CRC), cervical cancer, and, most recently, lung cancer have been developed and recommended by the U.S. Preventive Services Task Force (USPSTF). Among breast cancer, cervical cancer, and CRC, the screening rate for CRC remains lowest, at 58.6%.¹

The importance of screening for CRC is highlighted by the facts that:

• CRC is the third most commonly diagnosed form of cancer in the United States among both men and women
• CRC is the second leading cause of cancer-related death.²

The overall decrease in the incidence of CRC in the United States has been credited to improvements in screening and removal of potentially precancerous lesions.³

Harmful disparity puts the mentally ill at exceptional risk

Screening patterns for CRC among patients with mental illness are poorly characterized, but it is known that the overall cancer screening rate among patients with severe psychiatric illness lags significantly behind the rate in the general population.^4,5 In addition, studies have shown that mortality among patients with CRC who have a mental disorder is elevated, compared with CRC patients who do not have a psychiatric diagnosis.⁶

Why this disparity? It might be that CRC is more likely to be diagnosed at an advanced stage among these patients, or that they are less likely to receive cancer treatment after diagnosis, or are more likely to have a longer delay between diagnosis and initial treatment than patients who do not have a psychiatric diagnosis.⁷

Regardless, psychiatric practitioners can make a significant impact on reducing this health disparity by leveraging their unique therapeutic relationship to educate patients about screening options and dispel myths about cancer screening. In this article, we outline practical strategies for CRC screening and weigh the advantages and disadvantages for the use of several tools and guidelines in psychiatric patients.

What is the pathogenesis of colorectal cancer?

Most cases of CRC evolve from polyps, abnormal growths on the lining of the colon or rectum. Constituting an estimated 96% of all polyps, adenomas are by far the most common form in the colon and rectum.

Adenomas also are most likely to transform over time to dysplasia, and then to progress to cancer.⁸ Although all adenomas have malignant potential, <10% evolve to adenocarcinoma. This proposed adenoma➝carcinoma sequence is not well understood; however, it is known that CRC usually develops slowly—over 10 to 15 years.⁹ Detection and removal of adenomas and treatable, localized carcinomas form the basis of screening for CRC.

Risk factors for colorectal cancer

A number of risk factors for CRC have been identified.

Specific heritable conditions, such as Lynch syndrome and familial adenomatous polyposis, pose the greatest risk of CRC, particularly at younger ages and compared with people without such a history.¹⁰

Family history. One of the strongest risk factors for CRC remains a family history of the disease. People who have a first-degree relative with a diagnosis of CRC are at 2 to 3 times the risk of CRC, compared with people without a family history of the disease. This risk increases further if multiple family members are affected or if the diagnosis was made in a relative at a young age.^11,12

Other non-modifiable risk factors include a personal history of inflammatory bowel disease, type 2 diabetes mellitus, male sex, African American heritage, and increasing age.^13-15

Common modifiable risk factors include obesity, smoking, and alcohol consumption.^16-18

What is the role of screening?

CRC screening is only appropriate for patients who are asymptomatic. CRC generally is asymptomatic in early stages. Prognosis also is most favorable when CRC is detected in the asymptomatic stage.

As lesions of CRC grow, the presentation might include hematochezia, melena, abdominal pain, weight loss, occult anemia, constipation or diarrhea, and changes in stool caliber.¹⁹ These signs and symptoms are not highly specific for CRC, however, and might be indicative of other gastrointestinal pathology, including inflammatory bowel disease, diverticulitis, irritable bowel syndrome, infectious colitis, hemorrhoids, and mesenteric ischemia.

Symptomatic patients should be referred directly for diagnostic evaluation. Colonoscopy with biopsy is the standard for diagnosing CRC. Once a diagnosis of CRC is made, patients should be referred to a specialist to discuss treatment; options largely depend on the stage of the cancer at diagnosis.

What screening tests are available?

Unlike screening for other cancers, there are a number of reasonable options for CRC screening; Table 1¹⁵ compares their relative pros and cons. Each test has its benefits and drawbacks, allowing the screening strategy to be customized based on patient preference and characteristics, but this variability also can lead to confusion by patient and provider about those options.

Stool-based tests detect trace amounts of blood from early-stage treatable cancers. Highly sensitive fecal occult blood testing (FOBT) has been shown specifically to decrease mortality from CRC.²⁰ Stool-based tests are inexpensive and noninvasive, but require:

• more frequent testing
• that the patient collect the stool specimen
• follow-up colonoscopy when test results are positive.

Endoscopic and imaging tests detect polyps and early-stage treatable cancers; all require some degree of bowel preparation, and some require sedation. Testing intervals vary but, as a group, are longer than the interval between stool-based tests because polyps grow slowly. Because colonoscopy with biopsy is the preferred screening method for diagnosing CRC, it is the only screening option that also is a diagnostic procedure.

Where can screening guidelines be found?

Several professional organizations have developed guidelines for CRC screening. The 2 major

An update to both guidelines was released in 2008. Table 2^21,22 summarizes their recommendations.

Both guidelines recommend that screening begin at age 50 (Box). The primary differences between the 2 guidelines lie in the scope of recommended options for screening and the time frame for discontinuing screening:

• USPSTF requires a higher level of evidence for screening options and limits recommended options to FOBT, sigmoidoscopy combined with FOBT, and colonoscopy.
• ACS-MSTF-ACR emphasizes options that detect premalignant polyps, and generally is more inclusive of testing options; it also delineates tests as useful for either (1) early detection of cancer (stool-based studies) or (2) cancer prevention (endoscopic and imaging tests).

On the question of when to stop screening, ACS-MSTF-ACR bases its recommendations on life expectancy; USPSTF sets a specific age for ending screening.^21,22

Recommendations of a third entity, the American College of Gastroenterology (ACG), are similar to those of ACS-MSTF-ACR; however, ACG (1) recommends beginning screening African American patients at age 45 because of their increased risk of CRC and (2) gives preference to colonoscopy as the preferred screening modality.²³

Guidelines vary for high-risk patients (those with a history of familial adenomatous polyposis or another inherited syndrome associated with CRC; those with a family history of CRC in the young; those with a history of radiation exposure, history of CRC, or inflammatory bowel disease; and those with several first-degree relatives with CRC). Patients who fall into any of these categories should be referred for specialty care to establish the time of initial screening and the interval of subsequent screening.

CRC screening in the presence of psychiatric illness

Psychiatrists have an opportunity to support their patients when considering potentially confusing CRC screening recommendations. This opportunity might occur during a discussion about general preventive care, or a patient might come to an appointment after visiting a primary care provider, and ask for advice about screening options.

The potential benefits of CRC screening are negated if a patient is unable or unwilling to complete the test or undergo timely follow-up of positive results. It is important, therefore, to individualize screening recommendations—keeping in mind the degree of impairment from mental illness and the patient’s preferences and reliability to engage in follow-up. To date, there are no agreed-on screening guidelines specifically for patients with comorbid mental illness.

Adapting USPSTF guidelines for CRC screening of average-risk patients with mental illness, we offer the following recommendations:

Recommend screening. Begin routine screening at age 50. Patients with well-controlled or mild symptoms should be screened with a stool study with or without flexible sigmoidoscopy. Stool studies are safe, noninvasive, and require no bowel preparation; when used alone, however, they need to be performed yearly.

Screening accuracy is increased when a stool-based test is combined with flexible sigmoidoscopy; screening then can be performed less often. Unlike colonoscopy, flexible sigmoidoscopy does not involve sedation; a high-functioning patient might find this appealing and tolerate the greater frequency of screening. On the other hand, some patients might not accept the inconvenience of collecting the stool sample with the kit provided and returning it to the lab for processing.

Manage psychiatric illness optimally. For a patient with moderate or severe psychiatric symptoms, first attempt to optimize treatment of the underlying psychiatric condition before establishing a CRC screening program. If control of symptoms is likely to improve over the next 1 or 2 visits, it might be reasonable to defer screening until symptoms are better controlled and then reassess the patient before making specific screening recommendations. Screening should not be delayed, however, if significant improvement in symptoms is not expected in the near future. Lengthy delay might lead to failure in initiating screening at all.

We recommend that patients with persistent moderate or severe symptoms be screened with traditional colonoscopy. The sedation associated with colonoscopy (1) may be preferable to some patients with more severe illness and (2) allows for screening and diagnostic biopsy if needed during the same procedure. Screening with colonoscopy also:

• avoids the yearly adherence to a screening program that is needed with stool cards alone
• does not rely on patients collecting and returning stool kits for processing.

A potential challenge for patients with limited social support is the requirement to have someone accompany the patient on the day of colonoscopy.

Take steps to improve the screening rate. In addition to specific recommendations based on symptom severity, there are systems-level interventions that should be considered to improve the screening rate. These include:

• addressing transportation issues that are a barrier to screening
• considering the use of health navigators or peer advocates to help guide patients through the sometimes complex systems of care.

A more comprehensive systems-level intervention for mental health clinics that work primarily with persistent and severe mentally ill populations might include employing a care coordinator to organize referrals to primary care or even exploring reverse integration. In reverse integration, primary care providers co-locate within the mental health clinic, (1) allowing for “one-stop shopping” of mental health and primary care needs and (2) facilitating collaboration and shared treatment planning between primary care and mental health for complex patients.

Cancer screening is an important example of secondary prevention—the aim being to detect disease at an early stage, when treatment can prevent symptomatic disease. Over the years, screening tests for breast cancer, colorectal cancer (CRC), cervical cancer, and, most recently, lung cancer have been developed and recommended by the U.S. Preventive Services Task Force (USPSTF). Among breast cancer, cervical cancer, and CRC, the screening rate for CRC remains lowest, at 58.6%.¹

The importance of screening for CRC is highlighted by the facts that:

• CRC is the third most commonly diagnosed form of cancer in the United States among both men and women
• CRC is the second leading cause of cancer-related death.²

The overall decrease in the incidence of CRC in the United States has been credited to improvements in screening and removal of potentially precancerous lesions.³

Harmful disparity puts the mentally ill at exceptional risk

Screening patterns for CRC among patients with mental illness are poorly characterized, but it is known that the overall cancer screening rate among patients with severe psychiatric illness lags significantly behind the rate in the general population.^4,5 In addition, studies have shown that mortality among patients with CRC who have a mental disorder is elevated, compared with CRC patients who do not have a psychiatric diagnosis.⁶

Why this disparity? It might be that CRC is more likely to be diagnosed at an advanced stage among these patients, or that they are less likely to receive cancer treatment after diagnosis, or are more likely to have a longer delay between diagnosis and initial treatment than patients who do not have a psychiatric diagnosis.⁷

Regardless, psychiatric practitioners can make a significant impact on reducing this health disparity by leveraging their unique therapeutic relationship to educate patients about screening options and dispel myths about cancer screening. In this article, we outline practical strategies for CRC screening and weigh the advantages and disadvantages for the use of several tools and guidelines in psychiatric patients.

What is the pathogenesis of colorectal cancer?

Most cases of CRC evolve from polyps, abnormal growths on the lining of the colon or rectum. Constituting an estimated 96% of all polyps, adenomas are by far the most common form in the colon and rectum.

Adenomas also are most likely to transform over time to dysplasia, and then to progress to cancer.⁸ Although all adenomas have malignant potential, <10% evolve to adenocarcinoma. This proposed adenoma➝carcinoma sequence is not well understood; however, it is known that CRC usually develops slowly—over 10 to 15 years.⁹ Detection and removal of adenomas and treatable, localized carcinomas form the basis of screening for CRC.

Risk factors for colorectal cancer

A number of risk factors for CRC have been identified.

Specific heritable conditions, such as Lynch syndrome and familial adenomatous polyposis, pose the greatest risk of CRC, particularly at younger ages and compared with people without such a history.¹⁰

Family history. One of the strongest risk factors for CRC remains a family history of the disease. People who have a first-degree relative with a diagnosis of CRC are at 2 to 3 times the risk of CRC, compared with people without a family history of the disease. This risk increases further if multiple family members are affected or if the diagnosis was made in a relative at a young age.^11,12

Other non-modifiable risk factors include a personal history of inflammatory bowel disease, type 2 diabetes mellitus, male sex, African American heritage, and increasing age.^13-15

Common modifiable risk factors include obesity, smoking, and alcohol consumption.^16-18

What is the role of screening?

CRC screening is only appropriate for patients who are asymptomatic. CRC generally is asymptomatic in early stages. Prognosis also is most favorable when CRC is detected in the asymptomatic stage.

As lesions of CRC grow, the presentation might include hematochezia, melena, abdominal pain, weight loss, occult anemia, constipation or diarrhea, and changes in stool caliber.¹⁹ These signs and symptoms are not highly specific for CRC, however, and might be indicative of other gastrointestinal pathology, including inflammatory bowel disease, diverticulitis, irritable bowel syndrome, infectious colitis, hemorrhoids, and mesenteric ischemia.

Symptomatic patients should be referred directly for diagnostic evaluation. Colonoscopy with biopsy is the standard for diagnosing CRC. Once a diagnosis of CRC is made, patients should be referred to a specialist to discuss treatment; options largely depend on the stage of the cancer at diagnosis.

What screening tests are available?

Unlike screening for other cancers, there are a number of reasonable options for CRC screening; Table 1¹⁵ compares their relative pros and cons. Each test has its benefits and drawbacks, allowing the screening strategy to be customized based on patient preference and characteristics, but this variability also can lead to confusion by patient and provider about those options.

Stool-based tests detect trace amounts of blood from early-stage treatable cancers. Highly sensitive fecal occult blood testing (FOBT) has been shown specifically to decrease mortality from CRC.²⁰ Stool-based tests are inexpensive and noninvasive, but require:

• more frequent testing
• that the patient collect the stool specimen
• follow-up colonoscopy when test results are positive.

Endoscopic and imaging tests detect polyps and early-stage treatable cancers; all require some degree of bowel preparation, and some require sedation. Testing intervals vary but, as a group, are longer than the interval between stool-based tests because polyps grow slowly. Because colonoscopy with biopsy is the preferred screening method for diagnosing CRC, it is the only screening option that also is a diagnostic procedure.

Where can screening guidelines be found?

Several professional organizations have developed guidelines for CRC screening. The 2 major

An update to both guidelines was released in 2008. Table 2^21,22 summarizes their recommendations.

Both guidelines recommend that screening begin at age 50 (Box). The primary differences between the 2 guidelines lie in the scope of recommended options for screening and the time frame for discontinuing screening:

• USPSTF requires a higher level of evidence for screening options and limits recommended options to FOBT, sigmoidoscopy combined with FOBT, and colonoscopy.
• ACS-MSTF-ACR emphasizes options that detect premalignant polyps, and generally is more inclusive of testing options; it also delineates tests as useful for either (1) early detection of cancer (stool-based studies) or (2) cancer prevention (endoscopic and imaging tests).

On the question of when to stop screening, ACS-MSTF-ACR bases its recommendations on life expectancy; USPSTF sets a specific age for ending screening.^21,22

Recommendations of a third entity, the American College of Gastroenterology (ACG), are similar to those of ACS-MSTF-ACR; however, ACG (1) recommends beginning screening African American patients at age 45 because of their increased risk of CRC and (2) gives preference to colonoscopy as the preferred screening modality.²³

Guidelines vary for high-risk patients (those with a history of familial adenomatous polyposis or another inherited syndrome associated with CRC; those with a family history of CRC in the young; those with a history of radiation exposure, history of CRC, or inflammatory bowel disease; and those with several first-degree relatives with CRC). Patients who fall into any of these categories should be referred for specialty care to establish the time of initial screening and the interval of subsequent screening.

CRC screening in the presence of psychiatric illness

Psychiatrists have an opportunity to support their patients when considering potentially confusing CRC screening recommendations. This opportunity might occur during a discussion about general preventive care, or a patient might come to an appointment after visiting a primary care provider, and ask for advice about screening options.

The potential benefits of CRC screening are negated if a patient is unable or unwilling to complete the test or undergo timely follow-up of positive results. It is important, therefore, to individualize screening recommendations—keeping in mind the degree of impairment from mental illness and the patient’s preferences and reliability to engage in follow-up. To date, there are no agreed-on screening guidelines specifically for patients with comorbid mental illness.

Adapting USPSTF guidelines for CRC screening of average-risk patients with mental illness, we offer the following recommendations:

Recommend screening. Begin routine screening at age 50. Patients with well-controlled or mild symptoms should be screened with a stool study with or without flexible sigmoidoscopy. Stool studies are safe, noninvasive, and require no bowel preparation; when used alone, however, they need to be performed yearly.

Screening accuracy is increased when a stool-based test is combined with flexible sigmoidoscopy; screening then can be performed less often. Unlike colonoscopy, flexible sigmoidoscopy does not involve sedation; a high-functioning patient might find this appealing and tolerate the greater frequency of screening. On the other hand, some patients might not accept the inconvenience of collecting the stool sample with the kit provided and returning it to the lab for processing.

Manage psychiatric illness optimally. For a patient with moderate or severe psychiatric symptoms, first attempt to optimize treatment of the underlying psychiatric condition before establishing a CRC screening program. If control of symptoms is likely to improve over the next 1 or 2 visits, it might be reasonable to defer screening until symptoms are better controlled and then reassess the patient before making specific screening recommendations. Screening should not be delayed, however, if significant improvement in symptoms is not expected in the near future. Lengthy delay might lead to failure in initiating screening at all.

We recommend that patients with persistent moderate or severe symptoms be screened with traditional colonoscopy. The sedation associated with colonoscopy (1) may be preferable to some patients with more severe illness and (2) allows for screening and diagnostic biopsy if needed during the same procedure. Screening with colonoscopy also:

• avoids the yearly adherence to a screening program that is needed with stool cards alone
• does not rely on patients collecting and returning stool kits for processing.

A potential challenge for patients with limited social support is the requirement to have someone accompany the patient on the day of colonoscopy.

Take steps to improve the screening rate. In addition to specific recommendations based on symptom severity, there are systems-level interventions that should be considered to improve the screening rate. These include:

• addressing transportation issues that are a barrier to screening
• considering the use of health navigators or peer advocates to help guide patients through the sometimes complex systems of care.

A more comprehensive systems-level intervention for mental health clinics that work primarily with persistent and severe mentally ill populations might include employing a care coordinator to organize referrals to primary care or even exploring reverse integration. In reverse integration, primary care providers co-locate within the mental health clinic, (1) allowing for “one-stop shopping” of mental health and primary care needs and (2) facilitating collaboration and shared treatment planning between primary care and mental health for complex patients.

Cancer screening is an important example of secondary prevention—the aim being to detect disease at an early stage, when treatment can prevent symptomatic disease. Over the years, screening tests for breast cancer, colorectal cancer (CRC), cervical cancer, and, most recently, lung cancer have been developed and recommended by the U.S. Preventive Services Task Force (USPSTF). Among breast cancer, cervical cancer, and CRC, the screening rate for CRC remains lowest, at 58.6%.¹

The importance of screening for CRC is highlighted by the facts that:

• CRC is the third most commonly diagnosed form of cancer in the United States among both men and women
• CRC is the second leading cause of cancer-related death.²

The overall decrease in the incidence of CRC in the United States has been credited to improvements in screening and removal of potentially precancerous lesions.³

Harmful disparity puts the mentally ill at exceptional risk

Screening patterns for CRC among patients with mental illness are poorly characterized, but it is known that the overall cancer screening rate among patients with severe psychiatric illness lags significantly behind the rate in the general population.^4,5 In addition, studies have shown that mortality among patients with CRC who have a mental disorder is elevated, compared with CRC patients who do not have a psychiatric diagnosis.⁶

Why this disparity? It might be that CRC is more likely to be diagnosed at an advanced stage among these patients, or that they are less likely to receive cancer treatment after diagnosis, or are more likely to have a longer delay between diagnosis and initial treatment than patients who do not have a psychiatric diagnosis.⁷

Regardless, psychiatric practitioners can make a significant impact on reducing this health disparity by leveraging their unique therapeutic relationship to educate patients about screening options and dispel myths about cancer screening. In this article, we outline practical strategies for CRC screening and weigh the advantages and disadvantages for the use of several tools and guidelines in psychiatric patients.

What is the pathogenesis of colorectal cancer?

Most cases of CRC evolve from polyps, abnormal growths on the lining of the colon or rectum. Constituting an estimated 96% of all polyps, adenomas are by far the most common form in the colon and rectum.

Adenomas also are most likely to transform over time to dysplasia, and then to progress to cancer.⁸ Although all adenomas have malignant potential, <10% evolve to adenocarcinoma. This proposed adenoma➝carcinoma sequence is not well understood; however, it is known that CRC usually develops slowly—over 10 to 15 years.⁹ Detection and removal of adenomas and treatable, localized carcinomas form the basis of screening for CRC.

Risk factors for colorectal cancer

A number of risk factors for CRC have been identified.

Specific heritable conditions, such as Lynch syndrome and familial adenomatous polyposis, pose the greatest risk of CRC, particularly at younger ages and compared with people without such a history.¹⁰

Family history. One of the strongest risk factors for CRC remains a family history of the disease. People who have a first-degree relative with a diagnosis of CRC are at 2 to 3 times the risk of CRC, compared with people without a family history of the disease. This risk increases further if multiple family members are affected or if the diagnosis was made in a relative at a young age.^11,12

Other non-modifiable risk factors include a personal history of inflammatory bowel disease, type 2 diabetes mellitus, male sex, African American heritage, and increasing age.^13-15

Common modifiable risk factors include obesity, smoking, and alcohol consumption.^16-18

What is the role of screening?

CRC screening is only appropriate for patients who are asymptomatic. CRC generally is asymptomatic in early stages. Prognosis also is most favorable when CRC is detected in the asymptomatic stage.

As lesions of CRC grow, the presentation might include hematochezia, melena, abdominal pain, weight loss, occult anemia, constipation or diarrhea, and changes in stool caliber.¹⁹ These signs and symptoms are not highly specific for CRC, however, and might be indicative of other gastrointestinal pathology, including inflammatory bowel disease, diverticulitis, irritable bowel syndrome, infectious colitis, hemorrhoids, and mesenteric ischemia.

Symptomatic patients should be referred directly for diagnostic evaluation. Colonoscopy with biopsy is the standard for diagnosing CRC. Once a diagnosis of CRC is made, patients should be referred to a specialist to discuss treatment; options largely depend on the stage of the cancer at diagnosis.

What screening tests are available?

Unlike screening for other cancers, there are a number of reasonable options for CRC screening; Table 1¹⁵ compares their relative pros and cons. Each test has its benefits and drawbacks, allowing the screening strategy to be customized based on patient preference and characteristics, but this variability also can lead to confusion by patient and provider about those options.

Stool-based tests detect trace amounts of blood from early-stage treatable cancers. Highly sensitive fecal occult blood testing (FOBT) has been shown specifically to decrease mortality from CRC.²⁰ Stool-based tests are inexpensive and noninvasive, but require:

• more frequent testing
• that the patient collect the stool specimen
• follow-up colonoscopy when test results are positive.

Endoscopic and imaging tests detect polyps and early-stage treatable cancers; all require some degree of bowel preparation, and some require sedation. Testing intervals vary but, as a group, are longer than the interval between stool-based tests because polyps grow slowly. Because colonoscopy with biopsy is the preferred screening method for diagnosing CRC, it is the only screening option that also is a diagnostic procedure.

Where can screening guidelines be found?

Several professional organizations have developed guidelines for CRC screening. The 2 major

An update to both guidelines was released in 2008. Table 2^21,22 summarizes their recommendations.

Both guidelines recommend that screening begin at age 50 (Box). The primary differences between the 2 guidelines lie in the scope of recommended options for screening and the time frame for discontinuing screening:

• USPSTF requires a higher level of evidence for screening options and limits recommended options to FOBT, sigmoidoscopy combined with FOBT, and colonoscopy.
• ACS-MSTF-ACR emphasizes options that detect premalignant polyps, and generally is more inclusive of testing options; it also delineates tests as useful for either (1) early detection of cancer (stool-based studies) or (2) cancer prevention (endoscopic and imaging tests).

On the question of when to stop screening, ACS-MSTF-ACR bases its recommendations on life expectancy; USPSTF sets a specific age for ending screening.^21,22

Recommendations of a third entity, the American College of Gastroenterology (ACG), are similar to those of ACS-MSTF-ACR; however, ACG (1) recommends beginning screening African American patients at age 45 because of their increased risk of CRC and (2) gives preference to colonoscopy as the preferred screening modality.²³

Guidelines vary for high-risk patients (those with a history of familial adenomatous polyposis or another inherited syndrome associated with CRC; those with a family history of CRC in the young; those with a history of radiation exposure, history of CRC, or inflammatory bowel disease; and those with several first-degree relatives with CRC). Patients who fall into any of these categories should be referred for specialty care to establish the time of initial screening and the interval of subsequent screening.

CRC screening in the presence of psychiatric illness

Psychiatrists have an opportunity to support their patients when considering potentially confusing CRC screening recommendations. This opportunity might occur during a discussion about general preventive care, or a patient might come to an appointment after visiting a primary care provider, and ask for advice about screening options.

The potential benefits of CRC screening are negated if a patient is unable or unwilling to complete the test or undergo timely follow-up of positive results. It is important, therefore, to individualize screening recommendations—keeping in mind the degree of impairment from mental illness and the patient’s preferences and reliability to engage in follow-up. To date, there are no agreed-on screening guidelines specifically for patients with comorbid mental illness.

Adapting USPSTF guidelines for CRC screening of average-risk patients with mental illness, we offer the following recommendations:

Recommend screening. Begin routine screening at age 50. Patients with well-controlled or mild symptoms should be screened with a stool study with or without flexible sigmoidoscopy. Stool studies are safe, noninvasive, and require no bowel preparation; when used alone, however, they need to be performed yearly.

Screening accuracy is increased when a stool-based test is combined with flexible sigmoidoscopy; screening then can be performed less often. Unlike colonoscopy, flexible sigmoidoscopy does not involve sedation; a high-functioning patient might find this appealing and tolerate the greater frequency of screening. On the other hand, some patients might not accept the inconvenience of collecting the stool sample with the kit provided and returning it to the lab for processing.

Manage psychiatric illness optimally. For a patient with moderate or severe psychiatric symptoms, first attempt to optimize treatment of the underlying psychiatric condition before establishing a CRC screening program. If control of symptoms is likely to improve over the next 1 or 2 visits, it might be reasonable to defer screening until symptoms are better controlled and then reassess the patient before making specific screening recommendations. Screening should not be delayed, however, if significant improvement in symptoms is not expected in the near future. Lengthy delay might lead to failure in initiating screening at all.

We recommend that patients with persistent moderate or severe symptoms be screened with traditional colonoscopy. The sedation associated with colonoscopy (1) may be preferable to some patients with more severe illness and (2) allows for screening and diagnostic biopsy if needed during the same procedure. Screening with colonoscopy also:

• avoids the yearly adherence to a screening program that is needed with stool cards alone
• does not rely on patients collecting and returning stool kits for processing.

A potential challenge for patients with limited social support is the requirement to have someone accompany the patient on the day of colonoscopy.

Take steps to improve the screening rate. In addition to specific recommendations based on symptom severity, there are systems-level interventions that should be considered to improve the screening rate. These include:

• addressing transportation issues that are a barrier to screening
• considering the use of health navigators or peer advocates to help guide patients through the sometimes complex systems of care.

A more comprehensive systems-level intervention for mental health clinics that work primarily with persistent and severe mentally ill populations might include employing a care coordinator to organize referrals to primary care or even exploring reverse integration. In reverse integration, primary care providers co-locate within the mental health clinic, (1) allowing for “one-stop shopping” of mental health and primary care needs and (2) facilitating collaboration and shared treatment planning between primary care and mental health for complex patients.

One fine winter’s day when Piglet was brushing away the snow
in front of his house he happened to look up, and there was
Winnie-the-Pooh. Pooh was walking round and round in a circle,
thinking of something else…

So begins the 1926 Winnie-the-Pooh story.¹ In this chapter, the well-meaning yellow bear, Winnie-the-Pooh, has found strange tracks in the snow, which he believes belong to a “Woozle.” Pooh follows the tracks, not realizing that he’s walking in a circle. As such, he begins to notice that the tracks have multiplied, which he interprets as evidence of several Woozles.

This “Woozle Effect” has been well described in research settings and is believed to have resulted in conclusions that are not supported by or are inconsistent with the original data, which are then propagated through successive citations, resulting in a scientific “urban legend.”²

Throughout my training from medical school, through fellowship, and during my tenure as a faculty member, I have found myself, at times, searching for Woozles and often have joined my colleagues on these hunts. Herein, I would like to share with you 3 Woozles that have resulted in current false dogmas related to attention-deficit/hyperactivity disorder (ADHD) and stimulant psychopharmacology.

Stimulants worsen anxiety

FDA-required labeling for stimulants includes strong language noting that these drugs are “contraindicated in marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.”³ However, data from randomized controlled trials and meta-analyses consistently have failed to demonstrate this effect. Moreover, sequenced treatment trials involving adolescents with anxiety disorders and co-occurring ADHD suggest that stimulants actually could reduce anxiety symptoms.

A recent meta-analysis⁴ that evaluated nearly 2 dozen studies involving approximately 3,000 pediatric patients with ADHD reported that stimulant treatment was associated with a decreased relative risk of anxiety (relative risk: 0.86). The study also observed a dose-response relationship between stimulant dosage and anxiety (Figure, page 6).⁴ Although the authors note that it is possible that some individuals might experience increased anxiety with stimulants, many patients could show improvement in anxiety symptoms when treated with stimulants, and the authors also advise us, as clinicians, to “consider re-challenging children with ADHD who report … anxiety with psychostimulants, as these symptoms are much more likely to be coincidental rather than caused by psychostimulants.”⁴

More evidence of a lack of stimulant-induced anxiety comes from a large randomized controlled trial of pediatric patients (age 6 to 17) who met DSM-IV criteria for ADHD and a co-occurring anxiety disorder who were treated with methylphenidate (open-label) and then randomized to fluvoxamine or placebo for treatment of anxiety symptoms.⁵ However, in this trial >80% of the 32 medication-naïve youth improved after stimulant treatment to the point that they no longer had anxiety symptoms severe enough to be eligible for randomization to adjunctive fluvoxamine or placebo.

Stimulants are contraindicated in patients with tic disorders

The package inserts for most stimulant medications warn clinicians that stimulants are “contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome.” This is particularly concerning, especially because of the medicolegal implications of the term “contraindicated” and given that as many as 1 in 5 pediatric patients with ADHD have a tic disorder.⁶ Therefore, labels that list motor tics as a contraindication to stimulant use potentially eliminate the choice of stimulant pharmacotherapy—the most effective treatment for ADHD—for a large number of patients.

When hunting for the Woozle that linked stimulants and tics and led to this language in the package insert, it is worthwhile to review a recent meta-analysis of 22 studies (involving nearly 2,400 youths with ADHD) that suggested new-onset tics or worsening of tics to be present in 5.7% of patients receiving stimulants and in 6.5% of patients receiving placebo. In addition, in this meta-analysis the class of stimulant, dosage, treatment duration, or patient age did not seem to be associated with onset or worsening of tics.⁷

Polypharmacy represents a therapeutic failure and is not evidence-based

Although treatment guidelines generally have discouraged combination therapy for treating ADHD, there are—on the basis of efficacy—insufficient data to support this prohibition. Moreover, over the last decade, several studies have suggested benefits for combining ADHD medications that have complimentary mechanisms. In this regard, 2 extended-release formulations of α₂ agonists have received FDA approval for as adjunctive treatments in pediatric patients with ADHD (extended-release guanfacine and extended-release clonidine). However, despite these FDA indications as adjunctive treatments, many clinicians remain concerned about combination therapy.

Several months ago, a large, 8-week, National Institutes of Health–sponsored trial shed more light on the use of α₂agonist + stimulant combinations. Patients age 7 to 17 (N = 179) were randomized to (1) guanfacine + d-methylphenidate, (2) guanfacine monotherapy, or (3) d-methylphenidate monotherapy.⁸ In addition to clinical outcomes, the authors evaluated the effects of the medication on background cortical activity. Of interest, monotherapies differed between one another and the combination treatment in their effects on cortical activity. Guanfacine decreased alpha band power and methylphenidate administration was associated with an increase in frontal/central beta power, while combination treatment dampened theta band power and was associated with specific, focal increases in beta power.⁸ These results, although preliminary, suggest not only that medication results in changes in cortical activity that correlate with symptomatic improvement, but that combination treatment may be associated with a distinct cortical activity pattern that is more than the summation of the effects of the monotherapies. Moreover, these data raise the possibility that this synergistic effect on cortical activity may subtend—or at least—relate to the synergistic clinical effects of the 2 medications.

‘Think it over, think it under’

Having discussed several important Woozles that have inhabited the Hundred Acre Wood of ADHD for decades, it is important to remember there are countless Woozles in the larger “Thousand Acre Wood” of psychiatry and medicine. As we evaluate evidence for our interventions, whether psychopharmacologic or psychotherapeutic, we will do well to relentlessly question the “evidence” for our choices and in doing so strive to be like wise Christopher Robin rather than Winnie-the-Pooh.

One fine winter’s day when Piglet was brushing away the snow
in front of his house he happened to look up, and there was
Winnie-the-Pooh. Pooh was walking round and round in a circle,
thinking of something else…

So begins the 1926 Winnie-the-Pooh story.¹ In this chapter, the well-meaning yellow bear, Winnie-the-Pooh, has found strange tracks in the snow, which he believes belong to a “Woozle.” Pooh follows the tracks, not realizing that he’s walking in a circle. As such, he begins to notice that the tracks have multiplied, which he interprets as evidence of several Woozles.

This “Woozle Effect” has been well described in research settings and is believed to have resulted in conclusions that are not supported by or are inconsistent with the original data, which are then propagated through successive citations, resulting in a scientific “urban legend.”²

Throughout my training from medical school, through fellowship, and during my tenure as a faculty member, I have found myself, at times, searching for Woozles and often have joined my colleagues on these hunts. Herein, I would like to share with you 3 Woozles that have resulted in current false dogmas related to attention-deficit/hyperactivity disorder (ADHD) and stimulant psychopharmacology.

Stimulants worsen anxiety

FDA-required labeling for stimulants includes strong language noting that these drugs are “contraindicated in marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.”³ However, data from randomized controlled trials and meta-analyses consistently have failed to demonstrate this effect. Moreover, sequenced treatment trials involving adolescents with anxiety disorders and co-occurring ADHD suggest that stimulants actually could reduce anxiety symptoms.

A recent meta-analysis⁴ that evaluated nearly 2 dozen studies involving approximately 3,000 pediatric patients with ADHD reported that stimulant treatment was associated with a decreased relative risk of anxiety (relative risk: 0.86). The study also observed a dose-response relationship between stimulant dosage and anxiety (Figure, page 6).⁴ Although the authors note that it is possible that some individuals might experience increased anxiety with stimulants, many patients could show improvement in anxiety symptoms when treated with stimulants, and the authors also advise us, as clinicians, to “consider re-challenging children with ADHD who report … anxiety with psychostimulants, as these symptoms are much more likely to be coincidental rather than caused by psychostimulants.”⁴

More evidence of a lack of stimulant-induced anxiety comes from a large randomized controlled trial of pediatric patients (age 6 to 17) who met DSM-IV criteria for ADHD and a co-occurring anxiety disorder who were treated with methylphenidate (open-label) and then randomized to fluvoxamine or placebo for treatment of anxiety symptoms.⁵ However, in this trial >80% of the 32 medication-naïve youth improved after stimulant treatment to the point that they no longer had anxiety symptoms severe enough to be eligible for randomization to adjunctive fluvoxamine or placebo.

Stimulants are contraindicated in patients with tic disorders

The package inserts for most stimulant medications warn clinicians that stimulants are “contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome.” This is particularly concerning, especially because of the medicolegal implications of the term “contraindicated” and given that as many as 1 in 5 pediatric patients with ADHD have a tic disorder.⁶ Therefore, labels that list motor tics as a contraindication to stimulant use potentially eliminate the choice of stimulant pharmacotherapy—the most effective treatment for ADHD—for a large number of patients.

When hunting for the Woozle that linked stimulants and tics and led to this language in the package insert, it is worthwhile to review a recent meta-analysis of 22 studies (involving nearly 2,400 youths with ADHD) that suggested new-onset tics or worsening of tics to be present in 5.7% of patients receiving stimulants and in 6.5% of patients receiving placebo. In addition, in this meta-analysis the class of stimulant, dosage, treatment duration, or patient age did not seem to be associated with onset or worsening of tics.⁷

Polypharmacy represents a therapeutic failure and is not evidence-based

Although treatment guidelines generally have discouraged combination therapy for treating ADHD, there are—on the basis of efficacy—insufficient data to support this prohibition. Moreover, over the last decade, several studies have suggested benefits for combining ADHD medications that have complimentary mechanisms. In this regard, 2 extended-release formulations of α₂ agonists have received FDA approval for as adjunctive treatments in pediatric patients with ADHD (extended-release guanfacine and extended-release clonidine). However, despite these FDA indications as adjunctive treatments, many clinicians remain concerned about combination therapy.

Several months ago, a large, 8-week, National Institutes of Health–sponsored trial shed more light on the use of α₂agonist + stimulant combinations. Patients age 7 to 17 (N = 179) were randomized to (1) guanfacine + d-methylphenidate, (2) guanfacine monotherapy, or (3) d-methylphenidate monotherapy.⁸ In addition to clinical outcomes, the authors evaluated the effects of the medication on background cortical activity. Of interest, monotherapies differed between one another and the combination treatment in their effects on cortical activity. Guanfacine decreased alpha band power and methylphenidate administration was associated with an increase in frontal/central beta power, while combination treatment dampened theta band power and was associated with specific, focal increases in beta power.⁸ These results, although preliminary, suggest not only that medication results in changes in cortical activity that correlate with symptomatic improvement, but that combination treatment may be associated with a distinct cortical activity pattern that is more than the summation of the effects of the monotherapies. Moreover, these data raise the possibility that this synergistic effect on cortical activity may subtend—or at least—relate to the synergistic clinical effects of the 2 medications.

‘Think it over, think it under’

Having discussed several important Woozles that have inhabited the Hundred Acre Wood of ADHD for decades, it is important to remember there are countless Woozles in the larger “Thousand Acre Wood” of psychiatry and medicine. As we evaluate evidence for our interventions, whether psychopharmacologic or psychotherapeutic, we will do well to relentlessly question the “evidence” for our choices and in doing so strive to be like wise Christopher Robin rather than Winnie-the-Pooh.

One fine winter’s day when Piglet was brushing away the snow
in front of his house he happened to look up, and there was
Winnie-the-Pooh. Pooh was walking round and round in a circle,
thinking of something else…

So begins the 1926 Winnie-the-Pooh story.¹ In this chapter, the well-meaning yellow bear, Winnie-the-Pooh, has found strange tracks in the snow, which he believes belong to a “Woozle.” Pooh follows the tracks, not realizing that he’s walking in a circle. As such, he begins to notice that the tracks have multiplied, which he interprets as evidence of several Woozles.

This “Woozle Effect” has been well described in research settings and is believed to have resulted in conclusions that are not supported by or are inconsistent with the original data, which are then propagated through successive citations, resulting in a scientific “urban legend.”²

Throughout my training from medical school, through fellowship, and during my tenure as a faculty member, I have found myself, at times, searching for Woozles and often have joined my colleagues on these hunts. Herein, I would like to share with you 3 Woozles that have resulted in current false dogmas related to attention-deficit/hyperactivity disorder (ADHD) and stimulant psychopharmacology.

Stimulants worsen anxiety

FDA-required labeling for stimulants includes strong language noting that these drugs are “contraindicated in marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.”³ However, data from randomized controlled trials and meta-analyses consistently have failed to demonstrate this effect. Moreover, sequenced treatment trials involving adolescents with anxiety disorders and co-occurring ADHD suggest that stimulants actually could reduce anxiety symptoms.

A recent meta-analysis⁴ that evaluated nearly 2 dozen studies involving approximately 3,000 pediatric patients with ADHD reported that stimulant treatment was associated with a decreased relative risk of anxiety (relative risk: 0.86). The study also observed a dose-response relationship between stimulant dosage and anxiety (Figure, page 6).⁴ Although the authors note that it is possible that some individuals might experience increased anxiety with stimulants, many patients could show improvement in anxiety symptoms when treated with stimulants, and the authors also advise us, as clinicians, to “consider re-challenging children with ADHD who report … anxiety with psychostimulants, as these symptoms are much more likely to be coincidental rather than caused by psychostimulants.”⁴

More evidence of a lack of stimulant-induced anxiety comes from a large randomized controlled trial of pediatric patients (age 6 to 17) who met DSM-IV criteria for ADHD and a co-occurring anxiety disorder who were treated with methylphenidate (open-label) and then randomized to fluvoxamine or placebo for treatment of anxiety symptoms.⁵ However, in this trial >80% of the 32 medication-naïve youth improved after stimulant treatment to the point that they no longer had anxiety symptoms severe enough to be eligible for randomization to adjunctive fluvoxamine or placebo.

Stimulants are contraindicated in patients with tic disorders

The package inserts for most stimulant medications warn clinicians that stimulants are “contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome.” This is particularly concerning, especially because of the medicolegal implications of the term “contraindicated” and given that as many as 1 in 5 pediatric patients with ADHD have a tic disorder.⁶ Therefore, labels that list motor tics as a contraindication to stimulant use potentially eliminate the choice of stimulant pharmacotherapy—the most effective treatment for ADHD—for a large number of patients.

When hunting for the Woozle that linked stimulants and tics and led to this language in the package insert, it is worthwhile to review a recent meta-analysis of 22 studies (involving nearly 2,400 youths with ADHD) that suggested new-onset tics or worsening of tics to be present in 5.7% of patients receiving stimulants and in 6.5% of patients receiving placebo. In addition, in this meta-analysis the class of stimulant, dosage, treatment duration, or patient age did not seem to be associated with onset or worsening of tics.⁷

Polypharmacy represents a therapeutic failure and is not evidence-based

Although treatment guidelines generally have discouraged combination therapy for treating ADHD, there are—on the basis of efficacy—insufficient data to support this prohibition. Moreover, over the last decade, several studies have suggested benefits for combining ADHD medications that have complimentary mechanisms. In this regard, 2 extended-release formulations of α₂ agonists have received FDA approval for as adjunctive treatments in pediatric patients with ADHD (extended-release guanfacine and extended-release clonidine). However, despite these FDA indications as adjunctive treatments, many clinicians remain concerned about combination therapy.

Several months ago, a large, 8-week, National Institutes of Health–sponsored trial shed more light on the use of α₂agonist + stimulant combinations. Patients age 7 to 17 (N = 179) were randomized to (1) guanfacine + d-methylphenidate, (2) guanfacine monotherapy, or (3) d-methylphenidate monotherapy.⁸ In addition to clinical outcomes, the authors evaluated the effects of the medication on background cortical activity. Of interest, monotherapies differed between one another and the combination treatment in their effects on cortical activity. Guanfacine decreased alpha band power and methylphenidate administration was associated with an increase in frontal/central beta power, while combination treatment dampened theta band power and was associated with specific, focal increases in beta power.⁸ These results, although preliminary, suggest not only that medication results in changes in cortical activity that correlate with symptomatic improvement, but that combination treatment may be associated with a distinct cortical activity pattern that is more than the summation of the effects of the monotherapies. Moreover, these data raise the possibility that this synergistic effect on cortical activity may subtend—or at least—relate to the synergistic clinical effects of the 2 medications.

‘Think it over, think it under’

Having discussed several important Woozles that have inhabited the Hundred Acre Wood of ADHD for decades, it is important to remember there are countless Woozles in the larger “Thousand Acre Wood” of psychiatry and medicine. As we evaluate evidence for our interventions, whether psychopharmacologic or psychotherapeutic, we will do well to relentlessly question the “evidence” for our choices and in doing so strive to be like wise Christopher Robin rather than Winnie-the-Pooh.

Handling patient emergencies is one of the most challenging parts of clinical care. Not only does the provider have to consider the best care for the patient, he (she) must think through medicolegal considerations, as well as what systems are sustainable in a practice, and then develop a plan that addresses all those interests. Being on-call for emergencies in a solo private practice can be especially complex, because the provider is always, and solely, responsible for handling or redirecting these calls, which is one reason some physicians choose to be part of a group practice or be an employee.

First, let’s define a few different types of “emergencies” that you might encounter:

• A genuine life or death situation. A patient calls during planning, or after attempting, suicide.
• An urgent matter. A patient has run out of medication or she (he) is having discontinuation symptoms or adverse effects. Although there is no imminent danger, the patient may be experiencing significant discomfort.
• A matter of high anxiety. The patient is experiencing situations that provoke high affect, and she needs attention at that moment to lessen the burden.

Of course, you might not know the true extent of the emergency until you talk to the patient, but being able to delineate different procedures for patients based on the types of emergency situations could streamline your workflow.

With this foundation in place, let’s discuss the most common practice policies for dealing with these emergencies.

Instructing patients to call 911 or go to the emergency room (ER)

The pros.

• Meets minimum standards without any additional work.
• Reinforces work-life boundaries.
• Makes private practice tolerable.

The cons.

• Patients might not feel properly cared for.
• The patient might not want to call 911 in some situations (eg, suicidality).
• You might not know if your patient went to the ER unless hospital staff or the patient contacts you afterwards.

Using an answering service

The pros.

• Patients feel reassured that they can get your attention after hours and get a call back from you.
• Patients are familiar with this practice because it is widely used in the medical field.
• Operators are trained to screen for emergencies and can be given a script of questions to ask, and given clear guidelines so they know whether to contact you immediately.
• Establishes a healthy boundary between work and personal life.

The cons.

• Cost.
• Patients still might be frustrated if they can’t directly connect with you.
• Requires training and trusting the answering service staff.

Giving your home or cell number to patients

The pros.

• Patients might feel cared for and reassured that they can reach you directly at any time, which may, itself, be calming and reduce their need to contact you.
• Providers can maintain complete control over their practice at all times.
• Providers can market the practice as a “concierge” service.
• You can give your personal phone number to certain patients at certain times, rather than making it a practice-wide policy.

The cons.

• Providers may feel like they are working all the time. What if you go out of the country, or find yourself in a cell phone dead zone? You’ll need to have a colleague cover for you or refer patients to 911 or the ER.
• Some patients could abuse the privilege.
• Boundaries between work and personal life can crumble.
• Being available 24/7 over a 30-year career could feel onerous.

Be sure to discuss your policies with your patient at the first visit. Choosing the best policies for your practice involves providing good patient care, meeting or exceeding the standard of care, and finding the right fit for you.

Handling patient emergencies is one of the most challenging parts of clinical care. Not only does the provider have to consider the best care for the patient, he (she) must think through medicolegal considerations, as well as what systems are sustainable in a practice, and then develop a plan that addresses all those interests. Being on-call for emergencies in a solo private practice can be especially complex, because the provider is always, and solely, responsible for handling or redirecting these calls, which is one reason some physicians choose to be part of a group practice or be an employee.

First, let’s define a few different types of “emergencies” that you might encounter:

• A genuine life or death situation. A patient calls during planning, or after attempting, suicide.
• An urgent matter. A patient has run out of medication or she (he) is having discontinuation symptoms or adverse effects. Although there is no imminent danger, the patient may be experiencing significant discomfort.
• A matter of high anxiety. The patient is experiencing situations that provoke high affect, and she needs attention at that moment to lessen the burden.

Of course, you might not know the true extent of the emergency until you talk to the patient, but being able to delineate different procedures for patients based on the types of emergency situations could streamline your workflow.

With this foundation in place, let’s discuss the most common practice policies for dealing with these emergencies.

Instructing patients to call 911 or go to the emergency room (ER)

The pros.

• Meets minimum standards without any additional work.
• Reinforces work-life boundaries.
• Makes private practice tolerable.

The cons.

• Patients might not feel properly cared for.
• The patient might not want to call 911 in some situations (eg, suicidality).
• You might not know if your patient went to the ER unless hospital staff or the patient contacts you afterwards.

Using an answering service

The pros.

• Patients feel reassured that they can get your attention after hours and get a call back from you.
• Patients are familiar with this practice because it is widely used in the medical field.
• Operators are trained to screen for emergencies and can be given a script of questions to ask, and given clear guidelines so they know whether to contact you immediately.
• Establishes a healthy boundary between work and personal life.

The cons.

• Cost.
• Patients still might be frustrated if they can’t directly connect with you.
• Requires training and trusting the answering service staff.

Giving your home or cell number to patients

The pros.

• Patients might feel cared for and reassured that they can reach you directly at any time, which may, itself, be calming and reduce their need to contact you.
• Providers can maintain complete control over their practice at all times.
• Providers can market the practice as a “concierge” service.
• You can give your personal phone number to certain patients at certain times, rather than making it a practice-wide policy.

The cons.

• Providers may feel like they are working all the time. What if you go out of the country, or find yourself in a cell phone dead zone? You’ll need to have a colleague cover for you or refer patients to 911 or the ER.
• Some patients could abuse the privilege.
• Boundaries between work and personal life can crumble.
• Being available 24/7 over a 30-year career could feel onerous.

Be sure to discuss your policies with your patient at the first visit. Choosing the best policies for your practice involves providing good patient care, meeting or exceeding the standard of care, and finding the right fit for you.

Handling patient emergencies is one of the most challenging parts of clinical care. Not only does the provider have to consider the best care for the patient, he (she) must think through medicolegal considerations, as well as what systems are sustainable in a practice, and then develop a plan that addresses all those interests. Being on-call for emergencies in a solo private practice can be especially complex, because the provider is always, and solely, responsible for handling or redirecting these calls, which is one reason some physicians choose to be part of a group practice or be an employee.

First, let’s define a few different types of “emergencies” that you might encounter:

• A genuine life or death situation. A patient calls during planning, or after attempting, suicide.
• An urgent matter. A patient has run out of medication or she (he) is having discontinuation symptoms or adverse effects. Although there is no imminent danger, the patient may be experiencing significant discomfort.
• A matter of high anxiety. The patient is experiencing situations that provoke high affect, and she needs attention at that moment to lessen the burden.

Of course, you might not know the true extent of the emergency until you talk to the patient, but being able to delineate different procedures for patients based on the types of emergency situations could streamline your workflow.

With this foundation in place, let’s discuss the most common practice policies for dealing with these emergencies.

Instructing patients to call 911 or go to the emergency room (ER)

The pros.

• Meets minimum standards without any additional work.
• Reinforces work-life boundaries.
• Makes private practice tolerable.

The cons.

• Patients might not feel properly cared for.
• The patient might not want to call 911 in some situations (eg, suicidality).
• You might not know if your patient went to the ER unless hospital staff or the patient contacts you afterwards.

Using an answering service

The pros.

• Patients feel reassured that they can get your attention after hours and get a call back from you.
• Patients are familiar with this practice because it is widely used in the medical field.
• Operators are trained to screen for emergencies and can be given a script of questions to ask, and given clear guidelines so they know whether to contact you immediately.
• Establishes a healthy boundary between work and personal life.

The cons.

• Cost.
• Patients still might be frustrated if they can’t directly connect with you.
• Requires training and trusting the answering service staff.

Giving your home or cell number to patients

The pros.

• Patients might feel cared for and reassured that they can reach you directly at any time, which may, itself, be calming and reduce their need to contact you.
• Providers can maintain complete control over their practice at all times.
• Providers can market the practice as a “concierge” service.
• You can give your personal phone number to certain patients at certain times, rather than making it a practice-wide policy.

The cons.

• Providers may feel like they are working all the time. What if you go out of the country, or find yourself in a cell phone dead zone? You’ll need to have a colleague cover for you or refer patients to 911 or the ER.
• Some patients could abuse the privilege.
• Boundaries between work and personal life can crumble.
• Being available 24/7 over a 30-year career could feel onerous.

Be sure to discuss your policies with your patient at the first visit. Choosing the best policies for your practice involves providing good patient care, meeting or exceeding the standard of care, and finding the right fit for you.

Inattention and distractibility are highly prevalent, and can exist secondary to a number of underlying causes. When a patient (or the patient’s family) asks whether he (she) might have attention-deficit/hyperactivity disorder (ADHD), you must perform a comprehensive assessment to rule out other medical and psychiatric disorders that might be manifesting as inattention. It is important not to miss a diagnosis of ADHD, and it is vital not to mistake another medical or psychiatric condition as ADHD.

Pay attention to components of the differential diagnosis while you are evaluating a patient with possible ADHD.

Medical conditions. Several disorders can present with cognitive, attentional, and executive functioning deficits that resemble the presentation of ADHD. These include absence seizures and other types of seizures, Lyme disease, HIV infection, and encephalopathy.¹

People who have completed chemotherapy (particularly children) often exhibit attentional and executive functioning deficits similar to those found in ADHD.¹

Anxiety disorders, the most prevalent of psychiatric disorders, correlate highly with difficulty concentrating. Chronic stress can have negative effects on hippocampus- and prefrontal cortical-based memory and cognitive functions.² Be cautious, therefore, when diagnosing ADHD in a patient who suffers from significant, acute, or inadequately controlled anxiety—especially one who does not have a history of a childhood onset of attentional difficulties.

On the other hand, untreated ADHD can lead to anxiety symptoms.

Drugs. A number of substances of abuse—marijuana, cocaine, ecstasy, and caffeine—can produce symptoms of poor attention or impulsivity, similar to what is seen in ADHD, through their effects on the hippocampus and prefrontal cortex.^3,4 MRI studies of the brains of 8-year-olds prenatally exposed to cocaine have found changes in frontal lobes suggesting potential long-term effects on attention and impulse control in these children.^5,6

Use of certain medications, such as anticholinergics, also can contribute to attentional difficulties in some patient populations.

Abuse or trauma. Difficulty concentrating is one of the core symptoms of posttraumatic stress disorder (PTSD). Rule out PTSD and recent abuse or trauma when assessing for ADHD. Children with recent trauma often present with agitation, restlessness, and behavioral disturbance—symptoms that mimic ADHD.

Mood and adjustment disorders. Difficulty concentrating also is a criterion for major depressive disorder. On the other hand, untreated ADHD also can lead to, or contribute to, development of a depressive disorder. If a patient is experiencing a major depressive episode, obtain a thorough collateral history delineating a timeline of attention difficulties, which should allow for an accurate diagnosis.

In children, ADHD and bipolar disorder can have symptom overlap; both can present with distractibility, increased energy, and mood lability—therefore making a careful history a diagnostic necessity. Furthermore, ADHD and bipolar disorder can coexist in a small percentage of ADHD patients.

Hypothyroidism. Studies show a decrease in memory, attention, and concentration in patients with overt hypothyroidism, and at least a small decrease in these domains in patients with subclinical hypothyroidism.⁷ Decreased cerebral blood flow in brain regions that mediate attention and executive functioning, and decreased hippocampal volume, have been observed in patients with hypothyroidism.⁷ Therefore, the cognitive profile in these patients can look similar to, and can be confused with, ADHD, inattentive type.

Insomnia. Sleep plays a key role in memory consolidation and maintaining attention. Sleep disorders (eg, sleep apnea, restless legs syndrome, delayed sleep phase-onset disorder) can produce chronic tiredness and significantly affect attention, concentration, and cognitive functioning in children, adolescents, and adults.⁸

Studies in adults have shown that sleep deprivation is linked to attentional difficulty secondary to changes in prefrontal cortex activity.⁹ Other studies suggest that short sleep duration in healthy children is associated with inattention and poorer academic functioning, and also was found linked to teacher reports of inattention and a cognitive profile similar to what is seen in ADHD.⁸

Learning disorders and developmental disabilities. Children with an undiagnosed learning disorder often present with symptoms akin to those of ADHD.¹ An undiagnosed reading or mathematics disorder, for example, can have a significant impact on academic functioning, in which the child might not be paying attention because of his (her) restricted ability to grasp the subject matter.

On the other hand, keep in mind that ADHD is highly comorbid with learning disorders.¹⁰

Last, children and adults with a developmental disability can present with signs and symptoms similar to those of ADHD.¹

Summing up

Comprehensive assessment and management of any underlying condition is important to address the attention deficits you observe in a patient. A collateral history from parents and significant others, school reports, relevant laboratory tests, and a full physical examination are important tools for making an accurate diagnosis.

Inattention and distractibility are highly prevalent, and can exist secondary to a number of underlying causes. When a patient (or the patient’s family) asks whether he (she) might have attention-deficit/hyperactivity disorder (ADHD), you must perform a comprehensive assessment to rule out other medical and psychiatric disorders that might be manifesting as inattention. It is important not to miss a diagnosis of ADHD, and it is vital not to mistake another medical or psychiatric condition as ADHD.

Pay attention to components of the differential diagnosis while you are evaluating a patient with possible ADHD.

Medical conditions. Several disorders can present with cognitive, attentional, and executive functioning deficits that resemble the presentation of ADHD. These include absence seizures and other types of seizures, Lyme disease, HIV infection, and encephalopathy.¹

People who have completed chemotherapy (particularly children) often exhibit attentional and executive functioning deficits similar to those found in ADHD.¹

Anxiety disorders, the most prevalent of psychiatric disorders, correlate highly with difficulty concentrating. Chronic stress can have negative effects on hippocampus- and prefrontal cortical-based memory and cognitive functions.² Be cautious, therefore, when diagnosing ADHD in a patient who suffers from significant, acute, or inadequately controlled anxiety—especially one who does not have a history of a childhood onset of attentional difficulties.

On the other hand, untreated ADHD can lead to anxiety symptoms.

Drugs. A number of substances of abuse—marijuana, cocaine, ecstasy, and caffeine—can produce symptoms of poor attention or impulsivity, similar to what is seen in ADHD, through their effects on the hippocampus and prefrontal cortex.^3,4 MRI studies of the brains of 8-year-olds prenatally exposed to cocaine have found changes in frontal lobes suggesting potential long-term effects on attention and impulse control in these children.^5,6

Use of certain medications, such as anticholinergics, also can contribute to attentional difficulties in some patient populations.

Abuse or trauma. Difficulty concentrating is one of the core symptoms of posttraumatic stress disorder (PTSD). Rule out PTSD and recent abuse or trauma when assessing for ADHD. Children with recent trauma often present with agitation, restlessness, and behavioral disturbance—symptoms that mimic ADHD.

Mood and adjustment disorders. Difficulty concentrating also is a criterion for major depressive disorder. On the other hand, untreated ADHD also can lead to, or contribute to, development of a depressive disorder. If a patient is experiencing a major depressive episode, obtain a thorough collateral history delineating a timeline of attention difficulties, which should allow for an accurate diagnosis.

In children, ADHD and bipolar disorder can have symptom overlap; both can present with distractibility, increased energy, and mood lability—therefore making a careful history a diagnostic necessity. Furthermore, ADHD and bipolar disorder can coexist in a small percentage of ADHD patients.

Hypothyroidism. Studies show a decrease in memory, attention, and concentration in patients with overt hypothyroidism, and at least a small decrease in these domains in patients with subclinical hypothyroidism.⁷ Decreased cerebral blood flow in brain regions that mediate attention and executive functioning, and decreased hippocampal volume, have been observed in patients with hypothyroidism.⁷ Therefore, the cognitive profile in these patients can look similar to, and can be confused with, ADHD, inattentive type.

Insomnia. Sleep plays a key role in memory consolidation and maintaining attention. Sleep disorders (eg, sleep apnea, restless legs syndrome, delayed sleep phase-onset disorder) can produce chronic tiredness and significantly affect attention, concentration, and cognitive functioning in children, adolescents, and adults.⁸

Studies in adults have shown that sleep deprivation is linked to attentional difficulty secondary to changes in prefrontal cortex activity.⁹ Other studies suggest that short sleep duration in healthy children is associated with inattention and poorer academic functioning, and also was found linked to teacher reports of inattention and a cognitive profile similar to what is seen in ADHD.⁸

Learning disorders and developmental disabilities. Children with an undiagnosed learning disorder often present with symptoms akin to those of ADHD.¹ An undiagnosed reading or mathematics disorder, for example, can have a significant impact on academic functioning, in which the child might not be paying attention because of his (her) restricted ability to grasp the subject matter.

On the other hand, keep in mind that ADHD is highly comorbid with learning disorders.¹⁰

Last, children and adults with a developmental disability can present with signs and symptoms similar to those of ADHD.¹

Summing up

Comprehensive assessment and management of any underlying condition is important to address the attention deficits you observe in a patient. A collateral history from parents and significant others, school reports, relevant laboratory tests, and a full physical examination are important tools for making an accurate diagnosis.

Inattention and distractibility are highly prevalent, and can exist secondary to a number of underlying causes. When a patient (or the patient’s family) asks whether he (she) might have attention-deficit/hyperactivity disorder (ADHD), you must perform a comprehensive assessment to rule out other medical and psychiatric disorders that might be manifesting as inattention. It is important not to miss a diagnosis of ADHD, and it is vital not to mistake another medical or psychiatric condition as ADHD.

Pay attention to components of the differential diagnosis while you are evaluating a patient with possible ADHD.

Medical conditions. Several disorders can present with cognitive, attentional, and executive functioning deficits that resemble the presentation of ADHD. These include absence seizures and other types of seizures, Lyme disease, HIV infection, and encephalopathy.¹

People who have completed chemotherapy (particularly children) often exhibit attentional and executive functioning deficits similar to those found in ADHD.¹

Anxiety disorders, the most prevalent of psychiatric disorders, correlate highly with difficulty concentrating. Chronic stress can have negative effects on hippocampus- and prefrontal cortical-based memory and cognitive functions.² Be cautious, therefore, when diagnosing ADHD in a patient who suffers from significant, acute, or inadequately controlled anxiety—especially one who does not have a history of a childhood onset of attentional difficulties.

On the other hand, untreated ADHD can lead to anxiety symptoms.

Drugs. A number of substances of abuse—marijuana, cocaine, ecstasy, and caffeine—can produce symptoms of poor attention or impulsivity, similar to what is seen in ADHD, through their effects on the hippocampus and prefrontal cortex.^3,4 MRI studies of the brains of 8-year-olds prenatally exposed to cocaine have found changes in frontal lobes suggesting potential long-term effects on attention and impulse control in these children.^5,6

Use of certain medications, such as anticholinergics, also can contribute to attentional difficulties in some patient populations.

Abuse or trauma. Difficulty concentrating is one of the core symptoms of posttraumatic stress disorder (PTSD). Rule out PTSD and recent abuse or trauma when assessing for ADHD. Children with recent trauma often present with agitation, restlessness, and behavioral disturbance—symptoms that mimic ADHD.

Mood and adjustment disorders. Difficulty concentrating also is a criterion for major depressive disorder. On the other hand, untreated ADHD also can lead to, or contribute to, development of a depressive disorder. If a patient is experiencing a major depressive episode, obtain a thorough collateral history delineating a timeline of attention difficulties, which should allow for an accurate diagnosis.

In children, ADHD and bipolar disorder can have symptom overlap; both can present with distractibility, increased energy, and mood lability—therefore making a careful history a diagnostic necessity. Furthermore, ADHD and bipolar disorder can coexist in a small percentage of ADHD patients.

Hypothyroidism. Studies show a decrease in memory, attention, and concentration in patients with overt hypothyroidism, and at least a small decrease in these domains in patients with subclinical hypothyroidism.⁷ Decreased cerebral blood flow in brain regions that mediate attention and executive functioning, and decreased hippocampal volume, have been observed in patients with hypothyroidism.⁷ Therefore, the cognitive profile in these patients can look similar to, and can be confused with, ADHD, inattentive type.

Insomnia. Sleep plays a key role in memory consolidation and maintaining attention. Sleep disorders (eg, sleep apnea, restless legs syndrome, delayed sleep phase-onset disorder) can produce chronic tiredness and significantly affect attention, concentration, and cognitive functioning in children, adolescents, and adults.⁸

Studies in adults have shown that sleep deprivation is linked to attentional difficulty secondary to changes in prefrontal cortex activity.⁹ Other studies suggest that short sleep duration in healthy children is associated with inattention and poorer academic functioning, and also was found linked to teacher reports of inattention and a cognitive profile similar to what is seen in ADHD.⁸

Learning disorders and developmental disabilities. Children with an undiagnosed learning disorder often present with symptoms akin to those of ADHD.¹ An undiagnosed reading or mathematics disorder, for example, can have a significant impact on academic functioning, in which the child might not be paying attention because of his (her) restricted ability to grasp the subject matter.

On the other hand, keep in mind that ADHD is highly comorbid with learning disorders.¹⁰

Last, children and adults with a developmental disability can present with signs and symptoms similar to those of ADHD.¹

Summing up

Comprehensive assessment and management of any underlying condition is important to address the attention deficits you observe in a patient. A collateral history from parents and significant others, school reports, relevant laboratory tests, and a full physical examination are important tools for making an accurate diagnosis.

Even among healthy individuals, feelings of paranoia are not unusual. In modern psychiatry, we consider paranoia to be a pattern of unfounded thinking, centered on the fearful experience of perceived victimization or threat of intentional harm. This means that a patient with paranoia is, by nature, difficult to engage in treatment. A patient might perceive the clinician as attempting to mislead or manipulate him. A therapeutic alliance could require patience on the part of the clinician, creativity,¹ and abandoning attempts at rational “therapeutic” persuasion. The severity of symptoms determines the approach.

In this article, we review the nature of paranoia and the continuum of syndromes to which it is a central feature, as well as treatment approaches.

Categorization and etiology

Until recently, clinicians considered “paranoid” to be a subtype of schizophrenia (Box^2-7); in DSM-5 the limited diagnostic stability and reliability of the categorization rendered the distinction obsolete.⁸ There are several levels of severity of paranoia; this thought process can present in simple variations of normal fears and concerns or in severe forms, with highly organized delusional systems.

The etiology of paranoia is not clear. Over the years, it has been attributed to defense mechanisms of the ego, habitual fears from repetitive exposure, or irregular activity of the amygdala. It is possible that various types of paranoia could have different causes. Functional MRIs indicate that the amygdala is involved in anxiety and threat perception in both primates and humans.⁹

Rational fear vs paranoia

Under the right circumstances, anyone could sense that he (she) is being threatened. Such feelings are normal in occupied countries and nations at war, and are not pathologic in such contexts. Anxiety about potential danger and harassment under truly oppressive circumstances might be biologically ingrained and have value for survival. It is important to employ cultural sensitivity when distinguishing pathological and nonpathological paranoia because some immigrant populations might have increased prevalence rates but without a true mental illness.¹⁰

Perhaps the key to separating realistic fear from paranoia is the recognition of whether the environment is truly safe or hostile; sometimes this is not initially evident to the clinician. The first author (J.A.W.) experienced this when discovering that a patient who was thought to be paranoid was indeed being stalked by another patient.

Rapid social change makes sweeping explanations about the range of threats experienced by any one person of limited value. Persons living with serious and persistent mental illness experience stigma—harassment, abuse, disgrace—and, similar to victims of repeated sexual abuse and other violence, are not necessarily unreasonable in their inner experience of omnipresent threat. In addition, advances in surveillance technology, as well as the media proliferation of depictions of vulnerability and threat, can plant generalized doubt of historically trusted individuals and systems. Under conditions of severe social discrimination or life under a totalitarian regime, constant fear for safety and worry about the intentions of others is reasonable. We must remember that during the Cold War many people in Eastern Europe had legitimate concerns that their phones were tapped. There are still many places in the world where the fear of government or of one’s neighbors exists.

• paranoid personality disorder
• delusional disorder
• paranoia in schizophrenia (Table).

Paranoid personality disorder

The nature of any personality disorder is a long-standing psychological and behavioral pattern that differs significantly from the expectations of one’s culture. Such beliefs and behaviors typically are pervasive across most aspects of the individual’s interactions, and these enduring patterns of personality usually are evident by adolescence or young adulthood. Paranoid personality disorder is marked by pervasive distrust of others. Typical features include:

• suspicion about other people’s motives
• sensitivity to criticism
• keeping grudges against alleged offenders.⁸

The patient must have 4 of the following symptoms to confirm the diagnosis:

• suspicion of others and their motives
• reluctance to confide in others, due to lack of trust
• recurrent doubts about the fidelity of a significant other
• preoccupation with doubt regarding trusting others
• seeing threatening meanings behind benign remarks or events
• perception of attacks upon one’s character or reputation
• bears persistent grudges.⁸

Individuals with paranoid personality disorder tend to lead maladaptive lifestyles and might present as irritable, unpleasant, and emotionally guarded. Paranoid personality disorder is not a form of delusion, but is a pattern of habitual distrust of others.

The disorder generally is expressed verbally, and is seldom accompanied by hallucinations or unpredictable behavior. Distrust of others might result in social isolation and litigious behavior.⁸ Alternately, a patient with this disorder might not present for treatment until later in life after the loss of significant supporting factors, such as the death of parents or loss of steady employment. Examination of these older individuals is likely to reveal long-standing suspiciousness and distrust that previously was hidden by family members. For example, a 68-year-old woman might present saying that she can’t trust her daughter, but her recently deceased spouse would not let her discuss the topic outside of the home.

The etiology of paranoid personality disorder is unknown. Family studies suggest a possible a genetic connection to paranoia in schizophrenia.¹² Others hypothesize that this dysfunction of personality might originate in early feelings of anxiety and low self-esteem, learned from a controlling, cruel, or sadistic parent; the patient then expects others to reject him (her) as the parent did.^13,14 Such individuals might develop deep-seated distrust of others as a defense mechanism. Under stress, such as during a medical illness, patients could develop brief psychoses. Antipsychotic treatment might be useful in some cases of paranoid personality disorder, but should be limited.

Delusional disorder

Delusional disorder is a unique form of psychosis. Patients with delusional disorder might appear rational—as long as they are in independent roles—and their general functioning could go unnoticed. This could change when the delusions predominate their thoughts, or their delusional behavior is unacceptable in a structured environment. Such individuals often suffer from a highly specific delusion fixed on 1 topic. These delusions generally are the only psychotic feature. The most common theme is that of persecution. For example, a person firmly believes he is being followed by foreign agents or by a religious organization, which is blatantly untrue. Another common theme is infidelity.

Paranoia in delusional disorder is about something that is not actually occurring, but could.³ In other words, the delusion is not necessarily bizarre. The patient may have no evidence or could invent “evidence,” yet remain completely resistant to any logical argument against his belief system. In many situations, individuals with delusional disorder function normally in society, until the delusion becomes severe enough to prompt clinical attention.


Paranoia in schizophrenia

In patients with schizophrenia with paranoia, the typical symptoms of disorganization and disturbed affect are less prominent. The condition develops in young adulthood, but could start at any age. Its course typically is chronic and requires psychiatric treatment; the patient may require hospital care.

Although patients with delusional disorder and those with schizophrenia both have delusions, the delusions of the latter typically are bizarre and unlikely to be possible. For example, the patient might believe that her body has been replaced with the inner workings of an alien being or a robot. The paranoid delusions of persons with delusional disorder are much more mundane and could be plausible. Karl Jaspers, a clinician and researcher in the early 20th century, separated delusional disorder from paranoid schizophrenia by noting that the former could be “understandable, even if untrue” while the latter was “not within the realm of understandability.”⁵

A patient with schizophrenia with paranoid delusions usually experiences auditory hallucinations, such as voices threatening persecution or harm. When predominant, patients could be aroused by these fears and can be dangerous to others.^2,4,5

Other presentations of paranoia

Paranoia can occur in affective disorders as well.¹³ Although the cause is only now being understood, clinicians have put forth theories for many years. A depressed person might suffer from excessive guilt and feel that he deserves to be persecuted, while a manic patient might think she is being persecuted for her greatness. In the past, response to electroconvulsive therapy was used to distinguish affective paranoia from other types.²

Paranoia in organic states

Substance use. Psychostimulants, which are known for their motor activity and arousal enhancing properties, as well as the potential for abuse and other negative consequences, could lead to acute paranoid states in susceptible individuals.^15-17 In addition, tetrahydrocannabinol, the active chemical in Cannabis, can cause acute psychotic symptoms, such as paranoia,^18,19 in a dose-dependent manner. A growing body of evidence suggests that a combination of Cannabis use with a genetic predisposition to psychosis may put some individuals at high risk of decompensation.¹⁹ Of growing concern is the evidence that synthetic cannabinoids, which are among the most commonly used new psychoactive substances, could be associated with psychosis, including paranoia.²⁰

Dementia. Persons with dementia often are paranoid. In geriatric patients with dementia, a delusion of thievery is common. When a person has misplaced objects and can’t remember where, the “default” cognition is that someone has taken them. This confabulation may progress to a persistent paranoia and can be draining on caregivers.

Treating paranoia

A patient with paranoia usually has poor insight and cannot be reasoned with. Such individuals are quick to incorporate others into their delusional theories and easily develop notions of conspiracy. In acute psychosis, when the patient presents with fixed beliefs that are not amenable to reality orientation, and poses a threat to his well-being or that of others, alleviating underlying fear and anxiety is the first priority. Swift pharma­cologic measures are required to decrease the patient’s underlying anxiety or anger, before you can try to earn his trust.

Psychopharmacologic interventions should be specific to the diagnosis. Anti­psychotic medications generally will help decrease most paranoia, but affective syndromes usually require lithium or divalproex for best results.^14,21

Develop a therapeutic relationship. The clinician must approach the patient in a practical and straightforward manner, and should not expect a quick therapeutic alliance. Transference and countertransference develop easily in the context of paranoia. Focus on behaviors that are problematic for the patient or the milieu, such as to ensure a safe environment. The patient needs to be aware of how he could come across to others. Clear feedback about behavior, such as “I cannot really listen to you when you’re yelling,” may be effective. It might be unwise to confront delusional paranoia in an agitated patient. Honesty and respect must continue in all communications to build trust. During assessment of a paranoid individual, evaluate the level of dangerousness. Ask your patient if he feels like acting on his beliefs or harming the people that are the targets of his paranoia.

As the patient begins to manage his anxiety and fear, you can develop a therapeutic alliance. The goals of treatment need be those of the patient—such as staying out of the hospital, or behaving in a manner that is required for employment. Over time, work toward growing the patient’s capacity for social interaction and productive activity. Insight might be elusive; however, some patients with paranoia can learn to take a detached view of their thoughts and emotions, and consider them impermanent events of the mind that make their lives difficult. Practice good judgment when aiming for recovery in a patient who does not have insight. For example, a patient can recognize that although there could be a microchip in his brain, he feels better when he takes medication.

In the case of paranoid personality disorder, treatment, as with most personality disorders, can be difficult. The patient might be unlikely to accept help and could distrust caregivers. Cognitive-behavioral therapy could be useful, if the patient can be engaged in the therapeutic process. Although it might be difficult to obtain enhanced insight, the patient could accept logical explanations for situations that provoke distrust. As long as anxiety and anger can be kept under control, the individual might learn the value of adopting the lessons of therapy. Pharmacological treatments are aimed at reducing the anxiety and anger experienced by the paranoid individual. Antipsychotics may be useful for short periods or during a crisis.^14,21

The clinician must remain calm and reassuring when approaching an individual with paranoia, and not react to the projection of paranoid feelings from the patient. Respect for the patient can be conveyed without agreeing with delusions or bizarre thinking. The clinician must keep agreements and appointments with the client to prevent the erosion of trust. Paranoid conditions might respond slowly to pharmacological treatment, therefore establishing a consistent therapeutic relationship is essential.

Even among healthy individuals, feelings of paranoia are not unusual. In modern psychiatry, we consider paranoia to be a pattern of unfounded thinking, centered on the fearful experience of perceived victimization or threat of intentional harm. This means that a patient with paranoia is, by nature, difficult to engage in treatment. A patient might perceive the clinician as attempting to mislead or manipulate him. A therapeutic alliance could require patience on the part of the clinician, creativity,¹ and abandoning attempts at rational “therapeutic” persuasion. The severity of symptoms determines the approach.

In this article, we review the nature of paranoia and the continuum of syndromes to which it is a central feature, as well as treatment approaches.

Categorization and etiology

Until recently, clinicians considered “paranoid” to be a subtype of schizophrenia (Box^2-7); in DSM-5 the limited diagnostic stability and reliability of the categorization rendered the distinction obsolete.⁸ There are several levels of severity of paranoia; this thought process can present in simple variations of normal fears and concerns or in severe forms, with highly organized delusional systems.

The etiology of paranoia is not clear. Over the years, it has been attributed to defense mechanisms of the ego, habitual fears from repetitive exposure, or irregular activity of the amygdala. It is possible that various types of paranoia could have different causes. Functional MRIs indicate that the amygdala is involved in anxiety and threat perception in both primates and humans.⁹

Rational fear vs paranoia

Under the right circumstances, anyone could sense that he (she) is being threatened. Such feelings are normal in occupied countries and nations at war, and are not pathologic in such contexts. Anxiety about potential danger and harassment under truly oppressive circumstances might be biologically ingrained and have value for survival. It is important to employ cultural sensitivity when distinguishing pathological and nonpathological paranoia because some immigrant populations might have increased prevalence rates but without a true mental illness.¹⁰

Perhaps the key to separating realistic fear from paranoia is the recognition of whether the environment is truly safe or hostile; sometimes this is not initially evident to the clinician. The first author (J.A.W.) experienced this when discovering that a patient who was thought to be paranoid was indeed being stalked by another patient.

Rapid social change makes sweeping explanations about the range of threats experienced by any one person of limited value. Persons living with serious and persistent mental illness experience stigma—harassment, abuse, disgrace—and, similar to victims of repeated sexual abuse and other violence, are not necessarily unreasonable in their inner experience of omnipresent threat. In addition, advances in surveillance technology, as well as the media proliferation of depictions of vulnerability and threat, can plant generalized doubt of historically trusted individuals and systems. Under conditions of severe social discrimination or life under a totalitarian regime, constant fear for safety and worry about the intentions of others is reasonable. We must remember that during the Cold War many people in Eastern Europe had legitimate concerns that their phones were tapped. There are still many places in the world where the fear of government or of one’s neighbors exists.

• paranoid personality disorder
• delusional disorder
• paranoia in schizophrenia (Table).

Paranoid personality disorder

The nature of any personality disorder is a long-standing psychological and behavioral pattern that differs significantly from the expectations of one’s culture. Such beliefs and behaviors typically are pervasive across most aspects of the individual’s interactions, and these enduring patterns of personality usually are evident by adolescence or young adulthood. Paranoid personality disorder is marked by pervasive distrust of others. Typical features include:

• suspicion about other people’s motives
• sensitivity to criticism
• keeping grudges against alleged offenders.⁸

The patient must have 4 of the following symptoms to confirm the diagnosis:

• suspicion of others and their motives
• reluctance to confide in others, due to lack of trust
• recurrent doubts about the fidelity of a significant other
• preoccupation with doubt regarding trusting others
• seeing threatening meanings behind benign remarks or events
• perception of attacks upon one’s character or reputation
• bears persistent grudges.⁸

Individuals with paranoid personality disorder tend to lead maladaptive lifestyles and might present as irritable, unpleasant, and emotionally guarded. Paranoid personality disorder is not a form of delusion, but is a pattern of habitual distrust of others.

The disorder generally is expressed verbally, and is seldom accompanied by hallucinations or unpredictable behavior. Distrust of others might result in social isolation and litigious behavior.⁸ Alternately, a patient with this disorder might not present for treatment until later in life after the loss of significant supporting factors, such as the death of parents or loss of steady employment. Examination of these older individuals is likely to reveal long-standing suspiciousness and distrust that previously was hidden by family members. For example, a 68-year-old woman might present saying that she can’t trust her daughter, but her recently deceased spouse would not let her discuss the topic outside of the home.

The etiology of paranoid personality disorder is unknown. Family studies suggest a possible a genetic connection to paranoia in schizophrenia.¹² Others hypothesize that this dysfunction of personality might originate in early feelings of anxiety and low self-esteem, learned from a controlling, cruel, or sadistic parent; the patient then expects others to reject him (her) as the parent did.^13,14 Such individuals might develop deep-seated distrust of others as a defense mechanism. Under stress, such as during a medical illness, patients could develop brief psychoses. Antipsychotic treatment might be useful in some cases of paranoid personality disorder, but should be limited.

Delusional disorder

Delusional disorder is a unique form of psychosis. Patients with delusional disorder might appear rational—as long as they are in independent roles—and their general functioning could go unnoticed. This could change when the delusions predominate their thoughts, or their delusional behavior is unacceptable in a structured environment. Such individuals often suffer from a highly specific delusion fixed on 1 topic. These delusions generally are the only psychotic feature. The most common theme is that of persecution. For example, a person firmly believes he is being followed by foreign agents or by a religious organization, which is blatantly untrue. Another common theme is infidelity.

Paranoia in delusional disorder is about something that is not actually occurring, but could.³ In other words, the delusion is not necessarily bizarre. The patient may have no evidence or could invent “evidence,” yet remain completely resistant to any logical argument against his belief system. In many situations, individuals with delusional disorder function normally in society, until the delusion becomes severe enough to prompt clinical attention.


Paranoia in schizophrenia

In patients with schizophrenia with paranoia, the typical symptoms of disorganization and disturbed affect are less prominent. The condition develops in young adulthood, but could start at any age. Its course typically is chronic and requires psychiatric treatment; the patient may require hospital care.

Although patients with delusional disorder and those with schizophrenia both have delusions, the delusions of the latter typically are bizarre and unlikely to be possible. For example, the patient might believe that her body has been replaced with the inner workings of an alien being or a robot. The paranoid delusions of persons with delusional disorder are much more mundane and could be plausible. Karl Jaspers, a clinician and researcher in the early 20th century, separated delusional disorder from paranoid schizophrenia by noting that the former could be “understandable, even if untrue” while the latter was “not within the realm of understandability.”⁵

A patient with schizophrenia with paranoid delusions usually experiences auditory hallucinations, such as voices threatening persecution or harm. When predominant, patients could be aroused by these fears and can be dangerous to others.^2,4,5

Other presentations of paranoia

Paranoia can occur in affective disorders as well.¹³ Although the cause is only now being understood, clinicians have put forth theories for many years. A depressed person might suffer from excessive guilt and feel that he deserves to be persecuted, while a manic patient might think she is being persecuted for her greatness. In the past, response to electroconvulsive therapy was used to distinguish affective paranoia from other types.²

Paranoia in organic states

Substance use. Psychostimulants, which are known for their motor activity and arousal enhancing properties, as well as the potential for abuse and other negative consequences, could lead to acute paranoid states in susceptible individuals.^15-17 In addition, tetrahydrocannabinol, the active chemical in Cannabis, can cause acute psychotic symptoms, such as paranoia,^18,19 in a dose-dependent manner. A growing body of evidence suggests that a combination of Cannabis use with a genetic predisposition to psychosis may put some individuals at high risk of decompensation.¹⁹ Of growing concern is the evidence that synthetic cannabinoids, which are among the most commonly used new psychoactive substances, could be associated with psychosis, including paranoia.²⁰

Dementia. Persons with dementia often are paranoid. In geriatric patients with dementia, a delusion of thievery is common. When a person has misplaced objects and can’t remember where, the “default” cognition is that someone has taken them. This confabulation may progress to a persistent paranoia and can be draining on caregivers.

Treating paranoia

A patient with paranoia usually has poor insight and cannot be reasoned with. Such individuals are quick to incorporate others into their delusional theories and easily develop notions of conspiracy. In acute psychosis, when the patient presents with fixed beliefs that are not amenable to reality orientation, and poses a threat to his well-being or that of others, alleviating underlying fear and anxiety is the first priority. Swift pharma­cologic measures are required to decrease the patient’s underlying anxiety or anger, before you can try to earn his trust.

Psychopharmacologic interventions should be specific to the diagnosis. Anti­psychotic medications generally will help decrease most paranoia, but affective syndromes usually require lithium or divalproex for best results.^14,21

Develop a therapeutic relationship. The clinician must approach the patient in a practical and straightforward manner, and should not expect a quick therapeutic alliance. Transference and countertransference develop easily in the context of paranoia. Focus on behaviors that are problematic for the patient or the milieu, such as to ensure a safe environment. The patient needs to be aware of how he could come across to others. Clear feedback about behavior, such as “I cannot really listen to you when you’re yelling,” may be effective. It might be unwise to confront delusional paranoia in an agitated patient. Honesty and respect must continue in all communications to build trust. During assessment of a paranoid individual, evaluate the level of dangerousness. Ask your patient if he feels like acting on his beliefs or harming the people that are the targets of his paranoia.

As the patient begins to manage his anxiety and fear, you can develop a therapeutic alliance. The goals of treatment need be those of the patient—such as staying out of the hospital, or behaving in a manner that is required for employment. Over time, work toward growing the patient’s capacity for social interaction and productive activity. Insight might be elusive; however, some patients with paranoia can learn to take a detached view of their thoughts and emotions, and consider them impermanent events of the mind that make their lives difficult. Practice good judgment when aiming for recovery in a patient who does not have insight. For example, a patient can recognize that although there could be a microchip in his brain, he feels better when he takes medication.

In the case of paranoid personality disorder, treatment, as with most personality disorders, can be difficult. The patient might be unlikely to accept help and could distrust caregivers. Cognitive-behavioral therapy could be useful, if the patient can be engaged in the therapeutic process. Although it might be difficult to obtain enhanced insight, the patient could accept logical explanations for situations that provoke distrust. As long as anxiety and anger can be kept under control, the individual might learn the value of adopting the lessons of therapy. Pharmacological treatments are aimed at reducing the anxiety and anger experienced by the paranoid individual. Antipsychotics may be useful for short periods or during a crisis.^14,21

The clinician must remain calm and reassuring when approaching an individual with paranoia, and not react to the projection of paranoid feelings from the patient. Respect for the patient can be conveyed without agreeing with delusions or bizarre thinking. The clinician must keep agreements and appointments with the client to prevent the erosion of trust. Paranoid conditions might respond slowly to pharmacological treatment, therefore establishing a consistent therapeutic relationship is essential.

Even among healthy individuals, feelings of paranoia are not unusual. In modern psychiatry, we consider paranoia to be a pattern of unfounded thinking, centered on the fearful experience of perceived victimization or threat of intentional harm. This means that a patient with paranoia is, by nature, difficult to engage in treatment. A patient might perceive the clinician as attempting to mislead or manipulate him. A therapeutic alliance could require patience on the part of the clinician, creativity,¹ and abandoning attempts at rational “therapeutic” persuasion. The severity of symptoms determines the approach.

In this article, we review the nature of paranoia and the continuum of syndromes to which it is a central feature, as well as treatment approaches.

Categorization and etiology

Until recently, clinicians considered “paranoid” to be a subtype of schizophrenia (Box^2-7); in DSM-5 the limited diagnostic stability and reliability of the categorization rendered the distinction obsolete.⁸ There are several levels of severity of paranoia; this thought process can present in simple variations of normal fears and concerns or in severe forms, with highly organized delusional systems.

The etiology of paranoia is not clear. Over the years, it has been attributed to defense mechanisms of the ego, habitual fears from repetitive exposure, or irregular activity of the amygdala. It is possible that various types of paranoia could have different causes. Functional MRIs indicate that the amygdala is involved in anxiety and threat perception in both primates and humans.⁹

Rational fear vs paranoia

Under the right circumstances, anyone could sense that he (she) is being threatened. Such feelings are normal in occupied countries and nations at war, and are not pathologic in such contexts. Anxiety about potential danger and harassment under truly oppressive circumstances might be biologically ingrained and have value for survival. It is important to employ cultural sensitivity when distinguishing pathological and nonpathological paranoia because some immigrant populations might have increased prevalence rates but without a true mental illness.¹⁰

Perhaps the key to separating realistic fear from paranoia is the recognition of whether the environment is truly safe or hostile; sometimes this is not initially evident to the clinician. The first author (J.A.W.) experienced this when discovering that a patient who was thought to be paranoid was indeed being stalked by another patient.

Rapid social change makes sweeping explanations about the range of threats experienced by any one person of limited value. Persons living with serious and persistent mental illness experience stigma—harassment, abuse, disgrace—and, similar to victims of repeated sexual abuse and other violence, are not necessarily unreasonable in their inner experience of omnipresent threat. In addition, advances in surveillance technology, as well as the media proliferation of depictions of vulnerability and threat, can plant generalized doubt of historically trusted individuals and systems. Under conditions of severe social discrimination or life under a totalitarian regime, constant fear for safety and worry about the intentions of others is reasonable. We must remember that during the Cold War many people in Eastern Europe had legitimate concerns that their phones were tapped. There are still many places in the world where the fear of government or of one’s neighbors exists.

• paranoid personality disorder
• delusional disorder
• paranoia in schizophrenia (Table).

Paranoid personality disorder

The nature of any personality disorder is a long-standing psychological and behavioral pattern that differs significantly from the expectations of one’s culture. Such beliefs and behaviors typically are pervasive across most aspects of the individual’s interactions, and these enduring patterns of personality usually are evident by adolescence or young adulthood. Paranoid personality disorder is marked by pervasive distrust of others. Typical features include:

• suspicion about other people’s motives
• sensitivity to criticism
• keeping grudges against alleged offenders.⁸

The patient must have 4 of the following symptoms to confirm the diagnosis:

• suspicion of others and their motives
• reluctance to confide in others, due to lack of trust
• recurrent doubts about the fidelity of a significant other
• preoccupation with doubt regarding trusting others
• seeing threatening meanings behind benign remarks or events
• perception of attacks upon one’s character or reputation
• bears persistent grudges.⁸

Individuals with paranoid personality disorder tend to lead maladaptive lifestyles and might present as irritable, unpleasant, and emotionally guarded. Paranoid personality disorder is not a form of delusion, but is a pattern of habitual distrust of others.

The disorder generally is expressed verbally, and is seldom accompanied by hallucinations or unpredictable behavior. Distrust of others might result in social isolation and litigious behavior.⁸ Alternately, a patient with this disorder might not present for treatment until later in life after the loss of significant supporting factors, such as the death of parents or loss of steady employment. Examination of these older individuals is likely to reveal long-standing suspiciousness and distrust that previously was hidden by family members. For example, a 68-year-old woman might present saying that she can’t trust her daughter, but her recently deceased spouse would not let her discuss the topic outside of the home.

The etiology of paranoid personality disorder is unknown. Family studies suggest a possible a genetic connection to paranoia in schizophrenia.¹² Others hypothesize that this dysfunction of personality might originate in early feelings of anxiety and low self-esteem, learned from a controlling, cruel, or sadistic parent; the patient then expects others to reject him (her) as the parent did.^13,14 Such individuals might develop deep-seated distrust of others as a defense mechanism. Under stress, such as during a medical illness, patients could develop brief psychoses. Antipsychotic treatment might be useful in some cases of paranoid personality disorder, but should be limited.

Delusional disorder

Delusional disorder is a unique form of psychosis. Patients with delusional disorder might appear rational—as long as they are in independent roles—and their general functioning could go unnoticed. This could change when the delusions predominate their thoughts, or their delusional behavior is unacceptable in a structured environment. Such individuals often suffer from a highly specific delusion fixed on 1 topic. These delusions generally are the only psychotic feature. The most common theme is that of persecution. For example, a person firmly believes he is being followed by foreign agents or by a religious organization, which is blatantly untrue. Another common theme is infidelity.

Paranoia in delusional disorder is about something that is not actually occurring, but could.³ In other words, the delusion is not necessarily bizarre. The patient may have no evidence or could invent “evidence,” yet remain completely resistant to any logical argument against his belief system. In many situations, individuals with delusional disorder function normally in society, until the delusion becomes severe enough to prompt clinical attention.


Paranoia in schizophrenia

In patients with schizophrenia with paranoia, the typical symptoms of disorganization and disturbed affect are less prominent. The condition develops in young adulthood, but could start at any age. Its course typically is chronic and requires psychiatric treatment; the patient may require hospital care.

Although patients with delusional disorder and those with schizophrenia both have delusions, the delusions of the latter typically are bizarre and unlikely to be possible. For example, the patient might believe that her body has been replaced with the inner workings of an alien being or a robot. The paranoid delusions of persons with delusional disorder are much more mundane and could be plausible. Karl Jaspers, a clinician and researcher in the early 20th century, separated delusional disorder from paranoid schizophrenia by noting that the former could be “understandable, even if untrue” while the latter was “not within the realm of understandability.”⁵

A patient with schizophrenia with paranoid delusions usually experiences auditory hallucinations, such as voices threatening persecution or harm. When predominant, patients could be aroused by these fears and can be dangerous to others.^2,4,5

Other presentations of paranoia

Paranoia can occur in affective disorders as well.¹³ Although the cause is only now being understood, clinicians have put forth theories for many years. A depressed person might suffer from excessive guilt and feel that he deserves to be persecuted, while a manic patient might think she is being persecuted for her greatness. In the past, response to electroconvulsive therapy was used to distinguish affective paranoia from other types.²

Paranoia in organic states

Substance use. Psychostimulants, which are known for their motor activity and arousal enhancing properties, as well as the potential for abuse and other negative consequences, could lead to acute paranoid states in susceptible individuals.^15-17 In addition, tetrahydrocannabinol, the active chemical in Cannabis, can cause acute psychotic symptoms, such as paranoia,^18,19 in a dose-dependent manner. A growing body of evidence suggests that a combination of Cannabis use with a genetic predisposition to psychosis may put some individuals at high risk of decompensation.¹⁹ Of growing concern is the evidence that synthetic cannabinoids, which are among the most commonly used new psychoactive substances, could be associated with psychosis, including paranoia.²⁰

Dementia. Persons with dementia often are paranoid. In geriatric patients with dementia, a delusion of thievery is common. When a person has misplaced objects and can’t remember where, the “default” cognition is that someone has taken them. This confabulation may progress to a persistent paranoia and can be draining on caregivers.

Treating paranoia

A patient with paranoia usually has poor insight and cannot be reasoned with. Such individuals are quick to incorporate others into their delusional theories and easily develop notions of conspiracy. In acute psychosis, when the patient presents with fixed beliefs that are not amenable to reality orientation, and poses a threat to his well-being or that of others, alleviating underlying fear and anxiety is the first priority. Swift pharma­cologic measures are required to decrease the patient’s underlying anxiety or anger, before you can try to earn his trust.

Psychopharmacologic interventions should be specific to the diagnosis. Anti­psychotic medications generally will help decrease most paranoia, but affective syndromes usually require lithium or divalproex for best results.^14,21

Develop a therapeutic relationship. The clinician must approach the patient in a practical and straightforward manner, and should not expect a quick therapeutic alliance. Transference and countertransference develop easily in the context of paranoia. Focus on behaviors that are problematic for the patient or the milieu, such as to ensure a safe environment. The patient needs to be aware of how he could come across to others. Clear feedback about behavior, such as “I cannot really listen to you when you’re yelling,” may be effective. It might be unwise to confront delusional paranoia in an agitated patient. Honesty and respect must continue in all communications to build trust. During assessment of a paranoid individual, evaluate the level of dangerousness. Ask your patient if he feels like acting on his beliefs or harming the people that are the targets of his paranoia.

As the patient begins to manage his anxiety and fear, you can develop a therapeutic alliance. The goals of treatment need be those of the patient—such as staying out of the hospital, or behaving in a manner that is required for employment. Over time, work toward growing the patient’s capacity for social interaction and productive activity. Insight might be elusive; however, some patients with paranoia can learn to take a detached view of their thoughts and emotions, and consider them impermanent events of the mind that make their lives difficult. Practice good judgment when aiming for recovery in a patient who does not have insight. For example, a patient can recognize that although there could be a microchip in his brain, he feels better when he takes medication.

In the case of paranoid personality disorder, treatment, as with most personality disorders, can be difficult. The patient might be unlikely to accept help and could distrust caregivers. Cognitive-behavioral therapy could be useful, if the patient can be engaged in the therapeutic process. Although it might be difficult to obtain enhanced insight, the patient could accept logical explanations for situations that provoke distrust. As long as anxiety and anger can be kept under control, the individual might learn the value of adopting the lessons of therapy. Pharmacological treatments are aimed at reducing the anxiety and anger experienced by the paranoid individual. Antipsychotics may be useful for short periods or during a crisis.^14,21

The clinician must remain calm and reassuring when approaching an individual with paranoia, and not react to the projection of paranoid feelings from the patient. Respect for the patient can be conveyed without agreeing with delusions or bizarre thinking. The clinician must keep agreements and appointments with the client to prevent the erosion of trust. Paranoid conditions might respond slowly to pharmacological treatment, therefore establishing a consistent therapeutic relationship is essential.