David J. Castle, MD

Ms. A, a 21-year-old teacher, recalled always having been “sensitive,” but when she started her first job at age 19 she began to believe that she emitted an offensive odor. She experienced thoughts that she passed offensive flatus, her breath had a fecal odor, and people noticed and were offended.

Gradually Ms. A became more convinced of these distressing beliefs and began to think that she permeated fecal odor through her skin. She also became sure that colleagues were talking about her and that they complained about her “disgusting” smell.

Patients with olfactory reference syndrome (ORS) falsely believe they emit an offensive body odor. Prominent referential thinking—believing that other people perceive the odor—also is common. To introduce you to ORS, we discuss its clinical diagnosis and treatment based on our review of several hundred cases, including the largest reported series of patients with ORS.^1-4

Box 1

Clinical features of ors

Ms. A quit her job and felt confident enough to work again only when she performed a 2-hour daily cleansing routine, doused herself in per-fume, and placed an incontinence pad in her underwear. Despite these precautions, she still thought her colleagues avoided her.

She always averted her mouth when speaking, held her hand in front of her mouth, and sat far from others and close to the door in meetings. She tried to keep meeting room doors open and believed that colleagues held their hands to their noses to “protect” themselves from her odor.

ORS symptoms are most often reported as beginning when patients are in their mid 20s, although some reports suggest onset during puberty or adolescence.⁴ In clinical series, the ratio of men to women is approximately 2:1.

Preoccupation. Individuals with ORS are preoccupied with the belief that they emit an unpleasant or offensive body odor (Box 1),^1,2,5-9 most commonly:

• flatulence, fecal, or anal odors
  
• general body odor
  
• halitosis
  
• genital odors.^1-3
  

Other perceived odors include sweat, armpit odor, sperm, urine, and malodorous hands and feet.^1-3 Occasionally, the imagined odor resembles nonbodily smells, such as ammonia or detergent. The odor is perceived to emanate from corresponding body areas, such as the anus, skin, mouth, rectum, genitalia, feet, nose, or axillae.

Although most reports suggest that patients focus on one odor, some describe being concerned about several smells simultaneously or different odors over time.^10,11

Referential thinking. As the syndrome’s name implies, many ORS patients have delusions of reference, falsely believing that other people perceive the odor.³ They misinterpret the behavior of others, assuming it is a reaction to how the patient smells (Box 2).^2,3

They may misperceive comments (such as, “It’s stuffy in here”), receiving perfume or soap as a gift, or behaviors such as people sniffing, touching or rubbing their nose, clearing their throat, opening a window to get fresh air, putting a newspaper in front of their face, or looking or moving toward or away from the patient.^1,3,5,7

Because they are ashamed, embarrassed, and concerned about offending others with their odor,¹³ many patients engage in repetitive and “safety” behaviors intended to check, eliminate, or camouflage the supposed odor (Box 3).^1,3,7,12,14

Box 2

 

Functional impairment. Individuals with ORS often avoid other people or believe that others avoid them.¹² They are typically embarrassed and worried that others will be offended by the smell. They may:

• avoid activities such as dating
  
• break off engagements
  
• refuse to travel
  
• move to another town
  
• become housebound.^3,7,10,12
  

Patients may change jobs repeatedly or avoid school or work³ because of shame and embarrassment, a belief that other people talk about the supposed odor, or the patient’s excessive preoccupations and time-consuming repetitive and safety behaviors.^5,13,14

The distress and impaired functioning may lead to psychiatric hospitalization, depression, suicidal ideation, suicide attempts, and completed suicide.^7,10,12,15 Pryse-Phillips studied 36 patients with ORS and reported:

• nearly one-half (43%) experienced “suicidal ideas or action”
  
• 2 (5.6%) committed suicide.³
  

Illness course. Most authors suggest that ORS is usually chronic, persisting for years if not decades, with possible worsening over time if patients do not receive appropriate treatment.^11,15 In a 2-year follow-up study,³ ORS symptoms persisted relatively unchanged in 10 of 11 patients.

Some authors have questioned whether ORS can transform into schizophrenia, but others have found little evidence for this.^3,6

Psychiatric comorbidity. Depression is mentioned most often in the literature.^12,13 In Pryse-Phillips’ 36 ORS patients (who did not have a “primary” depressive disorder), depression symptoms tended to be severe.³ The depression generally is considered secondary to ORS, although Pryse-Phillips evaluated 50 additional patients with ORS symptoms whom she considered to have a “primary” depressive disorder.³ Other psychiatric comorbidities include bipolar disorder, personality disorder, schizophrenia, hypochondriasis, alcohol and/or drug abuse, obsessive-compulsive disorder (OCD), and body dysmorphic disorder.^3,7,15 In a study of 200 individuals with body dysmorphic disorder, 8 had comorbid ORS.¹⁶

Diagnosing ORS

Clinical clues to ORS (Table 1) probably are not present in all patients and some are not specific to ORS. They appear to be common features of the illness, however, and may alert you to its presence. Our clinical impression is that many patients with ORS are secretive about their symptoms because they are ashamed of them. Thus, you need to be alert to clues and specifically inquire about ORS symptoms to detect its presence.

Criteria. DSM-IV-TR and ICD-10 lack specific diagnostic criteria for ORS, instead applying criteria for delusional disorder. One problem with this approach is that delusional disorder criteria specify that any co-occurring mood symptoms must be brief relative to the duration of the delusional periods. This requirement may not be valid when applied to ORS.

In our experience, some patients have protracted depressive symptoms that appear secondary to “primary” ORS symptoms, and another diagnosis—such as psychotic depression—does not appear to account for their symptoms.

We propose working diagnostic criteria for ORS (Table 2), which are similar to those proposed by Lochner and Stein¹⁷ and require empiric validation. Suggested questions for the patient interview (Table 3) can help you identify and diagnose ORS.

Differential diagnosis. Keep in mind that a false belief that one emits a bad smell may be a symptom of schizophrenia, and this would trump an ORS diagnosis if other schizophrenia symptoms are present. Some patients with severe depression may believe they smell bad as part of a nihilistic delusional belief system (such as in Cotard’s syndrome—nihilistic delusions in severe depression).

Whether to conceptualize a false belief about body odor as a symptom of depression or as ORS with comorbid or secondary depression may be unclear from case to case.

Table 1

Clinical clues to the presence of olfactory reference syndrome

Referential thinking. Interpreting actions of others—such as opening a window, moving away, putting a hand to their nose, or making comments related to odors—as evidence that the person smells offensive
Excessive attempts to ‘disguise’ the smell, such as washing routines, clothes changing, clothes laundering, or using abundant perfume, deodorant, mouthwash, mints, or other forms of camouflage
Other excessive and repetitive behaviors, such as checking for or asking other people for reassurance about the odor
Social anxiety or avoidance of social activities, relationships, work, school, or other daily activities
Requests for treatment for the perceived odor from dentists, gastroenterologists, proctologists, or other nonpsychiatric physicians despite a negative medical workup

Table 2

Working diagnostic criteria for olfactory reference syndrome

A.	Persistent false belief that one emits a malodorous smell; this belief may encompass a range of insight and does not have to be delusional
B.	The belief is time-consuming and preoccupies the individual for at least 1 hour per day
C.	The belief causes clinically significant distress or results in significant impairment in social, occupational, or other important areas of functioning
D.	The belief is not better accounted for by another mental disorder or a general medical condition

 

Table 3

Diagnosing ORS: Suggested questions for patient interview

Do you have concerns about the way you smell (your body odor)? Do you believe that other people think you smell bad? How much time do you spend each day thinking about your body odor? Does your concern about how you smell upset you a lot? Does your concern about the way you smell interfere with daily activities, such as your job, relationships, school work, or socializing? (Ask the patient about multiple and specific areas of functioning.) Are there situations that you avoid (or wish you could avoid) because of the way you think you smell?

Treatment-seeking behavior

Ms. A consulted several proctologists and a dentist but was not convinced by their reassurance and continued to believe she “stank.” Her relationship with her boyfriend suffered because she continually asked for reassurance about how she smelled and avoided sexual intercourse because of her odor concerns.

Eventually she confronted her boss about her belief that her coworkers were complaining about her smell. Despite reassurance that she didn’t smell bad, she left her job.

Box 3

Medical, surgical, and dental interventions. Because individuals with ORS believe they have a physical problem, many seek evaluation and treatment from nonpsychiatric physicians or dentists.^1,2,12 Seeking a cure for perceived halitosis, they may consult dentists, general surgeons, or ear, nose, and throat specialists. For perceived anal odors, they may consult proctologists, surgeons, or gastroenterologists. Some patients have multiple medical workups.

Convincing patients such as Ms. A of the falsity of their beliefs can be difficult,¹ and some succeed in having medical procedures or surgery, such as excision of tonsils or axillary glands.^3,7,12 To our knowledge, controlled prospective studies of nonpsychiatric treatments have not been done, but it appears that such treatments usually are ineffective.^1,3,6,9

Psychiatric interventions. Convincing patients with ORS to obtain mental health treatment can be difficult.^2,6 Patients with delusional halitosis “would rather go in search of a ‘better dentist’ than go to a psychiatrist.”¹

To get patients to accept psychiatric treatment, we suggest an approach similar to that recommended for body dysmorphic disorder. It may be helpful, for example, to focus on the distress and disability caused by the odor preoccupation, rather than on whether the patient actually smells bad.

Medication and psychotherapy

Limited evidence. The ORS treatment literature is very limited, consisting largely of case reports and small case series. To our knowledge, no controlled treatment trials have been done, no treatments have been compared head to head, and most studies did not use standardized measurements of psychopathology.

Published data therefore must be interpreted cautiously. Some medication reports used relatively low doses and short treatment durations (although what constitutes an adequate therapeutic trial for ORS is not known). Psychotherapy reports often did not specify details of the intervention or the number and duration of sessions. It is not known whether adding a cognitive component to behavioral therapy enhances efficacy, and the combination of psychotherapy and medication has not been studied systematically. More methodologically rigorous treatment studies are needed.

Because of space limitations, we cite representative case reports in the following section of this treatment review, rather than all of the cases found in our literature search.

Antidepressants. Although most ORS patients are delusional, serotonin reuptake inhibitor (SRI) monotherapy has been reported to be efficacious in 10 of 15 cases (67%). Most of these patients received clomipramine.¹⁸ In reports of non-SRI antidepressants, 6 of 15 cases (43%) responded. Some patients’ symptoms responded to an antidepressant after failing to respond to antipsychotic treatment.¹⁹

Antipsychotics. Pimozide is the most studied medication for ORS, with 15 of 31 cases (48%) responding.^2,20 In a series of 12 patients, pimozide responders received 2 to 4 mg/d, except for one patient who needed 6 mg/d.²¹ Patients usually responded within 1 to 4 weeks (an average time to response was not reported). In 2 of these cases, ORS symptoms recurred after pimozide was discontinued and then remitted again after it was restarted.²¹ In another report,² 7 of 14 patients (50%) responded to pimozide.

 

Clinicians using other first-generation antipsychotics (trifluoperazine, thioridazine, and chlorpromazine) reported a positive response in only 2 of 19 cases (11%).^12,22

Combination therapy. Ten of 17 cases (59%) of ORS responded to combined treatment with an antidepressant and an antipsychotic.^2,12

Other somatic treatments. Several reports found benzodiazepine monotherapy lacked efficacy, as was the case for electroconvulsive therapy.^12,15 One report noted an unsuccessful outcome with leucotomy and a partial response with bilateral partial division of the thalamo-frontal tract.¹⁵

Psychosocial treatment. All reports of psychosocial therapies are single cases or small series, and none used a control intervention.^2,7,14

Behavioral treatment has been efficacious, although patients require months to years to habituate. Several reports totalling 14 patients describe behavioral treatment over weeks to months.^7,23 These treatments involved exposure to avoided social situations and response prevention, which consisted of refraining from repetitive or camouflaging behaviors such as showering, visits to the toilet, or deodorant use. Gomez-Perez and colleagues²³ noted that exposure therapy was less effective for ORS than for social phobia or OCD.

One report described a patient with flatulence concerns who responded to a paradoxical intention consisting of instructions to emit gas as soon as it was experienced; at 1-year follow-up, her symptoms had not recurred.²⁴

Psychodynamic interventions show no benefit for ORS symptoms.

Treatment summary

Ms. A became increasingly despondent and depressed. She eventually sought the help of her family doctor, who referred her to a psychiatrist. With a combination of a serotonergic antidepressant (escitalopram, 40 mg/d), a low-dose atypical antipsychotic (quetiapine, 50 mg at night), and cognitive-behavioral therapy, she started to re-engage in daily activities. During 6 months of treatment, the intensity of her belief about having body odor abated.

Limited data support the use of SRI monotherapy or an SRI plus an antipsychotic. Using SRI monotherapy for delusional patients may sound counterintuitive, but this approach appears efficacious for patients with delusional body dysmorphic disorder, which has similarities to ORS.^17,25,26

Clinically, we have found the use of atypical antipsychotics as an adjunct to SRIs to be helpful, although this strategy has not been subjected to clinical trials. Pimozide alone or in combination with an antidepressant also appears promising, as does exposure and response prevention. Do not combine pimozide with clomipramine because of the risk of cardiac toxicity.

Related resources

• Phillips KA, Gunderson C, Gruber U, Castle DJ. Delusions of body malodour: the olfactory reference syndrome. In: Brewer W, Castle D, Pantelis C. Olfaction and the brain. Cambridge, UK: Cambridge University Press; 2006:334-53.
  
• Pryse-Phillips W. An olfactory reference syndrome. Acta Psychiatr Scand 1971;47:484-509.
  

Drug brand names

• Chlorpromazine • Thorazine
  
• Clomipramine • Anafranil
  
• Escitalopram • Lexapro
  
• Pimozide • Orap
  
• Quetiapine • Seroquel
  
• Thioridazine • Mellaril
  
• Trifluoperazine • Stelazine
  

Disclosure

Dr. Phillips receives research support from the National Institute of Mental Health, the Food and Drug Administration, UCB Pharma, and Forest Pharmaceuticals.

Dr. Castle receives research support from Janssen-Cilag; is a consultant to Eli Lilly and Company., Bristol-Myers Squibb, and Lundbeck; and is a speaker for Eli Lilly and Co., sanofi-aventis, Bristol-Myers Squibb, Janssen-Cilag, Lundbeck, and Organon.

Acknowledgment

The authors would like to thank Craig Gunderson, MD, and Uschi Gruber, MB, for their assistance with a literature search on olfactory reference syndrome.

Ms. A, a 21-year-old teacher, recalled always having been “sensitive,” but when she started her first job at age 19 she began to believe that she emitted an offensive odor. She experienced thoughts that she passed offensive flatus, her breath had a fecal odor, and people noticed and were offended.

Gradually Ms. A became more convinced of these distressing beliefs and began to think that she permeated fecal odor through her skin. She also became sure that colleagues were talking about her and that they complained about her “disgusting” smell.

Patients with olfactory reference syndrome (ORS) falsely believe they emit an offensive body odor. Prominent referential thinking—believing that other people perceive the odor—also is common. To introduce you to ORS, we discuss its clinical diagnosis and treatment based on our review of several hundred cases, including the largest reported series of patients with ORS.^1-4

Box 1

Clinical features of ors

Ms. A quit her job and felt confident enough to work again only when she performed a 2-hour daily cleansing routine, doused herself in per-fume, and placed an incontinence pad in her underwear. Despite these precautions, she still thought her colleagues avoided her.

She always averted her mouth when speaking, held her hand in front of her mouth, and sat far from others and close to the door in meetings. She tried to keep meeting room doors open and believed that colleagues held their hands to their noses to “protect” themselves from her odor.

ORS symptoms are most often reported as beginning when patients are in their mid 20s, although some reports suggest onset during puberty or adolescence.⁴ In clinical series, the ratio of men to women is approximately 2:1.

Preoccupation. Individuals with ORS are preoccupied with the belief that they emit an unpleasant or offensive body odor (Box 1),^1,2,5-9 most commonly:

• flatulence, fecal, or anal odors
  
• general body odor
  
• halitosis
  
• genital odors.^1-3
  

Other perceived odors include sweat, armpit odor, sperm, urine, and malodorous hands and feet.^1-3 Occasionally, the imagined odor resembles nonbodily smells, such as ammonia or detergent. The odor is perceived to emanate from corresponding body areas, such as the anus, skin, mouth, rectum, genitalia, feet, nose, or axillae.

Although most reports suggest that patients focus on one odor, some describe being concerned about several smells simultaneously or different odors over time.^10,11

Referential thinking. As the syndrome’s name implies, many ORS patients have delusions of reference, falsely believing that other people perceive the odor.³ They misinterpret the behavior of others, assuming it is a reaction to how the patient smells (Box 2).^2,3

They may misperceive comments (such as, “It’s stuffy in here”), receiving perfume or soap as a gift, or behaviors such as people sniffing, touching or rubbing their nose, clearing their throat, opening a window to get fresh air, putting a newspaper in front of their face, or looking or moving toward or away from the patient.^1,3,5,7

Because they are ashamed, embarrassed, and concerned about offending others with their odor,¹³ many patients engage in repetitive and “safety” behaviors intended to check, eliminate, or camouflage the supposed odor (Box 3).^1,3,7,12,14

Box 2

 

Functional impairment. Individuals with ORS often avoid other people or believe that others avoid them.¹² They are typically embarrassed and worried that others will be offended by the smell. They may:

• avoid activities such as dating
  
• break off engagements
  
• refuse to travel
  
• move to another town
  
• become housebound.^3,7,10,12
  

Patients may change jobs repeatedly or avoid school or work³ because of shame and embarrassment, a belief that other people talk about the supposed odor, or the patient’s excessive preoccupations and time-consuming repetitive and safety behaviors.^5,13,14

The distress and impaired functioning may lead to psychiatric hospitalization, depression, suicidal ideation, suicide attempts, and completed suicide.^7,10,12,15 Pryse-Phillips studied 36 patients with ORS and reported:

• nearly one-half (43%) experienced “suicidal ideas or action”
  
• 2 (5.6%) committed suicide.³
  

Illness course. Most authors suggest that ORS is usually chronic, persisting for years if not decades, with possible worsening over time if patients do not receive appropriate treatment.^11,15 In a 2-year follow-up study,³ ORS symptoms persisted relatively unchanged in 10 of 11 patients.

Some authors have questioned whether ORS can transform into schizophrenia, but others have found little evidence for this.^3,6

Psychiatric comorbidity. Depression is mentioned most often in the literature.^12,13 In Pryse-Phillips’ 36 ORS patients (who did not have a “primary” depressive disorder), depression symptoms tended to be severe.³ The depression generally is considered secondary to ORS, although Pryse-Phillips evaluated 50 additional patients with ORS symptoms whom she considered to have a “primary” depressive disorder.³ Other psychiatric comorbidities include bipolar disorder, personality disorder, schizophrenia, hypochondriasis, alcohol and/or drug abuse, obsessive-compulsive disorder (OCD), and body dysmorphic disorder.^3,7,15 In a study of 200 individuals with body dysmorphic disorder, 8 had comorbid ORS.¹⁶

Diagnosing ORS

Clinical clues to ORS (Table 1) probably are not present in all patients and some are not specific to ORS. They appear to be common features of the illness, however, and may alert you to its presence. Our clinical impression is that many patients with ORS are secretive about their symptoms because they are ashamed of them. Thus, you need to be alert to clues and specifically inquire about ORS symptoms to detect its presence.

Criteria. DSM-IV-TR and ICD-10 lack specific diagnostic criteria for ORS, instead applying criteria for delusional disorder. One problem with this approach is that delusional disorder criteria specify that any co-occurring mood symptoms must be brief relative to the duration of the delusional periods. This requirement may not be valid when applied to ORS.

In our experience, some patients have protracted depressive symptoms that appear secondary to “primary” ORS symptoms, and another diagnosis—such as psychotic depression—does not appear to account for their symptoms.

We propose working diagnostic criteria for ORS (Table 2), which are similar to those proposed by Lochner and Stein¹⁷ and require empiric validation. Suggested questions for the patient interview (Table 3) can help you identify and diagnose ORS.

Differential diagnosis. Keep in mind that a false belief that one emits a bad smell may be a symptom of schizophrenia, and this would trump an ORS diagnosis if other schizophrenia symptoms are present. Some patients with severe depression may believe they smell bad as part of a nihilistic delusional belief system (such as in Cotard’s syndrome—nihilistic delusions in severe depression).

Whether to conceptualize a false belief about body odor as a symptom of depression or as ORS with comorbid or secondary depression may be unclear from case to case.

Table 1

Clinical clues to the presence of olfactory reference syndrome

Referential thinking. Interpreting actions of others—such as opening a window, moving away, putting a hand to their nose, or making comments related to odors—as evidence that the person smells offensive
Excessive attempts to ‘disguise’ the smell, such as washing routines, clothes changing, clothes laundering, or using abundant perfume, deodorant, mouthwash, mints, or other forms of camouflage
Other excessive and repetitive behaviors, such as checking for or asking other people for reassurance about the odor
Social anxiety or avoidance of social activities, relationships, work, school, or other daily activities
Requests for treatment for the perceived odor from dentists, gastroenterologists, proctologists, or other nonpsychiatric physicians despite a negative medical workup

Table 2

Working diagnostic criteria for olfactory reference syndrome

A.	Persistent false belief that one emits a malodorous smell; this belief may encompass a range of insight and does not have to be delusional
B.	The belief is time-consuming and preoccupies the individual for at least 1 hour per day
C.	The belief causes clinically significant distress or results in significant impairment in social, occupational, or other important areas of functioning
D.	The belief is not better accounted for by another mental disorder or a general medical condition

 

Table 3

Diagnosing ORS: Suggested questions for patient interview

Do you have concerns about the way you smell (your body odor)? Do you believe that other people think you smell bad? How much time do you spend each day thinking about your body odor? Does your concern about how you smell upset you a lot? Does your concern about the way you smell interfere with daily activities, such as your job, relationships, school work, or socializing? (Ask the patient about multiple and specific areas of functioning.) Are there situations that you avoid (or wish you could avoid) because of the way you think you smell?

Treatment-seeking behavior

Ms. A consulted several proctologists and a dentist but was not convinced by their reassurance and continued to believe she “stank.” Her relationship with her boyfriend suffered because she continually asked for reassurance about how she smelled and avoided sexual intercourse because of her odor concerns.

Eventually she confronted her boss about her belief that her coworkers were complaining about her smell. Despite reassurance that she didn’t smell bad, she left her job.

Box 3

Medical, surgical, and dental interventions. Because individuals with ORS believe they have a physical problem, many seek evaluation and treatment from nonpsychiatric physicians or dentists.^1,2,12 Seeking a cure for perceived halitosis, they may consult dentists, general surgeons, or ear, nose, and throat specialists. For perceived anal odors, they may consult proctologists, surgeons, or gastroenterologists. Some patients have multiple medical workups.

Convincing patients such as Ms. A of the falsity of their beliefs can be difficult,¹ and some succeed in having medical procedures or surgery, such as excision of tonsils or axillary glands.^3,7,12 To our knowledge, controlled prospective studies of nonpsychiatric treatments have not been done, but it appears that such treatments usually are ineffective.^1,3,6,9

Psychiatric interventions. Convincing patients with ORS to obtain mental health treatment can be difficult.^2,6 Patients with delusional halitosis “would rather go in search of a ‘better dentist’ than go to a psychiatrist.”¹

To get patients to accept psychiatric treatment, we suggest an approach similar to that recommended for body dysmorphic disorder. It may be helpful, for example, to focus on the distress and disability caused by the odor preoccupation, rather than on whether the patient actually smells bad.

Medication and psychotherapy

Limited evidence. The ORS treatment literature is very limited, consisting largely of case reports and small case series. To our knowledge, no controlled treatment trials have been done, no treatments have been compared head to head, and most studies did not use standardized measurements of psychopathology.

Published data therefore must be interpreted cautiously. Some medication reports used relatively low doses and short treatment durations (although what constitutes an adequate therapeutic trial for ORS is not known). Psychotherapy reports often did not specify details of the intervention or the number and duration of sessions. It is not known whether adding a cognitive component to behavioral therapy enhances efficacy, and the combination of psychotherapy and medication has not been studied systematically. More methodologically rigorous treatment studies are needed.

Because of space limitations, we cite representative case reports in the following section of this treatment review, rather than all of the cases found in our literature search.

Antidepressants. Although most ORS patients are delusional, serotonin reuptake inhibitor (SRI) monotherapy has been reported to be efficacious in 10 of 15 cases (67%). Most of these patients received clomipramine.¹⁸ In reports of non-SRI antidepressants, 6 of 15 cases (43%) responded. Some patients’ symptoms responded to an antidepressant after failing to respond to antipsychotic treatment.¹⁹

Antipsychotics. Pimozide is the most studied medication for ORS, with 15 of 31 cases (48%) responding.^2,20 In a series of 12 patients, pimozide responders received 2 to 4 mg/d, except for one patient who needed 6 mg/d.²¹ Patients usually responded within 1 to 4 weeks (an average time to response was not reported). In 2 of these cases, ORS symptoms recurred after pimozide was discontinued and then remitted again after it was restarted.²¹ In another report,² 7 of 14 patients (50%) responded to pimozide.

 

Clinicians using other first-generation antipsychotics (trifluoperazine, thioridazine, and chlorpromazine) reported a positive response in only 2 of 19 cases (11%).^12,22

Combination therapy. Ten of 17 cases (59%) of ORS responded to combined treatment with an antidepressant and an antipsychotic.^2,12

Other somatic treatments. Several reports found benzodiazepine monotherapy lacked efficacy, as was the case for electroconvulsive therapy.^12,15 One report noted an unsuccessful outcome with leucotomy and a partial response with bilateral partial division of the thalamo-frontal tract.¹⁵

Psychosocial treatment. All reports of psychosocial therapies are single cases or small series, and none used a control intervention.^2,7,14

Behavioral treatment has been efficacious, although patients require months to years to habituate. Several reports totalling 14 patients describe behavioral treatment over weeks to months.^7,23 These treatments involved exposure to avoided social situations and response prevention, which consisted of refraining from repetitive or camouflaging behaviors such as showering, visits to the toilet, or deodorant use. Gomez-Perez and colleagues²³ noted that exposure therapy was less effective for ORS than for social phobia or OCD.

One report described a patient with flatulence concerns who responded to a paradoxical intention consisting of instructions to emit gas as soon as it was experienced; at 1-year follow-up, her symptoms had not recurred.²⁴

Psychodynamic interventions show no benefit for ORS symptoms.

Treatment summary

Ms. A became increasingly despondent and depressed. She eventually sought the help of her family doctor, who referred her to a psychiatrist. With a combination of a serotonergic antidepressant (escitalopram, 40 mg/d), a low-dose atypical antipsychotic (quetiapine, 50 mg at night), and cognitive-behavioral therapy, she started to re-engage in daily activities. During 6 months of treatment, the intensity of her belief about having body odor abated.

Limited data support the use of SRI monotherapy or an SRI plus an antipsychotic. Using SRI monotherapy for delusional patients may sound counterintuitive, but this approach appears efficacious for patients with delusional body dysmorphic disorder, which has similarities to ORS.^17,25,26

Clinically, we have found the use of atypical antipsychotics as an adjunct to SRIs to be helpful, although this strategy has not been subjected to clinical trials. Pimozide alone or in combination with an antidepressant also appears promising, as does exposure and response prevention. Do not combine pimozide with clomipramine because of the risk of cardiac toxicity.

Related resources

• Phillips KA, Gunderson C, Gruber U, Castle DJ. Delusions of body malodour: the olfactory reference syndrome. In: Brewer W, Castle D, Pantelis C. Olfaction and the brain. Cambridge, UK: Cambridge University Press; 2006:334-53.
  
• Pryse-Phillips W. An olfactory reference syndrome. Acta Psychiatr Scand 1971;47:484-509.
  

Drug brand names

• Chlorpromazine • Thorazine
  
• Clomipramine • Anafranil
  
• Escitalopram • Lexapro
  
• Pimozide • Orap
  
• Quetiapine • Seroquel
  
• Thioridazine • Mellaril
  
• Trifluoperazine • Stelazine
  

Disclosure

Dr. Phillips receives research support from the National Institute of Mental Health, the Food and Drug Administration, UCB Pharma, and Forest Pharmaceuticals.

Dr. Castle receives research support from Janssen-Cilag; is a consultant to Eli Lilly and Company., Bristol-Myers Squibb, and Lundbeck; and is a speaker for Eli Lilly and Co., sanofi-aventis, Bristol-Myers Squibb, Janssen-Cilag, Lundbeck, and Organon.

Acknowledgment

The authors would like to thank Craig Gunderson, MD, and Uschi Gruber, MB, for their assistance with a literature search on olfactory reference syndrome.

Ms. A, a 21-year-old teacher, recalled always having been “sensitive,” but when she started her first job at age 19 she began to believe that she emitted an offensive odor. She experienced thoughts that she passed offensive flatus, her breath had a fecal odor, and people noticed and were offended.

Gradually Ms. A became more convinced of these distressing beliefs and began to think that she permeated fecal odor through her skin. She also became sure that colleagues were talking about her and that they complained about her “disgusting” smell.

Patients with olfactory reference syndrome (ORS) falsely believe they emit an offensive body odor. Prominent referential thinking—believing that other people perceive the odor—also is common. To introduce you to ORS, we discuss its clinical diagnosis and treatment based on our review of several hundred cases, including the largest reported series of patients with ORS.^1-4

Box 1

Clinical features of ors

Ms. A quit her job and felt confident enough to work again only when she performed a 2-hour daily cleansing routine, doused herself in per-fume, and placed an incontinence pad in her underwear. Despite these precautions, she still thought her colleagues avoided her.

She always averted her mouth when speaking, held her hand in front of her mouth, and sat far from others and close to the door in meetings. She tried to keep meeting room doors open and believed that colleagues held their hands to their noses to “protect” themselves from her odor.

ORS symptoms are most often reported as beginning when patients are in their mid 20s, although some reports suggest onset during puberty or adolescence.⁴ In clinical series, the ratio of men to women is approximately 2:1.

Preoccupation. Individuals with ORS are preoccupied with the belief that they emit an unpleasant or offensive body odor (Box 1),^1,2,5-9 most commonly:

• flatulence, fecal, or anal odors
  
• general body odor
  
• halitosis
  
• genital odors.^1-3
  

Other perceived odors include sweat, armpit odor, sperm, urine, and malodorous hands and feet.^1-3 Occasionally, the imagined odor resembles nonbodily smells, such as ammonia or detergent. The odor is perceived to emanate from corresponding body areas, such as the anus, skin, mouth, rectum, genitalia, feet, nose, or axillae.

Although most reports suggest that patients focus on one odor, some describe being concerned about several smells simultaneously or different odors over time.^10,11

Referential thinking. As the syndrome’s name implies, many ORS patients have delusions of reference, falsely believing that other people perceive the odor.³ They misinterpret the behavior of others, assuming it is a reaction to how the patient smells (Box 2).^2,3

They may misperceive comments (such as, “It’s stuffy in here”), receiving perfume or soap as a gift, or behaviors such as people sniffing, touching or rubbing their nose, clearing their throat, opening a window to get fresh air, putting a newspaper in front of their face, or looking or moving toward or away from the patient.^1,3,5,7

Because they are ashamed, embarrassed, and concerned about offending others with their odor,¹³ many patients engage in repetitive and “safety” behaviors intended to check, eliminate, or camouflage the supposed odor (Box 3).^1,3,7,12,14

Box 2

 

Functional impairment. Individuals with ORS often avoid other people or believe that others avoid them.¹² They are typically embarrassed and worried that others will be offended by the smell. They may:

• avoid activities such as dating
  
• break off engagements
  
• refuse to travel
  
• move to another town
  
• become housebound.^3,7,10,12
  

Patients may change jobs repeatedly or avoid school or work³ because of shame and embarrassment, a belief that other people talk about the supposed odor, or the patient’s excessive preoccupations and time-consuming repetitive and safety behaviors.^5,13,14

The distress and impaired functioning may lead to psychiatric hospitalization, depression, suicidal ideation, suicide attempts, and completed suicide.^7,10,12,15 Pryse-Phillips studied 36 patients with ORS and reported:

• nearly one-half (43%) experienced “suicidal ideas or action”
  
• 2 (5.6%) committed suicide.³
  

Illness course. Most authors suggest that ORS is usually chronic, persisting for years if not decades, with possible worsening over time if patients do not receive appropriate treatment.^11,15 In a 2-year follow-up study,³ ORS symptoms persisted relatively unchanged in 10 of 11 patients.

Some authors have questioned whether ORS can transform into schizophrenia, but others have found little evidence for this.^3,6

Psychiatric comorbidity. Depression is mentioned most often in the literature.^12,13 In Pryse-Phillips’ 36 ORS patients (who did not have a “primary” depressive disorder), depression symptoms tended to be severe.³ The depression generally is considered secondary to ORS, although Pryse-Phillips evaluated 50 additional patients with ORS symptoms whom she considered to have a “primary” depressive disorder.³ Other psychiatric comorbidities include bipolar disorder, personality disorder, schizophrenia, hypochondriasis, alcohol and/or drug abuse, obsessive-compulsive disorder (OCD), and body dysmorphic disorder.^3,7,15 In a study of 200 individuals with body dysmorphic disorder, 8 had comorbid ORS.¹⁶

Diagnosing ORS

Clinical clues to ORS (Table 1) probably are not present in all patients and some are not specific to ORS. They appear to be common features of the illness, however, and may alert you to its presence. Our clinical impression is that many patients with ORS are secretive about their symptoms because they are ashamed of them. Thus, you need to be alert to clues and specifically inquire about ORS symptoms to detect its presence.

Criteria. DSM-IV-TR and ICD-10 lack specific diagnostic criteria for ORS, instead applying criteria for delusional disorder. One problem with this approach is that delusional disorder criteria specify that any co-occurring mood symptoms must be brief relative to the duration of the delusional periods. This requirement may not be valid when applied to ORS.

In our experience, some patients have protracted depressive symptoms that appear secondary to “primary” ORS symptoms, and another diagnosis—such as psychotic depression—does not appear to account for their symptoms.

We propose working diagnostic criteria for ORS (Table 2), which are similar to those proposed by Lochner and Stein¹⁷ and require empiric validation. Suggested questions for the patient interview (Table 3) can help you identify and diagnose ORS.

Differential diagnosis. Keep in mind that a false belief that one emits a bad smell may be a symptom of schizophrenia, and this would trump an ORS diagnosis if other schizophrenia symptoms are present. Some patients with severe depression may believe they smell bad as part of a nihilistic delusional belief system (such as in Cotard’s syndrome—nihilistic delusions in severe depression).

Whether to conceptualize a false belief about body odor as a symptom of depression or as ORS with comorbid or secondary depression may be unclear from case to case.

Table 1

Clinical clues to the presence of olfactory reference syndrome

Referential thinking. Interpreting actions of others—such as opening a window, moving away, putting a hand to their nose, or making comments related to odors—as evidence that the person smells offensive
Excessive attempts to ‘disguise’ the smell, such as washing routines, clothes changing, clothes laundering, or using abundant perfume, deodorant, mouthwash, mints, or other forms of camouflage
Other excessive and repetitive behaviors, such as checking for or asking other people for reassurance about the odor
Social anxiety or avoidance of social activities, relationships, work, school, or other daily activities
Requests for treatment for the perceived odor from dentists, gastroenterologists, proctologists, or other nonpsychiatric physicians despite a negative medical workup

Table 2

Working diagnostic criteria for olfactory reference syndrome

A.	Persistent false belief that one emits a malodorous smell; this belief may encompass a range of insight and does not have to be delusional
B.	The belief is time-consuming and preoccupies the individual for at least 1 hour per day
C.	The belief causes clinically significant distress or results in significant impairment in social, occupational, or other important areas of functioning
D.	The belief is not better accounted for by another mental disorder or a general medical condition

 

Table 3

Diagnosing ORS: Suggested questions for patient interview

Do you have concerns about the way you smell (your body odor)? Do you believe that other people think you smell bad? How much time do you spend each day thinking about your body odor? Does your concern about how you smell upset you a lot? Does your concern about the way you smell interfere with daily activities, such as your job, relationships, school work, or socializing? (Ask the patient about multiple and specific areas of functioning.) Are there situations that you avoid (or wish you could avoid) because of the way you think you smell?

Treatment-seeking behavior

Ms. A consulted several proctologists and a dentist but was not convinced by their reassurance and continued to believe she “stank.” Her relationship with her boyfriend suffered because she continually asked for reassurance about how she smelled and avoided sexual intercourse because of her odor concerns.

Eventually she confronted her boss about her belief that her coworkers were complaining about her smell. Despite reassurance that she didn’t smell bad, she left her job.

Box 3

Medical, surgical, and dental interventions. Because individuals with ORS believe they have a physical problem, many seek evaluation and treatment from nonpsychiatric physicians or dentists.^1,2,12 Seeking a cure for perceived halitosis, they may consult dentists, general surgeons, or ear, nose, and throat specialists. For perceived anal odors, they may consult proctologists, surgeons, or gastroenterologists. Some patients have multiple medical workups.

Convincing patients such as Ms. A of the falsity of their beliefs can be difficult,¹ and some succeed in having medical procedures or surgery, such as excision of tonsils or axillary glands.^3,7,12 To our knowledge, controlled prospective studies of nonpsychiatric treatments have not been done, but it appears that such treatments usually are ineffective.^1,3,6,9

Psychiatric interventions. Convincing patients with ORS to obtain mental health treatment can be difficult.^2,6 Patients with delusional halitosis “would rather go in search of a ‘better dentist’ than go to a psychiatrist.”¹

To get patients to accept psychiatric treatment, we suggest an approach similar to that recommended for body dysmorphic disorder. It may be helpful, for example, to focus on the distress and disability caused by the odor preoccupation, rather than on whether the patient actually smells bad.

Medication and psychotherapy

Limited evidence. The ORS treatment literature is very limited, consisting largely of case reports and small case series. To our knowledge, no controlled treatment trials have been done, no treatments have been compared head to head, and most studies did not use standardized measurements of psychopathology.

Published data therefore must be interpreted cautiously. Some medication reports used relatively low doses and short treatment durations (although what constitutes an adequate therapeutic trial for ORS is not known). Psychotherapy reports often did not specify details of the intervention or the number and duration of sessions. It is not known whether adding a cognitive component to behavioral therapy enhances efficacy, and the combination of psychotherapy and medication has not been studied systematically. More methodologically rigorous treatment studies are needed.

Because of space limitations, we cite representative case reports in the following section of this treatment review, rather than all of the cases found in our literature search.

Antidepressants. Although most ORS patients are delusional, serotonin reuptake inhibitor (SRI) monotherapy has been reported to be efficacious in 10 of 15 cases (67%). Most of these patients received clomipramine.¹⁸ In reports of non-SRI antidepressants, 6 of 15 cases (43%) responded. Some patients’ symptoms responded to an antidepressant after failing to respond to antipsychotic treatment.¹⁹

Antipsychotics. Pimozide is the most studied medication for ORS, with 15 of 31 cases (48%) responding.^2,20 In a series of 12 patients, pimozide responders received 2 to 4 mg/d, except for one patient who needed 6 mg/d.²¹ Patients usually responded within 1 to 4 weeks (an average time to response was not reported). In 2 of these cases, ORS symptoms recurred after pimozide was discontinued and then remitted again after it was restarted.²¹ In another report,² 7 of 14 patients (50%) responded to pimozide.

 

Clinicians using other first-generation antipsychotics (trifluoperazine, thioridazine, and chlorpromazine) reported a positive response in only 2 of 19 cases (11%).^12,22

Combination therapy. Ten of 17 cases (59%) of ORS responded to combined treatment with an antidepressant and an antipsychotic.^2,12

Other somatic treatments. Several reports found benzodiazepine monotherapy lacked efficacy, as was the case for electroconvulsive therapy.^12,15 One report noted an unsuccessful outcome with leucotomy and a partial response with bilateral partial division of the thalamo-frontal tract.¹⁵

Psychosocial treatment. All reports of psychosocial therapies are single cases or small series, and none used a control intervention.^2,7,14

Behavioral treatment has been efficacious, although patients require months to years to habituate. Several reports totalling 14 patients describe behavioral treatment over weeks to months.^7,23 These treatments involved exposure to avoided social situations and response prevention, which consisted of refraining from repetitive or camouflaging behaviors such as showering, visits to the toilet, or deodorant use. Gomez-Perez and colleagues²³ noted that exposure therapy was less effective for ORS than for social phobia or OCD.

One report described a patient with flatulence concerns who responded to a paradoxical intention consisting of instructions to emit gas as soon as it was experienced; at 1-year follow-up, her symptoms had not recurred.²⁴

Psychodynamic interventions show no benefit for ORS symptoms.

Treatment summary

Ms. A became increasingly despondent and depressed. She eventually sought the help of her family doctor, who referred her to a psychiatrist. With a combination of a serotonergic antidepressant (escitalopram, 40 mg/d), a low-dose atypical antipsychotic (quetiapine, 50 mg at night), and cognitive-behavioral therapy, she started to re-engage in daily activities. During 6 months of treatment, the intensity of her belief about having body odor abated.

Limited data support the use of SRI monotherapy or an SRI plus an antipsychotic. Using SRI monotherapy for delusional patients may sound counterintuitive, but this approach appears efficacious for patients with delusional body dysmorphic disorder, which has similarities to ORS.^17,25,26

Clinically, we have found the use of atypical antipsychotics as an adjunct to SRIs to be helpful, although this strategy has not been subjected to clinical trials. Pimozide alone or in combination with an antidepressant also appears promising, as does exposure and response prevention. Do not combine pimozide with clomipramine because of the risk of cardiac toxicity.

Related resources

• Phillips KA, Gunderson C, Gruber U, Castle DJ. Delusions of body malodour: the olfactory reference syndrome. In: Brewer W, Castle D, Pantelis C. Olfaction and the brain. Cambridge, UK: Cambridge University Press; 2006:334-53.
  
• Pryse-Phillips W. An olfactory reference syndrome. Acta Psychiatr Scand 1971;47:484-509.
  

Drug brand names

• Chlorpromazine • Thorazine
  
• Clomipramine • Anafranil
  
• Escitalopram • Lexapro
  
• Pimozide • Orap
  
• Quetiapine • Seroquel
  
• Thioridazine • Mellaril
  
• Trifluoperazine • Stelazine
  

Disclosure

Dr. Phillips receives research support from the National Institute of Mental Health, the Food and Drug Administration, UCB Pharma, and Forest Pharmaceuticals.

Dr. Castle receives research support from Janssen-Cilag; is a consultant to Eli Lilly and Company., Bristol-Myers Squibb, and Lundbeck; and is a speaker for Eli Lilly and Co., sanofi-aventis, Bristol-Myers Squibb, Janssen-Cilag, Lundbeck, and Organon.

Acknowledgment

The authors would like to thank Craig Gunderson, MD, and Uschi Gruber, MB, for their assistance with a literature search on olfactory reference syndrome.

Mr. B, age 73, repeatedly complained to his landlord that people were trying to poison him by pumping noxious gas into his apartment. He barricaded himself inside, taped up all air vents and windows, and left only when absolutely necessary. At night, he could hear people working the “apparatus” that pumped the gas, and could “smell” the vapors.

On examination, he was physically well but suffered from mild neural deafness and myopia. He was suspicious and guarded but oriented and not cognitively impaired. He expressed paranoid beliefs and experienced auditory and olfactory hallucinations. There was no evidence of affective disturbance.

At first he refused psychiatric care but eventually agreed to take risperidone, 0.5 mg at night. He tolerated the agent well, and his psychotic symptoms slowly resolved.

As Mr. B’s case illustrates, schizophrenia—once thought to be strictly an early-onset disorder—commonly manifests late in life (Box). Too often, however, very late-onset schizophrenia goes undiagnosed because older patients with the disorder tend to be socially isolated. Their symptoms of paranoia and reluctance by family members to intervene also can prevent them from receiving treatment that could control psychotic symptoms and improve their quality of life.

Box

Psychosis presenting at any age, but especially in later life, requires careful evaluation to exclude organic pathology. Very late-onset schizophrenia differs substantially from psychosis associated with dementia, as in Alzheimer’s disease, both in terms of neuropsychological and brain imaging findings.

Although limited, data on late-life psychosis offer clues to its diagnosis and treatment. This article will address:

• risk factors and clinical presentations associated with late-onset schizophrenia
• pharmacologic and psychosocial treatment options based on available evidence.

Clinical presentation

Clinical presentation of schizophrenia with onset after age 60 differs from that of early-onset schizophrenia (Table 1). To those familiar with early-onset cases, the most obvious differences in late-onset patients are negligible rates of primary negative symptoms and formal thought disorder.

Persecutory delusions are common in both types and often are elaborate. The so-called “partition” delusion, which leads the patient to believe that people or objects can transgress impermeable barriers and access his or her home with malign intent, is more common in late-onset than in early-onset schizophrenia.³

Hallucinations in very late-onset schizophrenia are often prominent and can occur in multiple modalities, including auditory, visual, and olfactory. Sometimes the hallucination and delusion are clearly linked; for example, a patient claims to smell the noxious gas he believes is being pumped into his home.

Does the difference in presentation between early- and very late-onset schizophrenia reflect distinct disease processes or the disorder’s impact at different stages of brain maturation and degeneration? To answer that question, researchers have compared late-onset patients with young early-onset patents and with older patients who developed schizophrenia in their youth. Similar phenomena have been found in both early-onset groups,⁴ suggesting that age of onset causes the differences in clinical presentation.

Risk factors

As with early-onset schizophrenia, family history is the most common cause of very late-onset schizophrenia. Despite their limitations, family history studies almost all show a familial risk of very late-onset schizophrenia lower than that of early-onset patients but greater than that of the general population.⁵ Published studies do not tell us whether age of onset is genetically determined, in part because not all patients at risk for very late-onset schizophrenia live long enough to manifest its symptoms.

Family history has been associated with affective disorder in some patients with very late-onset schizophrenia. One casecontrolled series of family interviews⁶ found an approximate 1.3% rate of schizophrenia in relatives —about the same rate as that of the control group. The rate of depression among relatives of patients with very late-onset schizophrenia was 16.3%, compared with only 4.4% for controls (p = 0.003). Thus, late-onset psychosis and affective disorders may have etiologic links.⁷

 

Other possible risk factors for very late-onset schizophrenia include sensory deficits, premorbid personality disorder, social isolation, neuropsychological abnormalities, and female gender.

Sensory deficits. Several studies have reported that hearing and vision loss is more prevalent in older patients with very late-onset schizophrenia than in similarly aged controls. Most of these studies have associated either auditory or sensory impairment with very late-onset schizophrenia,⁸ but most did not include appropriate controls.

One case-control study (of younger patients)⁸ found that only uncorrected sensory deficits were over-represented in late-onset cases. This finding implies that one should find out if the patient is willing or able to get medical help for the sensory deficit, as well as whether that treatment has been adequate, before calling the sensory deficit a sequela of late-onset schizophrenia.

Premorbid personality disorder. Patients with very late-onset schizophrenia are widely reported to have gone through life reclusive and paranoid.⁵ Of interest is that unlike many of their early-onset counterparts, late-onset patients tend to have achieved fairly well in the workplace. Whether this success reflects a later onset of illness cannot be determined.

Social isolation is common among older persons and even more so among those with very late-onset schizophrenia.⁹ Whether this finding reflects patients’ premorbid personalities, the illness itself, or a risk factor for the disorder is open to conjecture.

Neuropsychological abnormalities. Assessments of patients with very late-onset schizophrenia reveal cognitive impairment patterns similar to those reported in patients with an earlier onset¹⁰ but distinct from those reported in patients with psychosis associated with dementia. CTand MRIstudies reveal focal (reduced left temporal lobe volume) and nonspecific (increased ventricular-to-brain ratios) structural abnormalities similar to those in younger patients.¹¹

Table 1

CLINICAL FEATURES OF SCHIZOPHRENIA: EARLY- VS. VERY LATE-ONSET TYPES

Clinical feature	Early onset	Very late onset
Persecutory delusions	Common (often elaborate)	Common (often elaborate)
Partition delusions	Rare	Common
Negative symptoms	Common	Rare
Formal thought disorder	Common	Rare
Hallucinations	Common, especially auditory	Often prominent (can manifest in multiple modalities)
Gender differences	Equally common in men, women	More common in women
Family history of schizophrenia	Common	Less common
Uncorrected auditory, visual impairments	No consistent relationship	Common; excessive in some patients
Premorbid personality	Maybe schizoid/schizotypal	Reclusive, suspicious
Social abilities	Social isolation	Social isolation
Marital status	Usually unmarried	Usually unmarried
Cognitive deficits, structural brain abnormalities	Similar for both groups	Similar for both groups

Researchers previously reported excessive white-matter abnormalities in late-onset patients compared with healthy controls—a consistent finding in patients with late-life depression. More recent studies that carefully excluded organic cerebral disorders have not replicated this finding, however.¹¹

Female gender. Very late-onset schizophrenia is more common in women than in men.¹² Female-to-male ratios ranging from 2.2:1 to 22.5:1 have been calculated. Although women generally live longer than men, this predominance is still greater than one would expect. It might also hide important clues regarding schizophrenia and related disorders across the life span, including the fact that the brains of men and women show sex-specific patterns of aging.¹²

Managing very late-onset schizophrenia

Initial assessment. Patients who present with a new-onset psychotic disorder at any age require careful evaluation to exclude an underlying organic cause. The following are strongly suggested in older patients with new-onset psychoses:

• comprehensive history (including medications)
• physical (including neurologic) examination
• laboratory investigations
• CTneuroimaging
• and cognitive screening, such as the Mini Mental State Examination.

Drug treatment. Despite the wealth of published data on the psychopharmacologic management of schizophrenia, few randomized, controlled trials have examined the use of drugs to treat the disorder’s very late-onset form. Case reports or small open studies comprise the available literature. Significant flaws in treatment studies have included diagnostic heterogeneity, mixing of early- and late-onset patients, inadequate outcome criteria, and lack of control groups.¹³

As with early-onset schizophrenia, however, antipsychotics appear to improve the acute symptoms of very late-onset schizophrenia and reduce the risk of relapse.¹⁴ Pearlson et al⁴ reported at least partial remission in 76% of patients with late-onset schizophrenia after neuroleptic regimens (complete remission occurred in 48%). The presence of thought disorder or a premorbid schizoid personality predicted poor response to treatment, whereas gender, family history, and first-rank symptoms (auditory hallucinations, delusions, social withdrawal) did not significantly affect outcome.

Very late-onset patients respond to about one-half the antipsychotic dosage required for younger patients.¹³ Sweet and Pollock¹⁵ found an average dosage of chlorpromazine equivalents, 148 mg/d, to be effective in older patients, compared with >300 mg/d in younger cohorts.

Neuroleptic side effects. Older patients are more susceptible than their younger counterparts to side effects and adverse reactions from typical neuroleptics, even at low dosages. Age-related differences in pharmacokinetics and pharmacodynamics, combined with the increased incidence of comorbid physical disease and polypharmacy among older patients, often complicate pharmacotherapy for late-onset schizophrenia.

 

Older patients taking antipsychotics face an increased risk of extrapyramidal symptoms (EPS), especially parkinsonism and akathisia.¹⁶ Anticholinergics are poorly tolerated and may cause urinary retention, constipation, blurred vision, exacerbation of glaucoma, and delirium. Cardiovascular side effects, especially orthostatic hypotension, may lead to falls and significant injury and may exacerbate coexisting cardiovascular disease.

Neuroleptic-induced tardive dyskinesia (TD) is another potential complication. Jeste et al found the cumulative annual incidence of drug-induced TD to be five times greater among older psychotic patients than among younger ones (26% vs. 5% after 1 year).¹⁷ Duration of exposure and total cumulative amount of prescribed neuroleptics remain significant risk factors for TD in older patients.

Atypical antipsychotics, with their less-adverse side-effect profiles and lower risk of EPS (and probably TD as well) are the preferred first-line drugs for late-onset schizophrenia. These agents also have been associated with improved cognition in younger patients with schizophrenia, a potentially significant benefit in the older patient.

Table 2

ANTIPSYCHOTIC DOSAGES RECOMMENDED FOR VERY LATE-ONSET SCHIZOPHRENIA

Drugs	Initial dosages	Maintenance dosages
Olanzapine	1 to 5 mg/d	2.5 to 15 mg/d
Risperidone	0.25 to 0.5 mg/d	0.5 to 3 mg/d
Quetiapine	12.5 to 25 mg/d	75 to 150 mg/d

No well-controlled trials of clozapine in very late-onset schizophrenia have been performed. According to one literature review,¹⁸ most older psychotic patients showed moderate to marked improvement at relatively low dosages (mean dosage 134 mg/d). The reviewers concluded that clozapine was safe and well tolerated but suggested that agranulocytosis may occur at higher rates in this group than in younger patients. Clozapine’s potent anticholinergic action and its marked sedative effects limit its use in very late-onset schizophrenia to treatmentresistant patients or those with severe TD.

Data on the use of other atypical agents in very late-onset schizophrenia are limited. Risperidone has been associated with significant improvements in older patients with schizophrenia.¹⁶ Risperidone, olanzapine, and quetiapine have all been found to be safe, well-tolerated, and effective in managing late-life psychotic disorders.^16,19,20 As with neuroleptics, recommended starting and maintenance dosages of the atypicals are lower than those used in younger patients (Table 2).¹³

A “start low, go slow” approach is warranted, and dosages should be adjusted according to clinical response. Communicate with the patient’s primary care physician to learn of any potential drug-drug interactions with medications being given for comorbid illnesses.

Electroconvulsive therapy has been reported to be useful in several studies, but data on its use in very late-onset schizophrenia are limited.²¹

Psychosocial interventions. One review of the role of non-biological treatment in very late-onset schizophrenia²² stressed the need to develop trust between patient and psychiatrist, so that the patient clearly views the treatment team as allies (Table 3). To that end, look for thoughts, feelings, or situations that may have precipitated the onset of psychosis, and explore their subjective meaning with the patient. Address any clear losses that are identified, such as the recent death of a spouse or other family member.

Table 3

DOs AND DON’Ts OF MANAGING AN OLDER PATIENT WITH SCHIZOPHRENIA

Do

Don’t

Offer practical solutions to perceived difficulties (e.g., help resolve familial conflicts or housing/financial difficulties rather than get involved with delusional interpretation of events) Assess degree of loneliness by exploring the patient’s wishes/fears of social contact Assess the patient’s social needs by talking with the patient, family physician, and (if applicable) nurse Contact family members early and involve them in planning Correct visual and hearing impairments as much as possible

Make initial demands on the patient. Often the patient is hostile at first; this can undermine treatment Confront delusional system directly. Acknowledge concerns but don’t directly challenge beliefs; otherwise the patient will become unresponsive ‘Take sides’ in paranoid disputes the patient may be having with neighbors or others Apply diagnostic labels early. Build patient rapport before rendering a diagnosis Act alone. Involve primary care physician and family as appropriate

Find out if the patient is isolated and to what degree he or she feels lonely. Encourage the patient to engage in activities that he or she once enjoyed, and subtly introduce the patient to an appropriate community support group. Suggesting participation in group leisure activities may also help. Ascertain the patient’s living arrangements and basic needs. You may need to refer the patient to a social agency for assistance with housing, finances, nutrition/diet, and transportation.

Reminiscence therapy, through which patients are encouraged to reflect on their lives, can be useful for patients with very late-onset schizophrenia. Through reflection, patients can review past successes and painful experiences and move toward ultimate resolution of conflict and current difficulties.²²

 

As in younger patients with schizophrenia, cognitivebehavioral therapy can help to modify delusional beliefs, gain control over hallucinations, and identify high-risk situations and appropriate coping strategies.²³

Include family members in the treatment plan, and offer them support, education, and practical assistance (e.g., strategies for dealing with delusions). Informed families can help patients comply with prescriptions and appointments and can also detect relapse in its early stages.

In some cases, the patient’s longstanding paranoia and paranoid personality can lead to resentment and conflict within the family. Before treatment can begin, you may also need to address this conflict by educating family members on how a loved one’s schizophrenia affects them. Counseling the family as a group may be appropriate in some cases.

Related resources

• Howard R, Rabins PV, Castle DJ, eds. Late onset schizophrenia. Petersfield, UK: Wrightson Biomedical; 1999.
• Howard R, Rabins PV, Seeman MV, et al. Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. Am J Psychiatry 2000; 157:172-8.

Drug brand names

• Clozapine • Clozaril
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal

Disclosure

The authors report no affiliation or financial arrangement with any of the companies whose products are mentioned in this article, or with manufacturers of competing products.

Acknowledgements

Dr. Lubman wishes to thank the Nauma Licht Fellowship, a bequest supporting schizophrenia research, for its support.

Mr. B, age 73, repeatedly complained to his landlord that people were trying to poison him by pumping noxious gas into his apartment. He barricaded himself inside, taped up all air vents and windows, and left only when absolutely necessary. At night, he could hear people working the “apparatus” that pumped the gas, and could “smell” the vapors.

On examination, he was physically well but suffered from mild neural deafness and myopia. He was suspicious and guarded but oriented and not cognitively impaired. He expressed paranoid beliefs and experienced auditory and olfactory hallucinations. There was no evidence of affective disturbance.

At first he refused psychiatric care but eventually agreed to take risperidone, 0.5 mg at night. He tolerated the agent well, and his psychotic symptoms slowly resolved.

As Mr. B’s case illustrates, schizophrenia—once thought to be strictly an early-onset disorder—commonly manifests late in life (Box). Too often, however, very late-onset schizophrenia goes undiagnosed because older patients with the disorder tend to be socially isolated. Their symptoms of paranoia and reluctance by family members to intervene also can prevent them from receiving treatment that could control psychotic symptoms and improve their quality of life.

Box

Psychosis presenting at any age, but especially in later life, requires careful evaluation to exclude organic pathology. Very late-onset schizophrenia differs substantially from psychosis associated with dementia, as in Alzheimer’s disease, both in terms of neuropsychological and brain imaging findings.

Although limited, data on late-life psychosis offer clues to its diagnosis and treatment. This article will address:

• risk factors and clinical presentations associated with late-onset schizophrenia
• pharmacologic and psychosocial treatment options based on available evidence.

Clinical presentation

Clinical presentation of schizophrenia with onset after age 60 differs from that of early-onset schizophrenia (Table 1). To those familiar with early-onset cases, the most obvious differences in late-onset patients are negligible rates of primary negative symptoms and formal thought disorder.

Persecutory delusions are common in both types and often are elaborate. The so-called “partition” delusion, which leads the patient to believe that people or objects can transgress impermeable barriers and access his or her home with malign intent, is more common in late-onset than in early-onset schizophrenia.³

Hallucinations in very late-onset schizophrenia are often prominent and can occur in multiple modalities, including auditory, visual, and olfactory. Sometimes the hallucination and delusion are clearly linked; for example, a patient claims to smell the noxious gas he believes is being pumped into his home.

Does the difference in presentation between early- and very late-onset schizophrenia reflect distinct disease processes or the disorder’s impact at different stages of brain maturation and degeneration? To answer that question, researchers have compared late-onset patients with young early-onset patents and with older patients who developed schizophrenia in their youth. Similar phenomena have been found in both early-onset groups,⁴ suggesting that age of onset causes the differences in clinical presentation.

Risk factors

As with early-onset schizophrenia, family history is the most common cause of very late-onset schizophrenia. Despite their limitations, family history studies almost all show a familial risk of very late-onset schizophrenia lower than that of early-onset patients but greater than that of the general population.⁵ Published studies do not tell us whether age of onset is genetically determined, in part because not all patients at risk for very late-onset schizophrenia live long enough to manifest its symptoms.

Family history has been associated with affective disorder in some patients with very late-onset schizophrenia. One casecontrolled series of family interviews⁶ found an approximate 1.3% rate of schizophrenia in relatives —about the same rate as that of the control group. The rate of depression among relatives of patients with very late-onset schizophrenia was 16.3%, compared with only 4.4% for controls (p = 0.003). Thus, late-onset psychosis and affective disorders may have etiologic links.⁷

 

Other possible risk factors for very late-onset schizophrenia include sensory deficits, premorbid personality disorder, social isolation, neuropsychological abnormalities, and female gender.

Sensory deficits. Several studies have reported that hearing and vision loss is more prevalent in older patients with very late-onset schizophrenia than in similarly aged controls. Most of these studies have associated either auditory or sensory impairment with very late-onset schizophrenia,⁸ but most did not include appropriate controls.

One case-control study (of younger patients)⁸ found that only uncorrected sensory deficits were over-represented in late-onset cases. This finding implies that one should find out if the patient is willing or able to get medical help for the sensory deficit, as well as whether that treatment has been adequate, before calling the sensory deficit a sequela of late-onset schizophrenia.

Premorbid personality disorder. Patients with very late-onset schizophrenia are widely reported to have gone through life reclusive and paranoid.⁵ Of interest is that unlike many of their early-onset counterparts, late-onset patients tend to have achieved fairly well in the workplace. Whether this success reflects a later onset of illness cannot be determined.

Social isolation is common among older persons and even more so among those with very late-onset schizophrenia.⁹ Whether this finding reflects patients’ premorbid personalities, the illness itself, or a risk factor for the disorder is open to conjecture.

Neuropsychological abnormalities. Assessments of patients with very late-onset schizophrenia reveal cognitive impairment patterns similar to those reported in patients with an earlier onset¹⁰ but distinct from those reported in patients with psychosis associated with dementia. CTand MRIstudies reveal focal (reduced left temporal lobe volume) and nonspecific (increased ventricular-to-brain ratios) structural abnormalities similar to those in younger patients.¹¹

Table 1

CLINICAL FEATURES OF SCHIZOPHRENIA: EARLY- VS. VERY LATE-ONSET TYPES

Clinical feature	Early onset	Very late onset
Persecutory delusions	Common (often elaborate)	Common (often elaborate)
Partition delusions	Rare	Common
Negative symptoms	Common	Rare
Formal thought disorder	Common	Rare
Hallucinations	Common, especially auditory	Often prominent (can manifest in multiple modalities)
Gender differences	Equally common in men, women	More common in women
Family history of schizophrenia	Common	Less common
Uncorrected auditory, visual impairments	No consistent relationship	Common; excessive in some patients
Premorbid personality	Maybe schizoid/schizotypal	Reclusive, suspicious
Social abilities	Social isolation	Social isolation
Marital status	Usually unmarried	Usually unmarried
Cognitive deficits, structural brain abnormalities	Similar for both groups	Similar for both groups

Researchers previously reported excessive white-matter abnormalities in late-onset patients compared with healthy controls—a consistent finding in patients with late-life depression. More recent studies that carefully excluded organic cerebral disorders have not replicated this finding, however.¹¹

Female gender. Very late-onset schizophrenia is more common in women than in men.¹² Female-to-male ratios ranging from 2.2:1 to 22.5:1 have been calculated. Although women generally live longer than men, this predominance is still greater than one would expect. It might also hide important clues regarding schizophrenia and related disorders across the life span, including the fact that the brains of men and women show sex-specific patterns of aging.¹²

Managing very late-onset schizophrenia

Initial assessment. Patients who present with a new-onset psychotic disorder at any age require careful evaluation to exclude an underlying organic cause. The following are strongly suggested in older patients with new-onset psychoses:

• comprehensive history (including medications)
• physical (including neurologic) examination
• laboratory investigations
• CTneuroimaging
• and cognitive screening, such as the Mini Mental State Examination.

Drug treatment. Despite the wealth of published data on the psychopharmacologic management of schizophrenia, few randomized, controlled trials have examined the use of drugs to treat the disorder’s very late-onset form. Case reports or small open studies comprise the available literature. Significant flaws in treatment studies have included diagnostic heterogeneity, mixing of early- and late-onset patients, inadequate outcome criteria, and lack of control groups.¹³

As with early-onset schizophrenia, however, antipsychotics appear to improve the acute symptoms of very late-onset schizophrenia and reduce the risk of relapse.¹⁴ Pearlson et al⁴ reported at least partial remission in 76% of patients with late-onset schizophrenia after neuroleptic regimens (complete remission occurred in 48%). The presence of thought disorder or a premorbid schizoid personality predicted poor response to treatment, whereas gender, family history, and first-rank symptoms (auditory hallucinations, delusions, social withdrawal) did not significantly affect outcome.

Very late-onset patients respond to about one-half the antipsychotic dosage required for younger patients.¹³ Sweet and Pollock¹⁵ found an average dosage of chlorpromazine equivalents, 148 mg/d, to be effective in older patients, compared with >300 mg/d in younger cohorts.

Neuroleptic side effects. Older patients are more susceptible than their younger counterparts to side effects and adverse reactions from typical neuroleptics, even at low dosages. Age-related differences in pharmacokinetics and pharmacodynamics, combined with the increased incidence of comorbid physical disease and polypharmacy among older patients, often complicate pharmacotherapy for late-onset schizophrenia.

 

Older patients taking antipsychotics face an increased risk of extrapyramidal symptoms (EPS), especially parkinsonism and akathisia.¹⁶ Anticholinergics are poorly tolerated and may cause urinary retention, constipation, blurred vision, exacerbation of glaucoma, and delirium. Cardiovascular side effects, especially orthostatic hypotension, may lead to falls and significant injury and may exacerbate coexisting cardiovascular disease.

Neuroleptic-induced tardive dyskinesia (TD) is another potential complication. Jeste et al found the cumulative annual incidence of drug-induced TD to be five times greater among older psychotic patients than among younger ones (26% vs. 5% after 1 year).¹⁷ Duration of exposure and total cumulative amount of prescribed neuroleptics remain significant risk factors for TD in older patients.

Atypical antipsychotics, with their less-adverse side-effect profiles and lower risk of EPS (and probably TD as well) are the preferred first-line drugs for late-onset schizophrenia. These agents also have been associated with improved cognition in younger patients with schizophrenia, a potentially significant benefit in the older patient.

Table 2

ANTIPSYCHOTIC DOSAGES RECOMMENDED FOR VERY LATE-ONSET SCHIZOPHRENIA

Drugs	Initial dosages	Maintenance dosages
Olanzapine	1 to 5 mg/d	2.5 to 15 mg/d
Risperidone	0.25 to 0.5 mg/d	0.5 to 3 mg/d
Quetiapine	12.5 to 25 mg/d	75 to 150 mg/d

No well-controlled trials of clozapine in very late-onset schizophrenia have been performed. According to one literature review,¹⁸ most older psychotic patients showed moderate to marked improvement at relatively low dosages (mean dosage 134 mg/d). The reviewers concluded that clozapine was safe and well tolerated but suggested that agranulocytosis may occur at higher rates in this group than in younger patients. Clozapine’s potent anticholinergic action and its marked sedative effects limit its use in very late-onset schizophrenia to treatmentresistant patients or those with severe TD.

Data on the use of other atypical agents in very late-onset schizophrenia are limited. Risperidone has been associated with significant improvements in older patients with schizophrenia.¹⁶ Risperidone, olanzapine, and quetiapine have all been found to be safe, well-tolerated, and effective in managing late-life psychotic disorders.^16,19,20 As with neuroleptics, recommended starting and maintenance dosages of the atypicals are lower than those used in younger patients (Table 2).¹³

A “start low, go slow” approach is warranted, and dosages should be adjusted according to clinical response. Communicate with the patient’s primary care physician to learn of any potential drug-drug interactions with medications being given for comorbid illnesses.

Electroconvulsive therapy has been reported to be useful in several studies, but data on its use in very late-onset schizophrenia are limited.²¹

Psychosocial interventions. One review of the role of non-biological treatment in very late-onset schizophrenia²² stressed the need to develop trust between patient and psychiatrist, so that the patient clearly views the treatment team as allies (Table 3). To that end, look for thoughts, feelings, or situations that may have precipitated the onset of psychosis, and explore their subjective meaning with the patient. Address any clear losses that are identified, such as the recent death of a spouse or other family member.

Table 3

DOs AND DON’Ts OF MANAGING AN OLDER PATIENT WITH SCHIZOPHRENIA

Do

Don’t

Offer practical solutions to perceived difficulties (e.g., help resolve familial conflicts or housing/financial difficulties rather than get involved with delusional interpretation of events) Assess degree of loneliness by exploring the patient’s wishes/fears of social contact Assess the patient’s social needs by talking with the patient, family physician, and (if applicable) nurse Contact family members early and involve them in planning Correct visual and hearing impairments as much as possible

Make initial demands on the patient. Often the patient is hostile at first; this can undermine treatment Confront delusional system directly. Acknowledge concerns but don’t directly challenge beliefs; otherwise the patient will become unresponsive ‘Take sides’ in paranoid disputes the patient may be having with neighbors or others Apply diagnostic labels early. Build patient rapport before rendering a diagnosis Act alone. Involve primary care physician and family as appropriate

Find out if the patient is isolated and to what degree he or she feels lonely. Encourage the patient to engage in activities that he or she once enjoyed, and subtly introduce the patient to an appropriate community support group. Suggesting participation in group leisure activities may also help. Ascertain the patient’s living arrangements and basic needs. You may need to refer the patient to a social agency for assistance with housing, finances, nutrition/diet, and transportation.

Reminiscence therapy, through which patients are encouraged to reflect on their lives, can be useful for patients with very late-onset schizophrenia. Through reflection, patients can review past successes and painful experiences and move toward ultimate resolution of conflict and current difficulties.²²

 

As in younger patients with schizophrenia, cognitivebehavioral therapy can help to modify delusional beliefs, gain control over hallucinations, and identify high-risk situations and appropriate coping strategies.²³

Include family members in the treatment plan, and offer them support, education, and practical assistance (e.g., strategies for dealing with delusions). Informed families can help patients comply with prescriptions and appointments and can also detect relapse in its early stages.

In some cases, the patient’s longstanding paranoia and paranoid personality can lead to resentment and conflict within the family. Before treatment can begin, you may also need to address this conflict by educating family members on how a loved one’s schizophrenia affects them. Counseling the family as a group may be appropriate in some cases.

Related resources

• Howard R, Rabins PV, Castle DJ, eds. Late onset schizophrenia. Petersfield, UK: Wrightson Biomedical; 1999.
• Howard R, Rabins PV, Seeman MV, et al. Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. Am J Psychiatry 2000; 157:172-8.

Drug brand names

• Clozapine • Clozaril
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal

Disclosure

The authors report no affiliation or financial arrangement with any of the companies whose products are mentioned in this article, or with manufacturers of competing products.

Acknowledgements

Dr. Lubman wishes to thank the Nauma Licht Fellowship, a bequest supporting schizophrenia research, for its support.

Mr. B, age 73, repeatedly complained to his landlord that people were trying to poison him by pumping noxious gas into his apartment. He barricaded himself inside, taped up all air vents and windows, and left only when absolutely necessary. At night, he could hear people working the “apparatus” that pumped the gas, and could “smell” the vapors.

On examination, he was physically well but suffered from mild neural deafness and myopia. He was suspicious and guarded but oriented and not cognitively impaired. He expressed paranoid beliefs and experienced auditory and olfactory hallucinations. There was no evidence of affective disturbance.

At first he refused psychiatric care but eventually agreed to take risperidone, 0.5 mg at night. He tolerated the agent well, and his psychotic symptoms slowly resolved.

As Mr. B’s case illustrates, schizophrenia—once thought to be strictly an early-onset disorder—commonly manifests late in life (Box). Too often, however, very late-onset schizophrenia goes undiagnosed because older patients with the disorder tend to be socially isolated. Their symptoms of paranoia and reluctance by family members to intervene also can prevent them from receiving treatment that could control psychotic symptoms and improve their quality of life.

Box

Psychosis presenting at any age, but especially in later life, requires careful evaluation to exclude organic pathology. Very late-onset schizophrenia differs substantially from psychosis associated with dementia, as in Alzheimer’s disease, both in terms of neuropsychological and brain imaging findings.

Although limited, data on late-life psychosis offer clues to its diagnosis and treatment. This article will address:

• risk factors and clinical presentations associated with late-onset schizophrenia
• pharmacologic and psychosocial treatment options based on available evidence.

Clinical presentation

Clinical presentation of schizophrenia with onset after age 60 differs from that of early-onset schizophrenia (Table 1). To those familiar with early-onset cases, the most obvious differences in late-onset patients are negligible rates of primary negative symptoms and formal thought disorder.

Persecutory delusions are common in both types and often are elaborate. The so-called “partition” delusion, which leads the patient to believe that people or objects can transgress impermeable barriers and access his or her home with malign intent, is more common in late-onset than in early-onset schizophrenia.³

Hallucinations in very late-onset schizophrenia are often prominent and can occur in multiple modalities, including auditory, visual, and olfactory. Sometimes the hallucination and delusion are clearly linked; for example, a patient claims to smell the noxious gas he believes is being pumped into his home.

Does the difference in presentation between early- and very late-onset schizophrenia reflect distinct disease processes or the disorder’s impact at different stages of brain maturation and degeneration? To answer that question, researchers have compared late-onset patients with young early-onset patents and with older patients who developed schizophrenia in their youth. Similar phenomena have been found in both early-onset groups,⁴ suggesting that age of onset causes the differences in clinical presentation.

Risk factors

As with early-onset schizophrenia, family history is the most common cause of very late-onset schizophrenia. Despite their limitations, family history studies almost all show a familial risk of very late-onset schizophrenia lower than that of early-onset patients but greater than that of the general population.⁵ Published studies do not tell us whether age of onset is genetically determined, in part because not all patients at risk for very late-onset schizophrenia live long enough to manifest its symptoms.

Family history has been associated with affective disorder in some patients with very late-onset schizophrenia. One casecontrolled series of family interviews⁶ found an approximate 1.3% rate of schizophrenia in relatives —about the same rate as that of the control group. The rate of depression among relatives of patients with very late-onset schizophrenia was 16.3%, compared with only 4.4% for controls (p = 0.003). Thus, late-onset psychosis and affective disorders may have etiologic links.⁷

 

Other possible risk factors for very late-onset schizophrenia include sensory deficits, premorbid personality disorder, social isolation, neuropsychological abnormalities, and female gender.

Sensory deficits. Several studies have reported that hearing and vision loss is more prevalent in older patients with very late-onset schizophrenia than in similarly aged controls. Most of these studies have associated either auditory or sensory impairment with very late-onset schizophrenia,⁸ but most did not include appropriate controls.

One case-control study (of younger patients)⁸ found that only uncorrected sensory deficits were over-represented in late-onset cases. This finding implies that one should find out if the patient is willing or able to get medical help for the sensory deficit, as well as whether that treatment has been adequate, before calling the sensory deficit a sequela of late-onset schizophrenia.

Premorbid personality disorder. Patients with very late-onset schizophrenia are widely reported to have gone through life reclusive and paranoid.⁵ Of interest is that unlike many of their early-onset counterparts, late-onset patients tend to have achieved fairly well in the workplace. Whether this success reflects a later onset of illness cannot be determined.

Social isolation is common among older persons and even more so among those with very late-onset schizophrenia.⁹ Whether this finding reflects patients’ premorbid personalities, the illness itself, or a risk factor for the disorder is open to conjecture.

Neuropsychological abnormalities. Assessments of patients with very late-onset schizophrenia reveal cognitive impairment patterns similar to those reported in patients with an earlier onset¹⁰ but distinct from those reported in patients with psychosis associated with dementia. CTand MRIstudies reveal focal (reduced left temporal lobe volume) and nonspecific (increased ventricular-to-brain ratios) structural abnormalities similar to those in younger patients.¹¹

Table 1

CLINICAL FEATURES OF SCHIZOPHRENIA: EARLY- VS. VERY LATE-ONSET TYPES

Clinical feature	Early onset	Very late onset
Persecutory delusions	Common (often elaborate)	Common (often elaborate)
Partition delusions	Rare	Common
Negative symptoms	Common	Rare
Formal thought disorder	Common	Rare
Hallucinations	Common, especially auditory	Often prominent (can manifest in multiple modalities)
Gender differences	Equally common in men, women	More common in women
Family history of schizophrenia	Common	Less common
Uncorrected auditory, visual impairments	No consistent relationship	Common; excessive in some patients
Premorbid personality	Maybe schizoid/schizotypal	Reclusive, suspicious
Social abilities	Social isolation	Social isolation
Marital status	Usually unmarried	Usually unmarried
Cognitive deficits, structural brain abnormalities	Similar for both groups	Similar for both groups

Researchers previously reported excessive white-matter abnormalities in late-onset patients compared with healthy controls—a consistent finding in patients with late-life depression. More recent studies that carefully excluded organic cerebral disorders have not replicated this finding, however.¹¹

Female gender. Very late-onset schizophrenia is more common in women than in men.¹² Female-to-male ratios ranging from 2.2:1 to 22.5:1 have been calculated. Although women generally live longer than men, this predominance is still greater than one would expect. It might also hide important clues regarding schizophrenia and related disorders across the life span, including the fact that the brains of men and women show sex-specific patterns of aging.¹²

Managing very late-onset schizophrenia

Initial assessment. Patients who present with a new-onset psychotic disorder at any age require careful evaluation to exclude an underlying organic cause. The following are strongly suggested in older patients with new-onset psychoses:

• comprehensive history (including medications)
• physical (including neurologic) examination
• laboratory investigations
• CTneuroimaging
• and cognitive screening, such as the Mini Mental State Examination.

Drug treatment. Despite the wealth of published data on the psychopharmacologic management of schizophrenia, few randomized, controlled trials have examined the use of drugs to treat the disorder’s very late-onset form. Case reports or small open studies comprise the available literature. Significant flaws in treatment studies have included diagnostic heterogeneity, mixing of early- and late-onset patients, inadequate outcome criteria, and lack of control groups.¹³

As with early-onset schizophrenia, however, antipsychotics appear to improve the acute symptoms of very late-onset schizophrenia and reduce the risk of relapse.¹⁴ Pearlson et al⁴ reported at least partial remission in 76% of patients with late-onset schizophrenia after neuroleptic regimens (complete remission occurred in 48%). The presence of thought disorder or a premorbid schizoid personality predicted poor response to treatment, whereas gender, family history, and first-rank symptoms (auditory hallucinations, delusions, social withdrawal) did not significantly affect outcome.

Very late-onset patients respond to about one-half the antipsychotic dosage required for younger patients.¹³ Sweet and Pollock¹⁵ found an average dosage of chlorpromazine equivalents, 148 mg/d, to be effective in older patients, compared with >300 mg/d in younger cohorts.

Neuroleptic side effects. Older patients are more susceptible than their younger counterparts to side effects and adverse reactions from typical neuroleptics, even at low dosages. Age-related differences in pharmacokinetics and pharmacodynamics, combined with the increased incidence of comorbid physical disease and polypharmacy among older patients, often complicate pharmacotherapy for late-onset schizophrenia.

 

Older patients taking antipsychotics face an increased risk of extrapyramidal symptoms (EPS), especially parkinsonism and akathisia.¹⁶ Anticholinergics are poorly tolerated and may cause urinary retention, constipation, blurred vision, exacerbation of glaucoma, and delirium. Cardiovascular side effects, especially orthostatic hypotension, may lead to falls and significant injury and may exacerbate coexisting cardiovascular disease.

Neuroleptic-induced tardive dyskinesia (TD) is another potential complication. Jeste et al found the cumulative annual incidence of drug-induced TD to be five times greater among older psychotic patients than among younger ones (26% vs. 5% after 1 year).¹⁷ Duration of exposure and total cumulative amount of prescribed neuroleptics remain significant risk factors for TD in older patients.

Atypical antipsychotics, with their less-adverse side-effect profiles and lower risk of EPS (and probably TD as well) are the preferred first-line drugs for late-onset schizophrenia. These agents also have been associated with improved cognition in younger patients with schizophrenia, a potentially significant benefit in the older patient.

Table 2

ANTIPSYCHOTIC DOSAGES RECOMMENDED FOR VERY LATE-ONSET SCHIZOPHRENIA

Drugs	Initial dosages	Maintenance dosages
Olanzapine	1 to 5 mg/d	2.5 to 15 mg/d
Risperidone	0.25 to 0.5 mg/d	0.5 to 3 mg/d
Quetiapine	12.5 to 25 mg/d	75 to 150 mg/d

No well-controlled trials of clozapine in very late-onset schizophrenia have been performed. According to one literature review,¹⁸ most older psychotic patients showed moderate to marked improvement at relatively low dosages (mean dosage 134 mg/d). The reviewers concluded that clozapine was safe and well tolerated but suggested that agranulocytosis may occur at higher rates in this group than in younger patients. Clozapine’s potent anticholinergic action and its marked sedative effects limit its use in very late-onset schizophrenia to treatmentresistant patients or those with severe TD.

Data on the use of other atypical agents in very late-onset schizophrenia are limited. Risperidone has been associated with significant improvements in older patients with schizophrenia.¹⁶ Risperidone, olanzapine, and quetiapine have all been found to be safe, well-tolerated, and effective in managing late-life psychotic disorders.^16,19,20 As with neuroleptics, recommended starting and maintenance dosages of the atypicals are lower than those used in younger patients (Table 2).¹³

A “start low, go slow” approach is warranted, and dosages should be adjusted according to clinical response. Communicate with the patient’s primary care physician to learn of any potential drug-drug interactions with medications being given for comorbid illnesses.

Electroconvulsive therapy has been reported to be useful in several studies, but data on its use in very late-onset schizophrenia are limited.²¹

Psychosocial interventions. One review of the role of non-biological treatment in very late-onset schizophrenia²² stressed the need to develop trust between patient and psychiatrist, so that the patient clearly views the treatment team as allies (Table 3). To that end, look for thoughts, feelings, or situations that may have precipitated the onset of psychosis, and explore their subjective meaning with the patient. Address any clear losses that are identified, such as the recent death of a spouse or other family member.

Table 3

DOs AND DON’Ts OF MANAGING AN OLDER PATIENT WITH SCHIZOPHRENIA

Do

Don’t

Offer practical solutions to perceived difficulties (e.g., help resolve familial conflicts or housing/financial difficulties rather than get involved with delusional interpretation of events) Assess degree of loneliness by exploring the patient’s wishes/fears of social contact Assess the patient’s social needs by talking with the patient, family physician, and (if applicable) nurse Contact family members early and involve them in planning Correct visual and hearing impairments as much as possible

Make initial demands on the patient. Often the patient is hostile at first; this can undermine treatment Confront delusional system directly. Acknowledge concerns but don’t directly challenge beliefs; otherwise the patient will become unresponsive ‘Take sides’ in paranoid disputes the patient may be having with neighbors or others Apply diagnostic labels early. Build patient rapport before rendering a diagnosis Act alone. Involve primary care physician and family as appropriate

Find out if the patient is isolated and to what degree he or she feels lonely. Encourage the patient to engage in activities that he or she once enjoyed, and subtly introduce the patient to an appropriate community support group. Suggesting participation in group leisure activities may also help. Ascertain the patient’s living arrangements and basic needs. You may need to refer the patient to a social agency for assistance with housing, finances, nutrition/diet, and transportation.

Reminiscence therapy, through which patients are encouraged to reflect on their lives, can be useful for patients with very late-onset schizophrenia. Through reflection, patients can review past successes and painful experiences and move toward ultimate resolution of conflict and current difficulties.²²

 

As in younger patients with schizophrenia, cognitivebehavioral therapy can help to modify delusional beliefs, gain control over hallucinations, and identify high-risk situations and appropriate coping strategies.²³

Include family members in the treatment plan, and offer them support, education, and practical assistance (e.g., strategies for dealing with delusions). Informed families can help patients comply with prescriptions and appointments and can also detect relapse in its early stages.

In some cases, the patient’s longstanding paranoia and paranoid personality can lead to resentment and conflict within the family. Before treatment can begin, you may also need to address this conflict by educating family members on how a loved one’s schizophrenia affects them. Counseling the family as a group may be appropriate in some cases.

Related resources

• Howard R, Rabins PV, Castle DJ, eds. Late onset schizophrenia. Petersfield, UK: Wrightson Biomedical; 1999.
• Howard R, Rabins PV, Seeman MV, et al. Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. Am J Psychiatry 2000; 157:172-8.

Drug brand names

• Clozapine • Clozaril
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal

Disclosure

The authors report no affiliation or financial arrangement with any of the companies whose products are mentioned in this article, or with manufacturers of competing products.

Acknowledgements

Dr. Lubman wishes to thank the Nauma Licht Fellowship, a bequest supporting schizophrenia research, for its support.