Evidence-Based Reviews

Slot System

Featured Buckets

Featured Buckets Admin

Can a vaccine prevent Alzheimer’s disease?

Article Type

Changed

Tue, 12/11/2018 - 15:09

Display Headline

Can a vaccine prevent Alzheimer’s disease?

Author(s)

Edmund S. Higgins, MD

Deposition of amyloid-β peptide (Aβ) is believed to contribute to Alzheimer’s disease (AD) pathogenesis. Derived from a larger precursor protein, Aβ aggregates into plaques, and may promote neuronal death and, ultimately, dementia.

Current treatments alleviate symptoms without slowing underlying neurodegeneration. The prospect of harnessing the immune system to target the Aβ peptide offers an intriguing option for preventing this devastating, increasingly common disease.

Anti-a BETA antibodies

Transgenic mice bred to overexpress AD genes have responded remarkably in studies using the immune system to target the amyloid-β peptide.³ Several mouse groups have shown plaque reduction (Figure 1) and improved cognitive performance. These findings substantiate the amyloid hypothesis in AD pathogenesis.

A host could acquire anti-Aβ antibodies though two basic approaches (Figure 2):²

Figure 1 Differences in amyloid deposition between control and immunized mice

Frontal cortex of an unvaccinated mouse (left) shows more amyloid deposits (dark spots) than that of a mouse producing antibodies against the amyloid-β peptide (right).

Source: Image by Cynthia A. Lemere, PhD. Used with permission.Active immunization exposes the subject to the antigen (in this case the Aβ peptide) and allows T cells and B cells to produce anti-Aβ antibodies. This approach has been studied in humans, but adverse effects have stymied its development.

Passive immunization, which involves developing anti-Aβ antibodies in a separate source, aims to clear Aβ peptide without requiring an immunologic response from the host. Large doses of antibodies administered weekly or monthly would be needed to build adequate plasma levels in the CNS, and large quantities of circulating antibodies could cause hemorrhagic stroke.

A troublesome trial

After successful preclinical and phase 1 testing of a vaccine against the Aβ peptide (called AN-1792), a phase 2a placebo-controlled trial in 2001 followed patients with mild to moderate AD. Drug administration was halted after 18 patients (6%) developed meningoencephalitis after several months.⁴ However, 300 patients with AD and 72 control patients had received at least one injection, and double-blind assessments were maintained for 12 months.

Figure 2 Methods for immunizing against Aβ peptide

Active immunization produces anti-Aβ antibodies via immunologic response to vaccination. With passive immunization, anti-Aβ antibodies are administered directly.

Illustration by Rich LaRocco.All patients with meningoencephalitis had received the vaccine but not all developed an immune response, suggesting that something other than the antibodies—such as T cells—caused the encephalitis. Twelve patients recovered, but six had persistent cognitive and neurologic deficits.

More-optimistic news

Of the 300 patients who received an active vaccine, 20% developed an adequate antibody response.⁵

The responders showed no significant difference from the placebo group in most outcome measures but showed less worsening in the nine-component Neuropsychological Test Battery (NTB) (P=0.02). Of particular interest, antibody responders showed significant improvement in the NTB—s memory domain (P=0.03). Further, subjects with higher IgG antibody titers showed greater improvement than did other responders.

More work ahead

Although the outcome of this initial AN-1792 trial is disappointing because of its discontinuation and mixed results, T cell infiltration and amyloid depletion were found during postmortem examinations of two vaccine recipients.⁶

Pharmaceutical companies are testing two compounds for AD immunotherapy:⁷

AAB-001, a human monoclonal antibody, targets all 42 Aβ amino acids via passive immunization and has entered phase 2 trials.
ACC-001, an Aβ immuno-conjugate designed to elicit an active antibody response, began phase 1 testing last fall.

These efforts suggest that an “Alzheimer’s vaccine” could be produced, provided it could attack the Aβ peptide without inducing a significant cellular reaction.

References

1. Neugroschl JA, Kolevzor A, Samuels SC, Marir DB. Dementia. In: Sadock BJ, Sadock VA (eds). Kaplan & Sadock’s comprehensive text-book of psychiatry (8th ed). Philadelphia: Lippincott Williams & Wilkins; 2005:1068-93.

2. Schenk D. Amyloid-beta immunotherapy for Alzheimer’s disease: the end of the beginning. Nat Rev Neurosci 2002;3:824-8.

3. Schenk D, Hagen M, Seubert P. Current progress in beta-amyloid immunotherapy. Current Opin Immunol 2004;16:599-606.

4. Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoen-cephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003;61:46-54.

5. Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005;64:1553-62.

6. Ferrer I, Boada Rovira M, Sanchez Guerra ML, et al. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathology 2004;14(1):11-20.

7. Sullivan MG. Immunotherapy studies for AD back on track. Psychiatry News 2005;33(11):69.-

Article PDF

Author and Disclosure Information

Edmund S. Higgins, MD
Clinical associate professor of family medicine and psychiatry, Medical University of South Carolina, Charleston

Issue

Current Psychiatry - 05(02)

Publications

Topics

Neurology

Alzheimer's & Cognition

Page Number

28-30

Read more about Can a vaccine prevent Alzheimer’s disease?

Sections

Author(s)

Edmund S. Higgins, MD

Author(s)

Edmund S. Higgins, MD

Author and Disclosure Information

Edmund S. Higgins, MD
Clinical associate professor of family medicine and psychiatry, Medical University of South Carolina, Charleston

Author and Disclosure Information

Edmund S. Higgins, MD
Clinical associate professor of family medicine and psychiatry, Medical University of South Carolina, Charleston

Article PDF

Article PDF

Anti-a BETA antibodies

A host could acquire anti-Aβ antibodies though two basic approaches (Figure 2):²

Figure 1 Differences in amyloid deposition between control and immunized mice

Frontal cortex of an unvaccinated mouse (left) shows more amyloid deposits (dark spots) than that of a mouse producing antibodies against the amyloid-β peptide (right).

A troublesome trial

Figure 2 Methods for immunizing against Aβ peptide

Active immunization produces anti-Aβ antibodies via immunologic response to vaccination. With passive immunization, anti-Aβ antibodies are administered directly.

More-optimistic news

Of the 300 patients who received an active vaccine, 20% developed an adequate antibody response.⁵

More work ahead

Pharmaceutical companies are testing two compounds for AD immunotherapy:⁷

AAB-001, a human monoclonal antibody, targets all 42 Aβ amino acids via passive immunization and has entered phase 2 trials.
ACC-001, an Aβ immuno-conjugate designed to elicit an active antibody response, began phase 1 testing last fall.

These efforts suggest that an “Alzheimer’s vaccine” could be produced, provided it could attack the Aβ peptide without inducing a significant cellular reaction.

Anti-a BETA antibodies

A host could acquire anti-Aβ antibodies though two basic approaches (Figure 2):²

Figure 1 Differences in amyloid deposition between control and immunized mice

Frontal cortex of an unvaccinated mouse (left) shows more amyloid deposits (dark spots) than that of a mouse producing antibodies against the amyloid-β peptide (right).

A troublesome trial

Figure 2 Methods for immunizing against Aβ peptide

Active immunization produces anti-Aβ antibodies via immunologic response to vaccination. With passive immunization, anti-Aβ antibodies are administered directly.

More-optimistic news

Of the 300 patients who received an active vaccine, 20% developed an adequate antibody response.⁵

More work ahead

Pharmaceutical companies are testing two compounds for AD immunotherapy:⁷

AAB-001, a human monoclonal antibody, targets all 42 Aβ amino acids via passive immunization and has entered phase 2 trials.
ACC-001, an Aβ immuno-conjugate designed to elicit an active antibody response, began phase 1 testing last fall.

These efforts suggest that an “Alzheimer’s vaccine” could be produced, provided it could attack the Aβ peptide without inducing a significant cellular reaction.

References

2. Schenk D. Amyloid-beta immunotherapy for Alzheimer’s disease: the end of the beginning. Nat Rev Neurosci 2002;3:824-8.

3. Schenk D, Hagen M, Seubert P. Current progress in beta-amyloid immunotherapy. Current Opin Immunol 2004;16:599-606.

4. Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoen-cephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003;61:46-54.

5. Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005;64:1553-62.

7. Sullivan MG. Immunotherapy studies for AD back on track. Psychiatry News 2005;33(11):69.-

References

2. Schenk D. Amyloid-beta immunotherapy for Alzheimer’s disease: the end of the beginning. Nat Rev Neurosci 2002;3:824-8.

3. Schenk D, Hagen M, Seubert P. Current progress in beta-amyloid immunotherapy. Current Opin Immunol 2004;16:599-606.

4. Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoen-cephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003;61:46-54.

5. Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005;64:1553-62.

7. Sullivan MG. Immunotherapy studies for AD back on track. Psychiatry News 2005;33(11):69.-

Issue

Current Psychiatry - 05(02)

Issue

Current Psychiatry - 05(02)

Page Number

28-30

Page Number

28-30

Publications

Publications

Topics

Alzheimer's & Cognition

Article Type

Display Headline

Can a vaccine prevent Alzheimer’s disease?

Display Headline

Can a vaccine prevent Alzheimer’s disease?

Sections

Article Source

PURLs Copyright

Inside the Article

Article PDF Media

CATIE’s surprises: In antipsychotics’ square-off, were there winners or losers?

Article Type

Changed

Tue, 12/11/2018 - 15:09

Display Headline

CATIE’s surprises: In antipsychotics’ square-off, were there winners or losers?

Author(s)

Henry A. Nasrallah, MD

Investigators faced a dilemma while designing the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). More than 200 enrollees with chronic schizophrenia had pre-existing tardive dyskinesia (TD). Would it be ethical to give them the antipsychotic most likely to worsen their TD? Would exempting them from taking that drug influence the trial’s outcome?

This issue and others had to be resolved before the largest controlled study of “real world” schizophrenia could begin. Now that data are unfolding, groups with diverse agendas are debating CATIE’s methods and surprising results. This article describes how the trial’s design and findings could transform public policy and clinical practice.

poll here

Efficacy vs Effectiveness

The National Institute of Mental Health funded the prospective CATIE schizophrenia study to compare the effectiveness of atypical antipsychotics versus each other and versus a first-generation (typical) antipsychotic.

All approved atypicals have shown similar efficacy compared with placebo in short-term trials (usually 6 weeks).¹ The CATIE trial’s rationale is that short-term efficacy studies required for FDA approval may not necessarily reflect the drugs’ effectiveness in long-term schizophrenia management. Effectiveness measures take into account efficacy as well as safety, tolerability, and unpredictable patient behaviors in the real world.

CATIE’s ‘Real World’ Patients

CATIE investigators enrolled a community sample of chronic schizophrenia patients similar to those many psychiatrists see. Very liberal inclusion and exclusion criteria (Table 1) allowed enrollees to have a history of substance abuse, comorbid psychiatric or medical disorders, be receiving other medications, or show evidence of TD. Their schizophrenia ranged from minimal to severe.^2,3

The 1,493 patients who completed the study (Table 2) were enrolled at 57 outpatient treatment settings. One site’s 33 patients were eliminated from analysis because of doubts about the integrity of the data, leaving a total of 1,460 subjects.⁴

Table 1

Criteria for enrolling patients in the CATIE schizophrenia trial

Inclusion criteria	Ages 18 to 65 yrs
	DSM-IV diagnosis of schizophrenia
	Able to take oral medication
	Able to give informed consent
Exclusion criteria	Diagnosis of schizoaffective disorder, mental retardation, or other cognitive disorders
	History of serious adverse reactions to one of the study medications
	Had only one schizophrenic episode
	History of treatment resistance, defined as persistence of severe symptoms despite adequate trials of one of the study antipsychotics or prior treatment with clozapine
	Pregnant or breast feeding
	Serious and unstable medical conditions

Table 2

CATIE’s 1,460 ‘real world’ schizophrenia patients at trial entry

Mean age	40.6±11.1 yrs
Mean age of first treatment	24.0±8.9 yrs
Mean duration of treatment	14.4±10.7 yrs
Gender	74% male
Race	60% white, 35% black, 5% other
Mean education	12.1±2.3 years
Marital status	59% never married
	29% previously married
	11% married
Employment status	85% unemployed
Mean PANSS total score	75.7±17.6
Mean CGI	4.0±0.9
Psychiatric comorbidities	29% drug dependence/abuse
	28% depression
	25% alcohol dependence/abuse
	14% anxiety disorder
	5% obsessive-compulsive disorder
Illness severity	4% severe
	20% marked
	47% moderate
	23% mild
	6% minimal
PANSS: Positive and Negative Syndrome Scale
CGI: Clinician-rated Clinical Global Impressions severity score
Source: Reference 5.

Medications. Before randomization, 28% of enrollees were not receiving antipsychotics. The remainder were receiving:

olanzapine (22%)
risperidone (19%)
quetiapine (7%)
ziprasidone (0%; approved after the trial began)
any combination of olanzapine, risperidone, and quetiapine (7%)
typical antipsychotics (16%).

Metabolic profile. These outpatients had a high rate of metabolic disorders: 42%—twice the rate in the general population—met criteria for metabolic syndrome,⁵ putting them at high risk to die of cardiovascular causes within 10 years.⁶ They had relatively poor physical health self-ratings and increased somatic preoccupation.⁷ Most worrisome, many were receiving no medications for their metabolic disorders, including 45% of those with diabetes, 89% with hyperlipidemia, and 62% with hypertension.⁸

Substance abuse. At enrollment, 40% of patients were abstinent from substance use, 22% were using substances without abuse or dependence, and 37% had substance abuse or dependence. Compared with nonusers, substance abusers tended to be male with more childhood problems, higher positive symptoms on the Positive and Negative Syndrome Scale (PANSS), and more likely to have had a recent illness exacerbation.⁹

Tardive dyskinesia. The 231 subjects who met criteria for probable TD¹⁰ were older than the overall sample with more years of antipsychotic treatment, especially with conventional neuroleptics and anticholinergics. Substance abuse was associated with TD, as were severity of psychopathology, extrapyramidal symptoms (EPS), and akathisia.¹¹

Violent behavior. A history of serious violent behavior was reported in:

5.4% of patients with high positive and low negative PANSS symptom scores
1.7% of patients with low positive and high negative PANSS symptom scores.

Consent. Patients’ capacity to give consent to participate in the study was assessed with the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR). Psychosis severity (PANSS positive symptom scale) was not found to affect decision-making capacity, but negative symptoms and diminished working memory did.¹²

CATIE’s Unique Design

Defining effectiveness. CATIE was designed in three phases (Figure). Phase 1—discussed here—was a blinded, controlled comparison of four atypical antipsychotics and perphenazine. Results of phases 2 and 3 have yet to be published. The primary effectiveness endpoint, “all-cause discontinuation,” was defined as:

lack of efficacy (patient was switched to another drug assigned at random)
lack of tolerability (patient requested a drug change)
safety problem (investigator initiated a switch)
patient’s decision for any reason (often dropping out of the study).

The longer subjects stayed on the first antipsychotic they received, the more effective that drug was considered to be.

Figure CATIE schizophrenia trial design

* Phase 1A: participants with tardive dyskinesia (N=231) do not get randomized to perphenazine; phase 1B: participants who fail perphenazine will be randomized to an atypical (olanzapine, quetiapine, or risperidone) before eligibility for phase 2.
Source: Reference 2.Medications. Three atypicals—risperidone, olanzapine, and quetiapine—were approved for schizophrenia when the trial began in 1999. Recruitment ended in June 2003, the last subject completed the 18-month trial in December 2004, and data analysis began in January 2005. Ziprasidone was added to phase 1 after 40% of the sample had been enrolled, and aripiprazole was included as an option in the unblinded phase 3.

Perphenazine was chosen to represent typical antipsychotics because it has medium potency and less risk of EPS than high-potency drugs such as haloperidol and is associated with less weight gain than low-potency drugs such as thioridazine.

Dosing. Pharmaceutical manufacturers donated the antipsychotics and were invited to recommend their respective drugs’ starting dosages, dose increments, and maximum dosages. Olanzapine’s maker requested a higher starting dosage (7.5 mg/d instead of 5.0 mg/d) and a maximum dosage 50% higher than the FDA-approved range (30 mg/d instead of 20 mg/d). The others recommended the FDA-approved dosage ranges or less:

quetiapine, 200 to 800 mg/d
risperidone, 1.5 to 6 mg/d
ziprasidone, 40 to 160 mg/d
perphenazine, 8 to 32 mg/d.

The study team accepted their recommendations.

The medications were packaged in identical capsules. Quetiapine and ziprasidone were given twice daily because of product labeling; risperidone, olanzapine, and perphenazine were given once daily to one-half the patients assigned to them and twice daily to the others to prevent raters from guessing which drug a patient was receiving.

Tardive dyskinesia. For ethical reasons, the 231 patients with TD at enrollment were randomly assigned in phase 1 to atypicals but not to perphenazine because of the well-established link between typical antipsychotics and TD. This exception could have contributed to the closer-than-expected differences in EPS and perhaps in efficacy, given reports that TD patients have more negative symptoms and cognitive dysfunction.¹³ However, a statistical analysis took that into account.

CATIE’s Key Findings

Discontinuation. A disappointingly high discontinuation rate (74% overall) within a few months was the most important finding (Table 3). A recent effectiveness study with a design similar to the CATIE trial found a similarly high rate of all-cause discontinuation (70%) in patients with first-episode psychosis.¹⁴ Thus, patient-initiated drug discontinuation appears to be a core illness behavior from schizophrenia onset to chronic illness.

The high discontinuation rate shows that we need to modify our approach to schizophrenia, emphasizing full adherence to antipsychotic therapy from the onset of the illness.

Table 3

All-cause discontinuation rates in the CATIE trial

Antipsychotic	Percent discontinued	Duration on antipsychotic (months)*	Dosage (mg/d)*
Olanzapine	64%	9.2	20.1
Perphenazine	75%	4.6	20.8
Quetiapine	82%	4.8	543.4
Risperidone	74%	5.6	3.9
Ziprasidone	79%	3.5	112.8
Overall	74%	Median 6.0; mean 8.3
Notes
*Mean modal
Olanzapine’s discontinuation rate was significantly lower than those of perphenazine, quetiapine, and risperidone but not of ziprasidone.
Olanzapine’s maximum dosage was 30 mg/d (50% higher than FDA-approved 20 mg/d); other agents were dosed within approved ranges.
Patients reached maximum daily antipsychotic dosages at these rates: 40% with olanzapine, 40% with perphenazine, 44% with quetiapine, 40% with risperidone, and 48% with ziprasidone.

Effectiveness—measured as all-cause discontinuation or switching—was the primary outcome of phase 1. The unexpected finding that perphenazine and the atypicals had similar effectiveness could influence clinical practice. Insurers, for example, might consider promoting cheaper typical antipsychotics for first-line use. CATIE’s cost-effectiveness arm (Rosenheck et al, submitted for publication) will provide additional data on this issue.

Before rushing to use older antipsychotics as first-line treatments for schizophrenia, however, policymakers should consider three factors in the study design that could have enhanced perphenazine’s efficacy and safety profiles.

First, perphenazine was given at lower dosages (up to 32 mg/d) than “real world” clinicians used a decade ago (up to 64 mg/d). Thus, lower rates of serious side effects, especially TD, might have occurred in the study than in past clinical practice. Since atypical antipsychotics were approved, clinicians see far fewer psychiatric patients with pill-rolling tremors, rigid posture, or a shuffling gait, compared with 10 to 15 years ago when typical antipsychotics were widely used.

Second, perphenazine was associated with the highest EPS rate (17%), though its mean modal dosage (20.8 mg/d) is considered moderate. Discontinuation because of EPS was highest with perphenazine and lowest with quetiapine.

Third, excluding enrollees with TD from perphenazine may have increased perphenazine’s effectiveness, whereas including them in the atypicals groups may have reduced the atypicals’ effectiveness. TD patients are at increased risk to develop EPS; they had more-severe illness and a higher substance abuse rate among CATIE patients.¹¹ Even so, investigators did control for TD in the data analysis and found no significant difference between typical and atypical antipsychotics.

No ‘Winners’ or ‘Losers’

Effectiveness, tolerability, and safety findings for each antipsychotic are compared in Tables 4A and 4B. Careful review shows no clear “winners” or “losers;” each agent has weaknesses but also strengths that may benefit individual patients.

Efficacy. Olanzapine showed a relatively higher efficacy and lower discontinuation rate but also had the highest risk of adverse metabolic effects. Some have attributed its greater efficacy to its higher dosing compared with the other antipsychotics. Some also have argued that the antipsychotics that showed lower efficacy, such as quetiapine and ziprasidone, were underdosed in this chronic schizophrenia population with a mean duration of illness of 14 years. Perphenazine, too, was dosed at the lower end of its range (mean modal dose 20.8 mg/d) compared with the old community standard of 36 to 64 mg/d.

Generally, a mean modal dosage of 20.1 mg/d for olanzapine is considered equivalent to ziprasidone, 160 mg; quetiapine, 800 mg; and risperidone, 6 mg. In CATIE phase 1, mean modal dosages were:

ziprasidone, 112.8 mg/d (30% below 160 mg)
quetiapine, 543.4 mg/d (32% below 800)
risperidone, 3.9 mg/d (35% below 6 mg).

Olanzapine’s starting dosage of 7.5 mg/d was relatively higher than those of the other atypicals, which may have produced more-rapid onset of efficacy.

Switching. Another potential “advantage” for olanzapine was that 22% of subjects were taking it when they enrolled. By random assignment, 23% of patients who were taking olanzapine stayed on olanzapine and did not switch. By comparison:

No patients assigned to ziprasidone were taking it before entering the trial.
Only 5% of those taking quetiapine stayed on that drug after randomization.
Few were receiving perphenazine before enrollment.

Switching antipsychotics may increase side effect risk or efficacy problems. For example, a patient switched from olanzapine or quetiapine to ziprasidone or perphenazine may experience insomnia during the transition, which may lead to tolerability complaints.

Metabolic side effects seen in this trial support past observations and reports that olanzapine is associated with higher risk for weight gain, hyperglycemia, and hyperlipidemia than other antipsychotics.¹⁵ Data on metabolic changes in CATIE patients taking olanzapine are being analyzed.

Hyperprolactinemia was most common with risperidone and practically nonexistent with other antipsychotics—even perphenazine. On the other hand, risperidone had the most favorable tolerability profile. This implies that elevated prolactin does not necessarily lead to antipsychotic discontinuation because of tolerability among patients with schizophrenia.

QTC interval and cataract data were benign across all antipsychotics. These findings appear to exonerate ziprasidone and quetiapine, respectively, which have been perceived as associated with these side effects.

COMING NEXT

When data become available, the next article in this series will discuss CATIE phase 2 findings. This phase includes patients who did not improve with the phase 1 regimens because of efficacy or tolerability problems and were switched to other antipsychotic therapies.

Related resources

Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study. www.catie.unc.edu/schizophrenia
Schizophrenia Research Forum. NARSAD, The Mental Health Research Association.www.schizophreniaforum.org

Drug brand names

Aripiprazole • Abilify
Olanzapine • Zyprexa
Perphenazine • Trilafon
Quetiapine • Seroquel
Risperidone • Risperdal
Ziprasidone • Geodon

Disclosures

Dr Nasrallah receives grants/research support from AstraZeneca, Janssen Pharmaceutica, Eli Lilly & Co., and Pfizer. He is a consultant, advisory board member, and speaker for Abbott Laboratories, AstraZeneca, Janssen Pharmaceutica, Pfizer, and Shire Pharmaceuticals Group.

References

1. Tandon R, Jibson MD. Efficacy of newer generation antipsychotics in the treatment of schizophrenia. Psychoneuroendocrinol 2003;28(suppl 1):9-26.

2. Stroup TS, McEvoy JP, Swartz MS, et al. The National Institute of Mental Health Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE). Project: schizophrenia trial design and protocol development. Schizophr Bull 2003;29:15-31.

3. Swartz MS, Perkins DO, Stroup TS, et al. Assessing clinical and functional outcomes in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial. Schizophr Bull 2003;29:33-43.

4. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-23.

5. McEvoy JP, Meyer JM, Goff DC, et al. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the CATIE schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res 2005;80:19-32.

6. Goff D, Sullivan LM, McEvoy JP, et al. A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls. Schizophr Res 2005;80:45-53.

7. Meyer JM, Nasrallah HA, McEvoy JP, et al. The Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) schizophrenia trial: clinical comparison of subgroups with and without the metabolic syndrome. Schizophr Res 2005;80:9-18.

8. Nasrallah HA, McEvoy JP, Meyer JM, et al. Low rates of treatment for metabolic disorders in the CATIE schizophrenia trial. Neuropsychopharmacol 2005;(suppl 1):204.-

9. Swartz MS, et al. (unpublished data).

10. Schooler NR, Kane JM. Research diagnosis for tardive dyskinesia. Arch Gen Psychiatry 1982;39:486-7.

11. Miller DD, McEvoy JP, Davis SM, et al. Clinical correlates of tardive dyskinesia in schizophrenia: baseline data from the CATIE schizophrenia trial. Schizophr Res 2005;80:33-43.

12. Stroup TS, Applebaum P, Swartz M, et al. Decision-making capacity for research participation among individuals in the CATIE schizophrenia trial. Schizophr Res 2005;80:1-8.

13. Waddington JL, Youssef HA, Dolphin C, et al. Cognitive function, negative symptoms and tardive dyskinesia in schizophrenia. Their association in relation to topography of involuntary movements and criterion of their abnormality. Arch Gen Psychiatry 1987;44:907-12.

14. Keefe R. The CAFÉ effectiveness study. Amsterdam: European College of Neuropsychopharmacology annual meeting, 2005;

15. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs, obesity, and diabetes. Diabetes Care 2004;27:596-601.

Article PDF

Author and Disclosure Information

Henry A. Nasrallah, MD
Professor of psychiatry, neurology, and neuroscience, Department of psychiatry, University of Cincinnati College of Medicine, Member, CATIE Study Investigators Group

Issue

Current Psychiatry - 05(02)

Publications

Page Number

49-65

Read more about CATIE’s surprises: In antipsychotics’ square-off, were there winners or losers?

Sections

Author(s)

Henry A. Nasrallah, MD

Author(s)

Henry A. Nasrallah, MD

Author and Disclosure Information

Henry A. Nasrallah, MD
Professor of psychiatry, neurology, and neuroscience, Department of psychiatry, University of Cincinnati College of Medicine, Member, CATIE Study Investigators Group

Author and Disclosure Information

Henry A. Nasrallah, MD
Professor of psychiatry, neurology, and neuroscience, Department of psychiatry, University of Cincinnati College of Medicine, Member, CATIE Study Investigators Group

Article PDF

Article PDF

poll here

Efficacy vs Effectiveness

CATIE’s ‘Real World’ Patients

Table 1

Criteria for enrolling patients in the CATIE schizophrenia trial

Inclusion criteria	Ages 18 to 65 yrs
	DSM-IV diagnosis of schizophrenia
	Able to take oral medication
	Able to give informed consent
Exclusion criteria	Diagnosis of schizoaffective disorder, mental retardation, or other cognitive disorders
	History of serious adverse reactions to one of the study medications
	Had only one schizophrenic episode
	History of treatment resistance, defined as persistence of severe symptoms despite adequate trials of one of the study antipsychotics or prior treatment with clozapine
	Pregnant or breast feeding
	Serious and unstable medical conditions

Table 2

CATIE’s 1,460 ‘real world’ schizophrenia patients at trial entry

Mean age	40.6±11.1 yrs
Mean age of first treatment	24.0±8.9 yrs
Mean duration of treatment	14.4±10.7 yrs
Gender	74% male
Race	60% white, 35% black, 5% other
Mean education	12.1±2.3 years
Marital status	59% never married
	29% previously married
	11% married
Employment status	85% unemployed
Mean PANSS total score	75.7±17.6
Mean CGI	4.0±0.9
Psychiatric comorbidities	29% drug dependence/abuse
	28% depression
	25% alcohol dependence/abuse
	14% anxiety disorder
	5% obsessive-compulsive disorder
Illness severity	4% severe
	20% marked
	47% moderate
	23% mild
	6% minimal
PANSS: Positive and Negative Syndrome Scale
CGI: Clinician-rated Clinical Global Impressions severity score
Source: Reference 5.

Medications. Before randomization, 28% of enrollees were not receiving antipsychotics. The remainder were receiving:

olanzapine (22%)
risperidone (19%)
quetiapine (7%)
ziprasidone (0%; approved after the trial began)
any combination of olanzapine, risperidone, and quetiapine (7%)
typical antipsychotics (16%).

Violent behavior. A history of serious violent behavior was reported in:

5.4% of patients with high positive and low negative PANSS symptom scores
1.7% of patients with low positive and high negative PANSS symptom scores.

CATIE’s Unique Design

lack of efficacy (patient was switched to another drug assigned at random)
lack of tolerability (patient requested a drug change)
safety problem (investigator initiated a switch)
patient’s decision for any reason (often dropping out of the study).

The longer subjects stayed on the first antipsychotic they received, the more effective that drug was considered to be.

Figure CATIE schizophrenia trial design

quetiapine, 200 to 800 mg/d
risperidone, 1.5 to 6 mg/d
ziprasidone, 40 to 160 mg/d
perphenazine, 8 to 32 mg/d.

The study team accepted their recommendations.

CATIE’s Key Findings

The high discontinuation rate shows that we need to modify our approach to schizophrenia, emphasizing full adherence to antipsychotic therapy from the onset of the illness.

Table 3

All-cause discontinuation rates in the CATIE trial

Antipsychotic	Percent discontinued	Duration on antipsychotic (months)*	Dosage (mg/d)*
Olanzapine	64%	9.2	20.1
Perphenazine	75%	4.6	20.8
Quetiapine	82%	4.8	543.4
Risperidone	74%	5.6	3.9
Ziprasidone	79%	3.5	112.8
Overall	74%	Median 6.0; mean 8.3
Notes
*Mean modal
Olanzapine’s discontinuation rate was significantly lower than those of perphenazine, quetiapine, and risperidone but not of ziprasidone.
Olanzapine’s maximum dosage was 30 mg/d (50% higher than FDA-approved 20 mg/d); other agents were dosed within approved ranges.
Patients reached maximum daily antipsychotic dosages at these rates: 40% with olanzapine, 40% with perphenazine, 44% with quetiapine, 40% with risperidone, and 48% with ziprasidone.

No ‘Winners’ or ‘Losers’

Generally, a mean modal dosage of 20.1 mg/d for olanzapine is considered equivalent to ziprasidone, 160 mg; quetiapine, 800 mg; and risperidone, 6 mg. In CATIE phase 1, mean modal dosages were:

ziprasidone, 112.8 mg/d (30% below 160 mg)
quetiapine, 543.4 mg/d (32% below 800)
risperidone, 3.9 mg/d (35% below 6 mg).

Olanzapine’s starting dosage of 7.5 mg/d was relatively higher than those of the other atypicals, which may have produced more-rapid onset of efficacy.

No patients assigned to ziprasidone were taking it before entering the trial.
Only 5% of those taking quetiapine stayed on that drug after randomization.
Few were receiving perphenazine before enrollment.

COMING NEXT

Related resources

Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study. www.catie.unc.edu/schizophrenia
Schizophrenia Research Forum. NARSAD, The Mental Health Research Association.www.schizophreniaforum.org

Drug brand names

Aripiprazole • Abilify
Olanzapine • Zyprexa
Perphenazine • Trilafon
Quetiapine • Seroquel
Risperidone • Risperdal
Ziprasidone • Geodon

Disclosures

poll here

Efficacy vs Effectiveness

CATIE’s ‘Real World’ Patients

Table 1

Criteria for enrolling patients in the CATIE schizophrenia trial

Inclusion criteria	Ages 18 to 65 yrs
	DSM-IV diagnosis of schizophrenia
	Able to take oral medication
	Able to give informed consent
Exclusion criteria	Diagnosis of schizoaffective disorder, mental retardation, or other cognitive disorders
	History of serious adverse reactions to one of the study medications
	Had only one schizophrenic episode
	History of treatment resistance, defined as persistence of severe symptoms despite adequate trials of one of the study antipsychotics or prior treatment with clozapine
	Pregnant or breast feeding
	Serious and unstable medical conditions

Table 2

CATIE’s 1,460 ‘real world’ schizophrenia patients at trial entry

Mean age	40.6±11.1 yrs
Mean age of first treatment	24.0±8.9 yrs
Mean duration of treatment	14.4±10.7 yrs
Gender	74% male
Race	60% white, 35% black, 5% other
Mean education	12.1±2.3 years
Marital status	59% never married
	29% previously married
	11% married
Employment status	85% unemployed
Mean PANSS total score	75.7±17.6
Mean CGI	4.0±0.9
Psychiatric comorbidities	29% drug dependence/abuse
	28% depression
	25% alcohol dependence/abuse
	14% anxiety disorder
	5% obsessive-compulsive disorder
Illness severity	4% severe
	20% marked
	47% moderate
	23% mild
	6% minimal
PANSS: Positive and Negative Syndrome Scale
CGI: Clinician-rated Clinical Global Impressions severity score
Source: Reference 5.

Medications. Before randomization, 28% of enrollees were not receiving antipsychotics. The remainder were receiving:

olanzapine (22%)
risperidone (19%)
quetiapine (7%)
ziprasidone (0%; approved after the trial began)
any combination of olanzapine, risperidone, and quetiapine (7%)
typical antipsychotics (16%).

Violent behavior. A history of serious violent behavior was reported in:

5.4% of patients with high positive and low negative PANSS symptom scores
1.7% of patients with low positive and high negative PANSS symptom scores.

CATIE’s Unique Design

lack of efficacy (patient was switched to another drug assigned at random)
lack of tolerability (patient requested a drug change)
safety problem (investigator initiated a switch)
patient’s decision for any reason (often dropping out of the study).

The longer subjects stayed on the first antipsychotic they received, the more effective that drug was considered to be.

Figure CATIE schizophrenia trial design

quetiapine, 200 to 800 mg/d
risperidone, 1.5 to 6 mg/d
ziprasidone, 40 to 160 mg/d
perphenazine, 8 to 32 mg/d.

The study team accepted their recommendations.

CATIE’s Key Findings

The high discontinuation rate shows that we need to modify our approach to schizophrenia, emphasizing full adherence to antipsychotic therapy from the onset of the illness.

Table 3

All-cause discontinuation rates in the CATIE trial

Antipsychotic	Percent discontinued	Duration on antipsychotic (months)*	Dosage (mg/d)*
Olanzapine	64%	9.2	20.1
Perphenazine	75%	4.6	20.8
Quetiapine	82%	4.8	543.4
Risperidone	74%	5.6	3.9
Ziprasidone	79%	3.5	112.8
Overall	74%	Median 6.0; mean 8.3
Notes
*Mean modal
Olanzapine’s discontinuation rate was significantly lower than those of perphenazine, quetiapine, and risperidone but not of ziprasidone.
Olanzapine’s maximum dosage was 30 mg/d (50% higher than FDA-approved 20 mg/d); other agents were dosed within approved ranges.
Patients reached maximum daily antipsychotic dosages at these rates: 40% with olanzapine, 40% with perphenazine, 44% with quetiapine, 40% with risperidone, and 48% with ziprasidone.

No ‘Winners’ or ‘Losers’

Generally, a mean modal dosage of 20.1 mg/d for olanzapine is considered equivalent to ziprasidone, 160 mg; quetiapine, 800 mg; and risperidone, 6 mg. In CATIE phase 1, mean modal dosages were:

ziprasidone, 112.8 mg/d (30% below 160 mg)
quetiapine, 543.4 mg/d (32% below 800)
risperidone, 3.9 mg/d (35% below 6 mg).

Olanzapine’s starting dosage of 7.5 mg/d was relatively higher than those of the other atypicals, which may have produced more-rapid onset of efficacy.

No patients assigned to ziprasidone were taking it before entering the trial.
Only 5% of those taking quetiapine stayed on that drug after randomization.
Few were receiving perphenazine before enrollment.

COMING NEXT

Related resources

Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study. www.catie.unc.edu/schizophrenia
Schizophrenia Research Forum. NARSAD, The Mental Health Research Association.www.schizophreniaforum.org

Drug brand names

Aripiprazole • Abilify
Olanzapine • Zyprexa
Perphenazine • Trilafon
Quetiapine • Seroquel
Risperidone • Risperdal
Ziprasidone • Geodon

Disclosures

References

1. Tandon R, Jibson MD. Efficacy of newer generation antipsychotics in the treatment of schizophrenia. Psychoneuroendocrinol 2003;28(suppl 1):9-26.

4. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-23.

6. Goff D, Sullivan LM, McEvoy JP, et al. A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls. Schizophr Res 2005;80:45-53.

8. Nasrallah HA, McEvoy JP, Meyer JM, et al. Low rates of treatment for metabolic disorders in the CATIE schizophrenia trial. Neuropsychopharmacol 2005;(suppl 1):204.-

9. Swartz MS, et al. (unpublished data).

10. Schooler NR, Kane JM. Research diagnosis for tardive dyskinesia. Arch Gen Psychiatry 1982;39:486-7.

11. Miller DD, McEvoy JP, Davis SM, et al. Clinical correlates of tardive dyskinesia in schizophrenia: baseline data from the CATIE schizophrenia trial. Schizophr Res 2005;80:33-43.

12. Stroup TS, Applebaum P, Swartz M, et al. Decision-making capacity for research participation among individuals in the CATIE schizophrenia trial. Schizophr Res 2005;80:1-8.

14. Keefe R. The CAFÉ effectiveness study. Amsterdam: European College of Neuropsychopharmacology annual meeting, 2005;

References

1. Tandon R, Jibson MD. Efficacy of newer generation antipsychotics in the treatment of schizophrenia. Psychoneuroendocrinol 2003;28(suppl 1):9-26.

4. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-23.

6. Goff D, Sullivan LM, McEvoy JP, et al. A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls. Schizophr Res 2005;80:45-53.

8. Nasrallah HA, McEvoy JP, Meyer JM, et al. Low rates of treatment for metabolic disorders in the CATIE schizophrenia trial. Neuropsychopharmacol 2005;(suppl 1):204.-

9. Swartz MS, et al. (unpublished data).

10. Schooler NR, Kane JM. Research diagnosis for tardive dyskinesia. Arch Gen Psychiatry 1982;39:486-7.

11. Miller DD, McEvoy JP, Davis SM, et al. Clinical correlates of tardive dyskinesia in schizophrenia: baseline data from the CATIE schizophrenia trial. Schizophr Res 2005;80:33-43.

12. Stroup TS, Applebaum P, Swartz M, et al. Decision-making capacity for research participation among individuals in the CATIE schizophrenia trial. Schizophr Res 2005;80:1-8.

14. Keefe R. The CAFÉ effectiveness study. Amsterdam: European College of Neuropsychopharmacology annual meeting, 2005;

Issue

Current Psychiatry - 05(02)

Issue

Current Psychiatry - 05(02)

Page Number

49-65

Page Number

49-65

Publications

Publications

Article Type

Display Headline

CATIE’s surprises: In antipsychotics’ square-off, were there winners or losers?

Display Headline

CATIE’s surprises: In antipsychotics’ square-off, were there winners or losers?

Sections

Article Source

PURLs Copyright

Inside the Article

Article PDF Media

Psychosis: 6 steps rule out medical causes in kids

Article Type

Changed

Tue, 12/11/2018 - 15:09

Display Headline

Psychosis: 6 steps rule out medical causes in kids

Author(s)

David A. Fohrman, MD

Martin T. Stein, MD

John, age 16, is admitted to our inpatient psychiatric unit, complaining of “a 2-week constant headache” caused by “voices arguing in my head.” He has lived in Mexico with an uncle for 6 months but returned home last week for medical evaluation of his headaches.

His parents report that John developed normally until 3 years ago, when he gradually lost interest in his favorite activities and became socially withdrawn. He has not attended school in 2 years. He has no history of illicit drug use and is not taking prescription or over the-counter medications.

Complete physical examination, neurologic exam, and routine screening lab test results are normal. Thinking that a high lead content of cookware used in Mexico might be causing John’s symptoms, we order a lead level: result-0.2 mg/dL (

We diagnose schizophreniform disorder, but John’s parents refuse to accept this diagnosis. They repeatedly ask if we can do more to identify a medical cause of their son’s psychiatric symptoms.

As in John’s case, young patients or their parents may resist the diagnosis of a chronic mental illness such as schizophrenia. Understandably, they may be invested in trying to identify “medically treatable” causes. You can address their anxieties by showing them that you have systematically evaluated medical causes of psychosis.

We offer such a tool: an algorithm and tables to help you identify common and rare medical conditions that may cause or exacerbate psychotic symptoms in patients ages 3 to 18.

An evidence-based algorithm

Multiple factors—developmental, psychological, family, environmental, or medical—typically cause psychotic symptoms in a child or adolescent. Evaluating all possibilities is essential, but guidelines tend to minimize medical causes. American Academy of Child and Adolescent Psychiatry guidelines, for example, recommend that “all medical disorders (including general medical conditions and substance-induced disorders) are ruled out,”¹ but they do not specify which medical conditions to consider.

To supplement existing guidelines, we searched the literature and developed an evidence-based algorithm to help you systematically consider medical causes of pediatric psychotic symptoms. We excluded children age 2

How to use it. The algorithm walks you through a medical systems review. You begin with a complete history, then address six causes of psychotic symptoms: substance abuse, medication reactions, general medical conditions, unexplained somatic symptoms (such as from toxic environmental exposures), developmental and learning disabilities, and atypical presentations.

Don’t stop if you find one possible cause of psychotic symptoms; continue to the end of the algorithm. The more factors you identify, the greater your chance of finding a treatable cause that may ameliorate your patient’s symptoms.

To make the algorithm clinically useful, we listed conditions in order of decreasing probability of causing psychotic symptoms. For example, the first cause listed is substance-induced disorders,³ which are most common among adolescent patients. We also “triaged” medical conditions from common to rare (based on estimated prevalence of association with psychotic symptoms), listing rare causes only in cases of atypical presentation or treatment resistance.

Supporting tables. The following discussion summarizes data that support the algorithm and its tables:

medications reported to cause psychosis (Table 1)
medical conditions most likely to cause psychosis (Table 2)
medical conditions that rarely cause psychosis (Table 3).

Table 1

Drugs that may cause psychotic symptoms

Drug class	Psychotic symptoms
Drug class	Bizarre behavior/delusions	Auditory or visual hallucinations
Amphetamine-like drugs	X	X
Anabolic steroids	X
Angiotensin-converting enzyme (ACE) inhibitors		X
Anticholinergics and atropine	X	X
Antidepressants, tricyclic		X
Antiepileptics	X
Barbiturates	X	X
Benzodiazepines	X	X
Beta-adrenergic blockers	X	X
Calcium channel blockers	X
Cephalosporins	X	X
Corticosteroids	X
Dopamine receptor agonists	X	X
Fluoroquinolone antibiotics	X	X
Histamine H1 receptor blockers		X
Histamine H2 receptor blockers	X
HMG-CoA reductase inhibitors	X
Nonsteroidal anti-inflammatory drugs	X
Opioids	X	X
Procaine derivatives (procainamide, procaine penicillin G)	X	X
Salicylates	X	X
Selective serotonin reuptake inhibitors		X
Sulfonamides		X
Source: Adapted from reference 10.

Table 2

Common medical conditions that may cause pediatric psychosis symptoms*

Category	Conditions not to forget	Common symptoms/comments
Rheumatologic	Lupus erythematosus	Joint pain, fever, facial butterfly rash, prolonged fatigue
Infectious	Viral encephalitis	Fever, headache, mental status change; may occur in perinatal period
Neurologic	Multiple sclerosis	Varied neurologic deficits, especially ophthalmologic changes and weakness
	Neurosyphilis	Personality change, ataxia, stroke, ophthalmic symptoms
	Seizure (temporal lobe epilepsy, interictal psychosis)	Paroxysmal periods of sudden change in mood, behavior, or motor activity with or without loss of consciousness
Toxicologic	Carbon monoxide poisoning	Shortness of breath, mild nausea, headache, dizziness
* Clinically significant symptoms that meet DSM-IV-TR criteria for a primary psychiatric disorder.
Click here to view citations supporting statements in this table

Table 3

Medical conditions that rarely cause pediatric psychosis symptoms*

Category/condition	Symptoms/comments
Endocrine
Hyperthyroidism	Tachycardia, weight loss, excessive sweating, tiredness, inability to sleep, diarrhea, shakiness, muscle weakness
Thymoma/myasthenia gravis	Shortness of breath, swelling of face, muscle weakness (especially around eyes)
Hematologic
Porphyria (acute intermittent porphyria, porphyria variegate)	Intermittent abdominal pain (severe) accompanied by dark urine
Genetic
Fabry’s disease	Burning sensations in hands and feet that worsen with exercise and hot weather
Niemann-Pick disease, type C	Vertical gaze palsy, hepatosplenomegaly, jaundice, ataxia
Prader-Willi syndrome	Obesity, hyperphagia, mild to moderate mental retardation, hypogonadism, tantrums, obsessive-compulsive disorder
Infectious
Epstein-Barr virus	Fever, sore throat, adenopathy, fatigue, poor concentration
Lyme disease	Target lesion, fever; high-risk geographic area
Malaria/typhoid fever	Fever, mental status change; endemic area
Mycoplasma pneumonia	Fever, mental status change; may occur in absence of pneumonia
Rabies	History of exposure
Metabolic
Citrullinemia	Mental status change, high plasma citrulline and ammonia
Tay-Sachs disease	Unsteadiness of gait and progressive neurologic deterioration
Homocystinuria	Dislocated lenses, blood clots, tall stature, some mental retardation
Juvenile metachromatic leukodystrophy	Cognitive decline, ataxia, pyramidal signs, peripheral neuropathy, dystonia; 60% of cases present before age 3
Neurologic
Central pontine myelinolysis	Suspect in patient with pathogenic polydipsia
Huntington’s disease	Chorea, myoclonic seizures, poor coordination, emotional lability
Moyamoya disease	Paresis, syncopal episodes
Narcolepsy	Excessive daytime sleepiness, cataplexy
Subacute sclerosing panencephalitis	Visual hallucinations, loss of developmental milestones
Traumatic brain injury	Occurring 4 to 5 years after a loss of consciousness >30 minutes
Wilson’s disease	Tremors, muscle spasticity, possible liver inflammation
Nutritional
Pellagra (vitamin B₆ deficiency)	Redness, swelling of mouth and tongue, diarrhea, rash, abnormal mental functioning; seen with isoniazid treatment for tuberculosis
Oncologic
Cancers (pancreatic, CNS papilloma, germinoma)	Postural headache, neurologic signs, increased intracranial pressure, early morning nausea, vomiting
Toxicologic
Lead intoxication	Headache, fatigue, mental status change
Mercury poisoning	Abdominal pain, bleeding gums, metallic taste; history of exposure
* Clinically significant symptoms that meet DSM-IV-TR criteria for a primary psychiatric disorder.
Click here to view citations supporting statements in this table

Substance abuse

Substance abuse is common among adolescents and adults with psychotic illnesses.⁴ Drug-induced states can cause delusions, hallucinations, paranoia, and disorganized behavior,⁵ which are reported most commonly during intoxication and withdrawal.⁶ Diagnosis is often straightforward because of the temporal association between the substance abuse and onset of psychotic symptoms.

Little evidence supports a causal relationship between drug use and the development of chronic psychotic symptoms, however. Case reports link use of 3,4-methylenedioxymethamphetamine (“Ecstasy”), lysergic acid diethylamide (LSD), and marijuana to chronic schizophrenia-like symptoms.⁷ The strongest evidence links long-term methamphetamine and cocaine use to chronic psychotic symptoms.^8,9

Medications

Side effects of at least 25 drug classes have been reported to mimic psychosis (Table 1),¹⁰ but little is known about the incidence and prevalence of this problem. Case reports and chart reviews provide the only data that associate most medications with psychotic symptoms. These disagree on what defines a “psychotic symptom,” and most fail to rule out delirium as a possible cause.

The relationship between glucocorticosteroids and psychotic symptoms has been studied extensively. A clear link has been found between corticosteroids at dosages >40 mg/d and a markedly elevated risk for transient psychotic symptoms.¹¹

Medical conditions

We identified 27 medical conditions that may cause or worsen clinical symptoms of psychosis (Tables 2 and 3) by searching PubMed, psychiatric journals, and neuropsychiatry and consult-liaison textbooks. We included only conditions:

shown to cause significant morbidity in pediatric populations
shown to have a statistically significant association with psychotic symptoms, or patients’ symptoms consistently resolved when the condition was treated.

Neurologic conditions. Many neurologic conditions had been reported to cause psychotic symptoms,¹² but only four met at least one of our inclusion criteria. Psychotic symptoms are statistically associated with epilepsy,¹³ Huntington’s disease,¹⁴ and Wilson’s disease;¹⁵ psychotic symptoms associated with multiple sclerosis resolve when the underlying medical condition is treated.¹⁶

Endocrine disorders. Behavioral disturbances (including psychosis) may be the earliest manifestation of an endocrine disorder.¹⁷ Cushing’s syndrome,¹⁸ hyperthyroidism,¹⁹ and hypothyroidism²⁰—met our inclusion criteria.

Cushing’s syndrome—caused by long-term systemic glucocorticoids and thyroid disorders—is not uncommon in children and adolescents but rarely presents with psychotic behaviors. For each endocrine disorder we included, however, at least one case report described delayed diagnosis because of prominent psychosis. Treating the endocrinopathies resolved the psychotic symptoms.

Genetic disorders. Genetically determined neurodevelopmental disorders usually present in very young children, but some may appear later. Genetic conditions that co-occur with psychotic symptoms at rates significantly greater than the population prevalence include Prader-Willi syndrome,²¹ metachromatic leukodystrophy,²² Turner’s syndrome,²¹ velocardiofacial syndrome,²³ and Wilson’s disease.¹⁵

Acute intermittent porphyria, GM₂ gangliosidosis (Tay-Sachs disease), and homocystinuria are rare conditions with unknown prevalence in patients with psychotic disorders. Still, they are important to consider when evaluating youths with psychosis because case reports link their treatment with psychotic symptom resolution.^24-26

Infectious disease. An infectious CNS disease does not usually present with psychotic symptoms only. When this does happen, making the correct diagnosis as soon as possible is critical because early treatment is associated with better outcomes.²⁷ Misdiagnosis as a primary psychotic disorder may expose a patient to psychotropics that may adversely affect clinical outcome.

Viruses that affect the CNS (viral encephalopathies) are the infections most likely to cause psychotic symptoms. By decreasing frequency, they are human simian virus, HIV, influenza, measles, Epstein-Barr virus, mumps, and rabies.^27,28 Bacterial infections that cause psychosis include mycoplasma pneumonia,²⁹ syphilis,³⁰ typhoid fever,³¹ and Lyme disease.³²

Brain tumor. Childhood brain tumors often present with behavioral symptoms associated with headache, vomiting, visual changes, and motor and cognitive symptoms. A CNS tumor rarely presents with isolated neuropsychiatric symptoms.³³ A few case reports describe intracranial tumors initially misdiagnosed as primary psychotic illness because of prominent psychotic symptoms.^34,35 In each case, these symptoms resolved with tumor resection.

A temporal relationship does not necessarily equate to a “causal” relationship, however. Tatter et al³⁶ describe a case of “reoccurrence” of manic symptoms initially thought to be caused by an arteriovenous malformation (AVM) 10 years after the AVM was successfully removed. The important point is that, although rarely, pediatric brain tumor can present with prominent psychotic symptoms.

Environmental toxin exposure may cause well-defined psychiatric syndromes,³⁷ although frank psychosis is uncommon at presentation. Most often, environmental toxins produce an encephalopathic process of which psychosis may be one symptom. A few toxic exposures—such as lead,³⁸ carbon monoxide,³⁹ and elemental mercury⁴⁰ —have presented with prominent psychotic symptoms without other encephalopathic symptoms.

Collagen vascular disease is associated with significantly elevated rates of psychiatric illness, especially depression, but only systemic lupus erythematosus (SLE) is known to be associated with prominent psychosis. Case series report delayed SLE diagnosis in patients with this presentation.⁴¹

High-dose pulse corticosteroids have been reported to effectively treat SLE-related psychotic symptoms,⁴² although high-dose corticosteroids can also cause psychotic symptoms. The timing and character of the symptoms can help you determine whether using corticosteroids is helping or making the patient worse.

Using the algorithm

John’s mother and father fear that the inpatient team’s diagnosis of a primary psychotic disorder means that a medical cause has been permanently “ruled out.” To reassure them, we use the algorithm to explain in concrete terms the thought process that led us to John’s psychiatric diagnosis. We walk them through the algorithm and its tables, explaining how we used evidence to rationally rule out all known medical causes of psychotic symptoms in pediatric patients.

John’s parents are relieved to know that the case is not closed, even though we found no medical cause for their son’s condition. If more clinical data become available, we remain open to considering the possibility that medical conditions could be causing or worsening their son’s symptoms.

Related resources

American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry 2001;40(7 Suppl):4S-23S.
Schiffer RB, Klein RF, Sider RC. The medical evaluation of psychiatric patients. New York: Plenum Medical Book Co.; 1998.
National Organization for Rare Disorders (NORD). www.rarediseases.org.

References

1. American Academy of Child and Adolescent Psychiatry. Summary of the practice parameters for the assessment and treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry 2000;39(12):1580-92.

2. Behrman RE (ed). Nelson textbook of pediatrics (17th ed). Philadelphia: WB Saunders; 2003:397-518.

3. Dalmau A, Bergman B, Brismar B. Psychotic disorders among inpatients with abuse of cannabis, amphetamine and opiates. Do dopaminergic stimulants facilitate psychiatric illness? Eur Psychiatry 1999;14(7):366-71.

4. Breslow RE, Klinger BI, Erickson BJ. Acute intoxication and substance abuse among patients presenting to a psychiatric emergency service. Gen Hosp Psychiatry 1996;18(3):183-91.

5. Poole R, Brabbins C. Drug-induced psychosis. Br J Psychiatry 1996;168:137.-

6. DiSclafani A, 2nd, Hall RC, Gardner ER. Drug-induced psychosis: emergency diagnosis and management. Psychosomatics 1981;22(10):845-55.

7. Cohen SI. Substance-induced psychosis. Br J Psychiatry 1996;168(5):651-2.

8. Farrell M, Boys A, Bebbington P, et al. Psychosis and drug dependence: results from a national survey of prisoners. Br J Psychiatry 2002;181:393-8.

9. Ujike H, Sato M. Clinical features of sensitization to methamphetamine observed in patients with methamphetamine dependence and psychosis. Ann NY Acad Sci 2004;1025:279-87.

10. Drugs that may cause psychiatric symptoms. Med Lett Drugs Ther 2002;44:29-62.

11. Lewis DA, Smith RE. Steroid-induced psychiatric symptoms; a report of 14 cases and a review of the literature. J Affect Disord 1983;5(4):319-32.

12. Cummings JL. Organic psychosis. Psychosomatics 1988;29(1):16-26.

13. Roy AK, Rajesh SV, Iby N, et al. A study of epilepsy-related psychosis. Neurol India 2003;51(3):359-60.

14. Mendez MF. Huntington’s disease: update and review of neuropsychiatric aspects. Int J Psychiatry Med 1994;24:189-208.

15. Brewer GJ. Recognition and management of Wilson’s disease. Proc Soc Exp Biol Med 2000;223:39-46.

16. Mendhekar DN, Mehta R, Puri V. Successful steroid therapy in multiple sclerosis presented as acute psychosis. J Assoc Physicians India 2004;52:512-3.

17. Reus VI. Behavioral disturbances associated with endocrine disorders. Ann Rev Med 1986;37:205-14.

18. Hirsch D, Orr G, Kantarovich V, et al. Cushing’s syndrome presenting as a schizophrenia-like psychotic state. Isr J Psychiatry Relat Sci 2000;37(1):46-50.

19. Lu CL, Lee YC, Tsai SJ, et al. Psychiatric disturbances associated with hyperthyroidism: an analysis report of 30 cases. Zhonghua Yi Xue Za Zhi (Taipei) 1995;56(6):393-8.

20. Bhatara V, Alshari MG, Warhol P, et al. Coexistent hypothyroidism, psychosis, and severe obsessions in an adolescent: a 10-year follow-up. J Child Adolesc Psychopharmacol 2004;14(2):315-23.

21. Prior TI, Chue PS, Tibbo P. Investigation of Turner syndrome in schizophrenia. Am J Med Genet 2000;96(3):373-8.

22. Hyde TM, Ziegler JC, Weinberger DR. Psychiatric disturbances in metachromatic leukodystrophy. Insights into the neurobiology of psychosis. Arch Neurol 1992;49(4):401-6.

23. Briegel W, Cohen M. Chromosome 22q11 deletion syndrome and its relevance for child and adolescent psychiatry. An overview of etiology, physical symptoms, aspects of child development and psychiatric disorders. Z Kinder Jugendpsychiatr Psychother 2004;32(2):107-15.

24. Crimlisk HL. The great imitator-porphyria: a neuropsychiatric disorder. J Neurol Neurosurg Psychiatry 2001;62(4):319-28.

25. Ryan MM, Sidhu RK, Alexander J, Megerian JT. Homocystinuria presenting as psychosis in an adolescent. J Child Neurol 2002;17(11):859-60.

26. MacQueen GM, Rosebush PI, Mazurek MF. Neuropsychiatric aspects of the adult variant of Tay-Sachs disease. J Neuropsychiatry Clin Neurosci 1998;10(1):10-9.

27. Caroff SN, Mann SC, Gliatto MF, et al. Psychiatric manifestations of acute viral encephalitis. Psych Annals 2001;31(3):193-204.

28. Caplan R, Tanguay PE, Szekely AG. Subacute sclerosing panencephalitis presenting as childhood psychosis. J Am Acad Child Adolesc Psychiatry 1987;26(3):440-3.

29. Gillberg C. Schizophreniform psychosis in a case of mycoplasma pneumoniae encephalitis. J Autism Dev Disord 1980;10(2):153-8.

30. Gliatto MF, Caroff SN. Neurosyphilis: a history and clinical review. Psych Annals 2001;31(3):153-61.

31. Venkatesh S, Grell GA. Neuropsychiatric manifestations of typhoid fever. West Indian Med J 1989;38(3):137-41.

32. Tager FA, Fallon B. Psychiatric and cognitive features of Lyme disease. Psych Annals 2001;31(3):173-92.

33. Stein MT, Duffner PK, Wery JS, Trauner D. School refusal and emotional liability in a 6 year old boy. J Dev Behav Pediatr 2001;22(suppl):29-32.

34. Carson BS, Weingart JD, Guarnieri M, Fisher PG. Third ventricular choroid plexus papilloma with psychosis. Case report. J Neurosurg 1997;87(1):103-5.

35. Craven C. Pineal germinoma and psychosis. J Am Acad Child Adolesc Psychiatry 2001;40(1):6.-

36. Tatter SB, Ogilvy CS. Recurrent manic episode 10 years after arteriovenous malformation resection. J Clin Psychiatry 1995;56(2):83.-

37. Hartman DE. Missed diagnosis and misdiagnosis of environmental toxicants exposure: the psychiatry of toxic exposure and multiple chemical sensitivity. Psychiatr Clin North Am 1998;21(3):659-70.

38. Bahiga LM, Kotb NA, El-Dessoukey EA. Neurological syndromes produced by some toxic metals encountered industrially or environmentally. Z Ernahrungswiss 1978;17(2):84-8.

39. Olson KR. Carbon monoxide poisoning: mechanisms, presentation, and controversies in management. J Emerg Med 1984;1(3):233-43.

40. Fagala GE, Wigg CL. Psychiatric manifestations of mercury poisoning. J Am Acad Child Adolesc Psychiatry 1992;31(2):306-11.

41. Turkel SB, Miller JH, Reiff A. Case series: neuropsychiatric symptoms with pediatric systemic lupus erythematosus. J Am Acad Child Adolesc Psychiatry 2001;40(4):482-5.

42. Baca V, Lavalle C, Garcia R, et al. Favorable response to intravenous methylprednisolone and cyclophosphamide in children with severe neuropsychiatric lupus. J Rheumatol 1999;26(2):432-9.

Article PDF

0502CP_article2.pdf

Author and Disclosure Information

David A. Fohrman, MD
Board-certified child, adolescent, and adult psychiatrist, Private practice, Children’s Hospital, San Diego

Martin T. Stein, MD
Professor of clinical pediatrics, Director, developmental and behavioral pediatrics, University of California, San Diego, Children’s Hospital, San Diego

Issue

Current Psychiatry - 05(02)

Publications

Page Number

35-47

Read more about Psychosis: 6 steps rule out medical causes in kids

Sections