An expert panel review of clinical challenges in psychiatry

Accreditation Statement

This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. 

Credit Designation

The Mount Sinai School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)^TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement

It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer reviewed and approved by Eric Hollander, MD, Chair and Professor of Psychiatry at the Mount Sinai School of Medicine. Review Date: September 11, 2007.

Statement of Need and Purpose

Schizophrenia is a chronic mental disorder characterized by psychosis, delusional behavior, and hallucinations. Research has demonstrated that the prognosis for schizophrenia is affected by the amount of time between the initial onset of psychotic symptoms and adequate pharmacologic treatment. Research has unveiled biological markers that correlate with schizophrenia symptoms and support the importance of early intervention for patients with schizophrenia. Neuroimaging studies have demonstrated that there is a neurodegenerative syndrome associated with the cognitive decline that accompanies first-episode psychosis and that loss of gray matter is most significant during early psychosis. In order to achieve a full neuroprotective effect, symptoms must be treated early and to full remission. Both conventional and atypical antipsychotics are effective for treating the symptoms of schizophrenia later in the course of illness, although atypicals appear to have a more significant neuroprotective effect at the time of initial psychosis. Patients who discontinue pharmacologic treatment run a higher risk of relapse with each episode. Managing medication side effects, as well as use of psychosocial interventions, can improve treatment adherence. Given the overall burden of schizophrenia, new efforts at early detection and early treatment with effective antipsychotics are essential. Clinicians must be vigilant in looking for symptoms of schizophrenia and aggressive in treating the disorder once the patient has been diagnosed.

Target Audience

This activity is designed to meet the educational needs of psychiatrists.

Goal of the Activity

To educate physicians on the model of schizophrenia as a limited neurodegenerative disease. Progression of this disease may be prevented by early intervention with antipsychotic treatment and other adjunctive therapies.

Learning Objectives

• Recognize the latest evidence of neurodegeneration associated with cognitive decline in schizophrenia.
• Explain the benefits and risks of pharmacologic treatments.
• Describe the impact of relapse and the need for compliance in limiting the burden of illness in patients with schizophrenia.

Faculty Affiliations and Disclosures

Dr. Lieberman is chairman of the Department of Psychiatry at Columbia University College of Physicians and Surgeons, director of the New York State Psychiatric Institute and the Lieber Center for Schizophrenia Research, and psychiatrist-in-chief of the New York-Presbyterian Hospital and Columbia University Medical Center in New York City.

Dr. Lieberman is a consultant to Eli Lilly and Pfizer; is on the advisory boards of AstraZeneca, Eli Lilly, GlaxoSmithKline, Lundbeck, Organon, and Pfizer; receives grant/research support from Acadia, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Merck, Organon, and Pfizer; and is a patent holder for Repligen. He receives no financial compensation or salary support for participation as a consultant or member of an advisory board. 

Dr. Buckley is professor and chairman in the Department of Psychiatry and Health Behavior at the Medical College of Georgia, in Augusta.

Dr. Buckley is a consultant to Abbott, Alamo, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, Merck, Roche, Solvay, and Wyeth; receives grant/research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, National Institute of Mental Health, Pfizer, Solvay, and Wyeth; and receives honoraria/expenses from Abbott, Alamo, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, and Pfizer. 

Dr. Perkins is professor of psychiatry, medical director of Outreach and Support Intervention Services, and director of the Schizophrenia Treatment and Evaluation Program at the University of North Carolina at Chapel Hill.

Dr. Perkins, receives research support from Janssen; consulting fees from Bristol-Myers Squibb; and compensation for services on the advisory boards as well as honoraria from AstraZeneca, Bristol-Myers Squibb, and Eli Lilly.

Acknowledgment of Commercial Support

Funding for this activity has been provided by an educational grant from Eli Lilly and Company.

Peer Reviewers

David L. Ginsberg, MD, receives honoraria and research support from AstraZeneca, Cyberonics, and GlaxoSmithKline.

Eric Hollander, MD, reports no financial, academic, or other support that may pose a conflict of interest.

To Receive Credit for this Activity

Read this supplement, reflect on the information presented, and complete the CME posttest and evaluation. To obtain credit, you should score 70% or better. Early submission of this posttest is encouraged. Please submit this posttest by October 1, 2009 to be eligible for credit.

Release date: October 1, 2007

Termination date: October 31, 2009

The estimated time to complete this activity is 2 hours.

Abstract

Intervention in the progression of schizophrenia is an effort not just to deter psychosis but also to protect the brain from physiologic deterioration. Neurodegeneration is believed to result from neurochemical dysregulation during the onset of schizophrenia. Deterioration accrued over recurring psychotic episodes causes cumulative loss of cell processes, loss of gray matter volume, and apoptosis. Neurodegeneration ultimately results in persistent symptomology and functional impairment. Functional decline occurs early in the course of schizophrenia, and the symptoms that emerge during the prodromal stage may derail the normal adolescent neurodevelopment. Both first-episode psychosis and the prodrome may be opportunities to forestall neurodegeneration. Unfortunately, people with schizophrenia often experience a long duration of untreated psychosis. Treatment of first-episode psychosis with antipsychotic agents shows robust response. However, early-stage patients have very high rates of medication noncompliance. Treatment in the prodrome may offer the best chance to delay the onset of illness, mitigate its severity after onset, or even prevent onset of symptoms entirely. Nonpharmacologic treatments during the prodrome, such as education, treatment for substance use, and cognitive-behavioral therapy, are low-risk interventions that are potentially beneficial. Pharmacologic interventions during the prodrome are also effective in delaying onset of illness, but carry the risk of adversely affecting patients who are false positives for prodromal schizophrenia.

In this Expert Roundtable Supplement, Jeffrey A. Lieberman, MD, provides an overview of the neurobiological basis of neurodegeneration and the concept of neuroprotection. Next, Peter F. Buckley, MD, reviews the importance of first-episode psychosis, including duration of untreated illness and medication adherence. Finally, Diana O. Perkins, MD, MPH, reviews treatment strategies for prodromal schizophrenia.

Neurobiological Basis of Neurodegeneration and Neuroprotection

Jeffrey A. Lieberman, MD

Neuropathology of Schizophrenia

Intervention in the progression of schizophrenia is premised on the desire to prevent deterioration and limit the cumulative morbidity of the illness. It is based both on original observations of the natural history of schizophrenia and on a new understanding of the underlying pathophysiology of the illness.

The natural history of schizophrenia was first vividly described in the 19th century by psychiatrists, including Emil Kraepelin, who observed that schizophrenia evolves in clinical stages. Today, it is understood that the disease has origins in genetic effects on brain development, and that the phenotype is not expressed until people enter a period of risk during adolescence or early adulthood (Slide 1).¹ During the period of risk, between the ages of 15 and 30 years, symptom expression begins gradually and iteratively. This has been termed a prodromal phase. When symptoms coalesce into a syndromal level that is diagnosable, a person is said to experience the onset of the illness; this is usually a first psychotic episode.

The likelihood of a person experiencing only a single psychotic episode but no recurrence is extremely unusual. The vast majority of people with schizophrenia, even those who recover fully from a first episode, go on to experience recurring psychotic relapses. It is in the context of these recurrences, particularly in the early stage of the illness, that a phenomenon described by Kraepelin as “clinical deterioration” occurs. Clinical deterioration indicates that people with schizophrenia do not recover from subsequent psychotic episodes as quickly or thoroughly as they have from initial episodes, and they also experience greater degrees of residual symptomatology and disability. However, this deteriorating process is not one that goes on inexorably to the point of death, as one sees in Alzheimer’s disease or other classic neurodegenerative brain diseases. Schizophrenia reaches a stable phase in which people are persistently symptomatic and functionally impaired, but their condition does not decline a great deal more. This is the chronic residual phase of the illness.

Recently, we have come to understand that these clinical stages may have distinct underlying pathophysiological processes. During the premorbid phase, the brain undergoes a process of abnormal development but does not yet experience dysfunction or behavioral disturbance. During the age of risk, the patient experiences onset of illness. The neural circuits made vulnerable during the early stages of development are overstressed, their capacity is exceeded, and they become dysregulated. Excessive activity of the dopamine, glutamate, and neural chemical systems produces the symptoms by which clinicians recognize and diagnose schizophrenia.

Treatment, when it is introduced at the prodromal stage, is very effective at stabilizing this process and enabling the patient to remit and perhaps recover. However, when patients experience recurrence of this deterioration, the outlook is less optimistic. It is believed that the deterioration may occur because neurochemical dysregulation can, if it occurs repeatedly or lasts too long, produce structural pathology in terms of loss of cell processes in neurons. This understanding of the illness suggests that early intervention and prevention of recurrence can prevent the development of cumulative morbidity. If intervention takes place early enough, it is hoped that one can even prevent the onset of the illness.

Imaging Evidence of Neurodegeneration

During the process of deterioration, gray matter volume changes at a dramatic rate. Thompson and colleagues² observed the gray matter of people with schizophrenia and people without schizophrenia over a 5-year period (Slide 2). The adolescents without schizophrenia, at an average age of 16 years, showed no loss of gray matter. This is because adolescents do not lose brain tissue in an age-dependent fashion. In those with schizophrenia, the loss of gray matter ranged from 1% to 3% in the temporal lobe, the frontal lobe, and the parietal lobe. It is believed that this gray matter volume loss is associated with the process of degeneration observed in schizophrenia. If this gray matter volume reduction could be prevented, deterioration might not occur.

A coronal plane magnetic resonance imaging (MRI) series shows a patient at three different points of illness. After the patient’s first episode, his brain looked completely normal. It had a very well developed cerebral cortex, narrow lateral ventricles, fully developed third ventricle, and medial temporal lobe structures. After this patient recovered from his first episode, he suffered two subsequent relapses. At his third episode, the MRI showed some loss of gray matter tissue, widening of the lateral and third ventricles, and expansion of the temporal horns around the hippocampus. He did not recover from his third relapse. From that point on, the patient was persistently symptomatic with residual psychotic symptoms. Three years later, the MRI showed further loss of gray matter and enlargement of the patient’s ventricular system and subarachnoid space. This serves as an example of how the illness evolves and what occurs correspondently in the brain.

The question becomes: What is the mechanism producing these changes in the gross brain structure and volume in people with schizophrenia? Many neuropathology postmortem studies show that that people with schizophrenia have brains that are smaller in size, volume, and weight, with larger ventricles than the control brains. However, they do not have massive amount of cell loss.

People with schizophrenia and bipolar disorder have fewer cells in specific populations of cell types. Lewis and colleagues³ studied stainings of γ-aminobutyric acid (GABA) interneuron cells from the frontal cortex of people with schizophrenia, people with bipolar disorder, and control subjects (Slide 3). Subjects with schizophrenia had fewer GABA interneurons. However, this is a relatively small subpopulation of cells. For the most part, people with schizophrenia have the same number of brain cells as do individuals without schizophrenia. Schizophrenia is not a disease that kills massive amounts of cells, the way Alzheimer’s disease does. The brains of people with schizophrenia are different in size and shape primarily because of a loss of cell processes, not because of the loss of cells.

Loss of Cell Processes

The dysregulation of chemical neurotransmission occurs at the synapse, causing too much dopamine to overstimulate the postsynaptic receptors (Slide 4). In glutamate neurons, this dysregulation causes an excessive release of glutamate, presumably in an effort to overcome hypofunctioning in N-methyl-D-aspartate glutamate receptors. The excessive chemicals in both of these excitatory neurotransmitters, and the overstimulation of postsynaptic receptors, produce functional disturbances that are expressed as symptoms. If this process is not stopped or stabilized by treatment, it can cause an ablation of the synapse and a loss of the cell process. The chemical toxicity of excessive dysregulation causes a “pruning” of the dendritic arbor—the large tree of dendrites and dendritic spines that form synaptic connections. The loss of these cell processes, this neuropil, is detected with MRI as a volume reduction.



A postmortem study by Black and colleagues⁴ reflects this process (Slide 5). Postmortem cells taken from the brain tissue of control subjects have longer dendrites than tissue taken from subjects with schizophrenia. Subjects with schizophrenia also have fewer dendritic spines than control subjects. The prevailing hypothesis is that this results from the chemical neurotoxicity that occurs during fulminating and psychotic episodes.

Role of Apoptosis

While it seems that the neuropathology of schizophrenia results in the loss of synapses and cell processes rather than a massive loss in cell numbers, certain subpopulations of cells do seem to experience some loss. This was indicated in the aforementioned study³ of GABA interneurons. Several studies^5-8 suggest that apoptosis might play a role in schizophrenia (Slide 6).

Cell death in the brain can occur in two ways. It can occur through necrosis, infection, inflammation, or toxicity. It can also occur through apoptosis, a highly regulated form of cell viability and death that is programmed into cells to regulate the cell population. It occurs in normal development. However, apoptosis can be triggered pathologically in illnesses such as Huntingdon’s disease, Parkinson’s disease, and Alzheimer’s disease. It is thought that there may be a similar mechanism in schizophrenia that inappropriately induces apoptosis in selected cell populations.

Neurobiological Basis of Neuroprotection

If the pathophysiology of schizophrenia leads from a disturbance in chemical neurotransmission to a loss of cell processes, a reduction in cell volume, and atrophy of the brain, how can treatment prevent this (Slide 7)? Possibilities include the fact that some of the antipsychotic drugs, particularly clozapine-like, second-generation drugs in preclinical studies, have been shown to inhibit glutamate activity. If glutamate is responsible for excessive stimulation and excitatory toxicity, the inhibition of glutamate will be therapeutic and beneficial.

Another possibility is that some medications have the ability to stimulate chemical entities, or molecules, in cells that enhance resilience. Cell resilience is the ability to withstand any type of endogenous physiologic insult. These medications also stimulate the production of trophic factors, such as brain-derived neurotrophic factor or neurotrophin-3, and factors secreted by cells that stimulate growth.

It is also possible that some medications are able to stimulate not just trophic effects but also the actual production of new cells through neurogenesis. This would have seemed preposterous not too long ago. However, in recent years mood stabilizers, such as lithium with antidepressants, have been shown to stimulate neurogenesis in the dentate gyrus of the hippocampus and the olfactory bulb.⁹ Perhaps these mood stabilizers or other medications, such as certain atypical antipsychotics, will be able to promote neurogenesis in a way that contributes to a putative neuroprotective effect.

Schizophrenia, in some ways, can be thought of as a Humpty Dumpty syndrome. That is, it is easier to prevent the damage from being done than it is to repair it after it has occurred. By correctly using our current medications, we can prevent people with schizophrenia from experiencing great decline and residual persistent morbidity, but once they have already descended that slippery slope those treatments are not very good at restoring them to their former selves. Therefore, emphasis must be placed on early detection and intervention in the early stages of schizophrenia, during the first episode or even the prodromal phase of the illness.

References

1. Lieberman JA, Perkins D, Belger A, et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry. 2001;50(11):884-897.
2. Thompson PM, Vidal C, Giedd JN, et al. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci U S A. 2001;98(20):11650-11655.
3. Lewis DA, Austin MC, Pierri JN, et al. Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyricacid neurons in subjects with schizophrenia. Arch Gen Psychiatry. 2000;57(3):237-245.    
4. Black JE, Kodish IM, Grossman AW, et al. Pathology of layer V pyramidal neurons in the prefrontal cortex of patients with schizophrenia. Am J Psychiatry. 2004; 161:742-744.
5. Margolis RL, Chuang DM, Post RM. Programmed cell death: implications for neuropsychiatric disorders. Biol Psychiatry. 1994;35(12):946-956.
6. Akbarian S, Kim JJ, Potkin SG, Hetrick WP, Bunney WE, Jones EG. Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients. Arch Gen Psychiatry. 1996;53(5):425-436.
7. Woods BT. Is schizophrenia a progressive neurodevelopmental disorder? Toward a unitary pathogenetic mechanism. Am J Psychiatry. 1998;155(12):1661-1670.
8. Jarskog LF, Gilmore JH, Selinger ES, Lieberman JA. Cortical bcl-2 protein expression and apoptotic regulation in schizophrenia. Biol Psychiatry. 2000;48(7):641-650.
9. Manji HK, Duman RS. Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. Psychopharmacol Bull. 2001;35(2):5-49.

Treatment of First-Episode Psychosis

Peter F. Buckley, MD

First-Episode Psychosis as a Window of Opportunity

Many wonder why researchers and clinicians focus largely on the first episode of schizophrenia, which is generally viewed as an early stage in the disease progression of chronic illness. Treatment of the first episode presents clinicians with a window of opportunity for several reasons. First, several complex diagnostic and evaluative issues are relayed by a person’s first presentation. For example, first-episode psychosis is often complicated by comorbid substance abuse. In addition, there is often an early emergence of depression as well as an episode of depression following treatment.

Early treatment is important because the opportunity for response is greater earlier in the illness than in later-stage chronic schizophrenia. Treatment during the first episode offers good patient outcome, and treatment in the prodromal stage may provide an even better outcome. The initial treatment is also important because it tends to set the stage for potentially lifelong treatment.

Duration of Untreated Psychosis

The issue of early treatment is made more urgent by the prolonged length of time required to get a psychotic patient into treatment. Several studies of first-episode psychosis show the actual length of time that passes before a person who is floridly psychotic enters into treatment, known as the duration of untreated psychosis. A variety of international studies, and two published meta-analyses by Marshall and colleagues¹ and Menezes and colleagues,² found a very long duration of untreated psychosis (Slide 1). There is variability across studies, which one can assume results from differences in research settings, some of which are naturalistic first-episode studies. The variability very likely accurately reflects the population seen in clinical practices.

An obvious question is: Why is there such a long duration of untreated psychosis? (Slide 2). Patients experiencing an evolving psychotic process are unlikely to realize immediately that they have schizophrenia and seek out a psychiatrist. The very lack of insight that is a fundamental core symptom of schizophrenia results in difficulty assessing one’s own condition and reluctance to seek treatment.

Moreover, it may simply be unclear that a person is having a psychotic episode. The psychotic episode may be misattributed to drugs, oddities of behavior, or adolescent maturational behaviors. Family members may not recognize—and certainly would not ask psychiatrists about—phenomenology such as delusions or hallucination, and they may see withdrawal behavior as either typical of adolescence or as mild depression. They may also be in denial about both the problem and its severity. Indeed, there may be a fear of stigma because schizophrenia is a highly stigmatizing condition.

In addition, people in the first episode of psychosis present through myriad access portals. They do not always present to a psychiatrist who has expertise in schizophrenia. They may present to an internist, a family practice doctor, a counselor, or a religious advisor. This variety of access portals sometimes results in a failure to recognize or appreciate the meaning of the presentation, further adding to the prolonged duration of untreated psychosis.

There are also very complex system issues that pertain to the management of mental health services and access to these services. In many ways, mental health services are oriented toward chronic patients and tend to be crisis-driven, largely confronting psychotic presentations in emergency rooms. People who experience a first episode of psychosis may not encounter clinicians or clinics employing primary or secondary preventative approaches to intervention.

Treatment Options and Effectiveness

Understanding the need to intervene and stabilize the neurodegenerative effects of schizophrenia, and understanding the inherent difficulties of getting people into treatment in early stages of the illness, clinicians are left to wonder whether there are any promising treatment options. It is a vexing issue. The most recent iteration of the Texas Medication Algorithm Project considered which medications should be administered to someone suffering from a first episode of psychosis (Slide 3).

Most clinicians agree that although clozapine is a powerful antipsychotic, it is not a first-line medication, and should be reserved for later stages of illness. Several researchers have found clozapine to be helpful in first-episode patients, but it is generally not the first drug that should be used. One is faced with the option of either a first-generation antipsychotic (FGA) or a second-generation antipsychotic (SGA).

The treatment of a first episode of psychosis is quite robust irrespective of which antipsychotic agent, an FGA or SGA, is used. A comparison of FGAs and SGAs illustrates this early vigorous responsiveness (Slide 4). Representative studies of treatment of first-episode psychosis also show robust response rates ranging from 60% to 81%.^3-6

Beyond controlling the first episode, one must try to prevent or delay subsequent recurrences, which are associated with greater morbidity and potentially toxic effects. An international study by Schooler and colleagues⁶ compared the SGA risperidone to the FGA haloperidol over a substantial period of time (Slide 5). An industrial standard measure of effectiveness is a ≥20% decrease on the Positive and Negative Syndrome Scale (PANSS). The study showed a robust response in both drugs: risperidone showed a 74% decrease in PANSS, and haloperidol showed a 76% decrease in PANSS. When these first-episode patients were followed over time, there was less relapse with risperidone (42%) compared to haloperidol (55%).

Medication Adherence

McEvoy and colleagues^7-9 conducted a 1-year trial of the comparative efficacy of olanzapine, quetiapine, and risperidone in treating first-episode schizophrenia (Slide 6). More than 70% of patients discontinued participation before the end of the study. Reasons for discontinuation included patient decision, side effects, inadequate therapeutic effect, and administrative causes. The three drugs fared similarly in terms of all-cause discontinuation. The study demonstrated a concern for treating the first-episode population that extends beyond medication effectiveness. Clinicians are faced with the challenge of getting people new to a ragged mental health system with a compromised level of insight to stay on a medication because it will ultimately work to reduce relapses and morbidity. The Hillside First Episode Study showed that medication nonadherence in first-episode patients increases the likelihood of relapse 5-fold (Slide 7).¹⁰

The issue of medication adherence is a very important, particularly because treatment in the first episode offers a rare window of opportunity to forestall neurobiological deterioration. It is important, too, because medicines have a high level of effectiveness in early-stage patients and because compliance issues are even greater in this population.

Issues with medication nonadherence can be broadly separated into four categories (Slide 8).^11-13 Medication-related factors are lack of efficacy, distressing side effects, high doses, medication types, and regime complexity. Patients will not take medications that do not work or that have significant side effects. If the regimen is disruptive or complex, patients are likely to stop taking the medication consistently. Patient-related factors include compromised insight, which is a powerful obstacle to taking medicine. Cognitive impairment, a history of substance abuse, previous nonadherence to other drugs, and healthcare beliefs, are other obstacles. Clinician factors include therapeutic alliance and attitudes of staff. Patients must trust their doctor and medical staff, and believe that they are working in the patient’s best interest. Environmental issues include family support, cost of treatment, caregiver support, and a whole host of practical barriers such as access to pharmacies. 

  

Conclusion

There are overarching themes in treating first-episode psychosis (Slide 9). It is important to provide prompt access to specialized care. There is a range of effective treatment options for the first-episode population. Considerations of the risk-benefit profile of the medicines are even sharper in first-episode patients because the capacity of medication to counteract the illness is severely impeded by noncompliance at this early stage. Noncompliance itself is an extraordinarily complex and underappreciated issue. 

   

References

1. Marshall M, Lewis S, Lockwood A, Drake R, Jones P, Croudace T. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch Gen Psychiatry. 2005;62(9):975-983.
2. Menezes NM, Arenovich T, Zipursky RB. A systematic review of longitudinal outcome studies of first-episode psychosis. Psychol Med. 2006;36(10):1349-1362.
3. Emsley RA. Risperidone in the treatment of first-episode psychotic patients: a double-blind multicenter study. Risperidone Working Group. Schizophr Bull. 1999;25(4):721-729.
4. Lieberman JA, Tollefson G, Tohen M, et al. Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol. Am J Psychiatry. 2003;160(8):1396-1404.
5. Lieberman JA, Tollefson GD, Charles C, et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry. 2005;62(4):361-370.
6. Schooler N, Rabinowitz J, Davidson M, et al. Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial. Am J Psychiatry. 2005;162(5):947-953.
7. McEvoy JP, Lieberman JA, Perkins DO, et al. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry. 2007;164(7):1050-1060.
8. Lieberman J, McEvoy JP, Perkins D, Hamer RH. Comparison of atypicals in first-episode psychosis: a randomized, 52-week comparison of olanzapine, quetiapine, and risperidone. Eur Neuropsychopharmacol. 2005;15(Suppl 3):S526.
9. Marx CE. Comparison of atypicals in first-episode psychosis (CAFE): a randomized, double-blind, 52-week comparison of olanzapine, quetiapine, and risperidone. Paper presented at: 8th World Congress of Biological Psychiatry; June 28–July 3, 2005; Vienna, Austria.
10. Robinson DG, Woerner MG, Alvir JM, et al. Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry. 1999;156(4):544-549.
11. Perkins DO, Johnson JL, Hamer RM, et al. Predictors of antipsychotic medication adherence in patients recovering from a first psychotic episode. Schizophr Res. 2006;83(1):53-63.
12. Lacro JP, Dunn LB, Dolder CR, Leckband SG, Jeste DV. Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry. 2002;63(10):892-909.
13. Buckley PF, Wirshing DA, Pierre J, Bushen P, Resnick S, Wishing SC. Lack of insight and treatment adherence in schizophrenia. CNS Drugs. 2007;21:129-141.

Early Detection and Intervention

Diana O. Perkins, MD, MPH

Prodromal Treatment Potential

Treatment paradigms for first-episode schizophrenia are usually initiated sometime after the onset of psychosis, often with substantial delays (Slide 1). The illness develops during adolescence and early adulthood, which is a critical time for psychological, social, and cognitive development, and the emerging symptoms of the prodrome likely derail this neurodevelopment process. Functional decline occurs early in the course of the illness. At first presentation, most of the functional decline seen in schizophrenia has already occurred.

The onset of the prodromal symptoms, the first stages of schizophrenia, may portend the inevitable development of the disorder. However, the prodromal period may be an at-risk state that requires environmental triggers, such as stress or drug use, for the full disorder to develop. If treatment occurs during the prodromal stage, it could potentially prevent the development of psychosis, and might offer opportunities to address the decline in function (Slide 2). Alternatively, prodromal treatment might delay illness onset, giving patients further opportunity to reach developmental milestones. The course of illness itself might be less severe and associated with less functional disability.

The potential benefits of early identification and treatment are clear (Slide 3). The goal is to prevent development of schizophrenia and the associated risks of dangerous behaviors, emergency hospitalizations, and social and vocational costs. The ability to intervene during the prodrome depends on accurate ascertainment, especially to minimize the risk of false positives. Identifying someone as being at-risk for psychosis does carry some potential risks. Particularly, there may be stigma from being labeled potentially psychotic, and the family and patient may worry about psychosis risk. They may unnecessarily minimize developmentally appropriate challenges, or the patient may be denied opportunities. It is therefore critical in this early period to minimize the risks of false positives.

Prodromal Case Study

John is an 18-year-old high school senior. He had been an A student until his sophomore year, after which his performance declined to a C average. He attributed his academic decline to  “just not caring anymore.” He saw his friends less often, and he quit the lacrosse team because he thought other players were mocking and criticizing him. He began to suspect that fellow students’ laughter was directed at him. In the past year, John reported occasionally feeling as though he were being watched while alone, but he realized this was probably not true. He reported frequent episodes of feeling strange, and described these episodes by saying, “I am not me, everything seems unreal, like a dream.” He also became a pagan with many superstitions, believing that lucky numbers and phases of the moon influenced events. While alone, John occasionally heard his name called. He saw shadows and shapes out of the corner of his eye, but would see nothing when he turned to look. On one occasion, he saw a person run in front of his car and stopped abruptly, only to realize his that mind was “playing tricks on him.” His parents reported that he was more irritable, and he reported feeling depressed and anxious at times. He smoked pot and drank three to four beers on weekend nights.

John was experiencing symptoms that patients describe in the prodromal stage of schizophrenia: attenuated psychosis, brief psychosis, negative symptoms, affective symptoms, cognitive impairment, and behavioral disturbances (Slide 4). Attenuated positive symptoms of psychosis are used as diagnostic criteria for an at-risk or prodromal state. These include ideas of reference, such as John’s suspicion of other students, and the emergence of unusual thought content, such as John’s uncharacteristic pagan beliefs. Perceptual abnormalities, including visual or auditory illusions and rare frank hallucinations, derealization, and disorganization of thought process and speech are other attenuated symptom of psychosis. Brief intermittent psychosis can be a single episode or rare episode that is brief in duration, such as hearing a voice or a sentence. Negative symptoms can involve the emotional/affective blunting and diminished drive. John’s lack of motivation at school is an example of diminished drive.

Affective symptoms are also very common. Almost all patients report some dysphoric moods, such as John’s anxiety and depression. Some patients also report subjective problems in cognitive function, such as worsening attention or easy distractibility, impairment in initiating and maintaining a train of thought, intrusive thoughts that do not make sense, or difficulty comprehending written or spoken language. All of these symptoms can lead to behavioral disturbances, such as declining school function, social withdrawal, aggressive behaviors, or suicidal ideation or attempts. It seems likely, considering his symptoms, that John is at high risk of developing schizophrenia.

Prodromal Studies

The North American Longitudinal Prodromal Study (NAPLS) developed a database of 291 individuals who met diagnostic criteria for the prodromal state (Slide 5).¹ These criteria, known as the Criteria of Prodromal States (COPS), heavily depend on the presence of attenuated positive symptoms with some interference in function.

At the end of 2.5 years, 35% of the 291 patients who presented with COPS symptoms had developed a psychotic disorder (Slide 6). None of the healthy subjects developed a psychotic disorder during this period. The incidence of risk of psychosis in the general population, ages 15–25 years, is 0.15%. The participants with COPS had a risk of developing psychosis in any given year that was relatively low. However, over the course of a decade, 1% of those individuals will develop a psychotic disorder, meaning the relative risk is quite high, at ~235 times greater than the risk of the general population.

While the risk was relatively high for the NAPLS subjects, 65% did not develop a psychotic disorder during the 2.5-year follow-up period. What will happen to these subjects long term is unknown, but for many, symptoms seem to have resolved and their function has improved. They may, in fact, be at low risk for developing psychosis.

Improving Diagnostic Criteria

The next step in prodromal diagnosis is to determine if there are additional diagnostic criteria to improve diagnostic specificity and minimize false positives. NAPLS criteria include significant decline in social function, having a first-degree relative with a psychotic disorder, experiencing symptoms more severely, or abusing drugs, all of which is associated with a risk of approximately double (Slide 7).

Other studies^2-4 showed that neurocognitive deficits, gray matter loss, or biomarkers might predict risk of developing psychosis. Emerging neuroimaging studies show that the characteristic loss of gray matter in frontal and temporal regions may begin during the prodrome. Recently published work has suggested that genetic markers may one day be used to diagnose or improve risk prediction. In particular, a polymorphism with the gene neuregulin has been associated with psychosis risk, offering the hope that genetic tools for diagnosing prodromal symptoms are just over the horizon.⁵ Today, however, a great deal of work remains.

Treatment Strategies for Prodromal Schizophrenia

There have been three clinical trials looking at treatment strategies to prevent psychosis in individuals with prodromal symptoms (Slide 8). McGorry and colleagues⁶ conducted a randomized, unblinded comparison of risperidone plus psychotherapy versus treatment as usual. McGlashan and colleagues⁷ conducted a randomized double-blind comparison of olanzapine versus placebo. Morisson and colleagues⁸ ran an unblinded comparison of cognitive-behavioral therapy (CBT) plus treatment as usual versus symptom monitoring.

The study by McGorry and colleagues⁶ offered 6 months of intervention with risperidone plus therapy to some subjects and treatment as usual to others, and then followed subjects for 1 year (Slide 9). Risperidone plus CBT significantly prevented risk of psychosis. Of the 28 subjects who received treatment as usual, ~35% developed psychosis during the 6-month follow-up. Of the subjects in the intervention group, <10% developed psychosis. At the 1-year follow-up, these trends persisted. A few more subjects in the intervention group went on to develop psychosis, but fewer than those in the treatment-as-usual group. There is some indication that risperidone plus psychotherapy might prevent, or at least delay, onset of psychosis.

In a study by McGlashan and colleagues,⁷ >35% of placebo-treated patients developed psychosis, compared to ~15% of olanzapine-treated patients (Slide 10). This was significant at a trend level, though sample sizes were relatively small. In fact, the four or five olanzapine-treated patients who developed a psychotic disorder did so within a week of starting the treatment trial. It may have been that these patients were really at immediate risk of psychosis and that treatment was not initiated soon enough.

Morrison and colleagues⁸ conducted a psychotherapy study comparing CBT to symptom monitoring (Slide 11). In the symptom-monitored group, ~27% of subjects developed psychosis. In the CBT group, ~6% of subjects developed psychosis. The CBT may have some benefit in either delaying or preventing psychosis.

In treating patients in the prodromal stage, clinicians have the options of pharmacologic and nonpharmacologic interventions (Slide 12). Pharmacologic interventions still face the problem of false positives. Clinicians will need to weigh the risk of treatment and its benefits, knowing that while a patient may be at risk for psychosis, he or she may not necessarily develop a psychotic disorder.  Monitoring is vital because earlier treatment for psychosis yields better prognosis. However, it is often difficult to decide precisely when to institute pharmacologic treatment in a patient with declining function and worsening positive symptoms.

Nonpharmacologic interventions carry much lower risk, and potentially may help. These include educating patients and families about the potential causes of psychotic disorders, the course of the illness, and the importance of monitoring. Treatment for any ongoing substance use could decrease risk as well, because substance use, especially marijuana use, may increase vulnerability. Psychotherapy has a relatively low risk and may be quite beneficial. These therapies include CBT, supportive family therapy, and stress management/relaxation techniques. Using both pharmacologic and nonpharmacologic interventions in this patient population may potentially prevent schizophrenia.

References

1. Addington J, Cadenhead KS, Cannon TD, et al. North American prodrome longitudinal study: a collaborative multisite approach to prodromal schizophrenia research. Schizophr Bull. 2007;33(3):665-672.
2. Keefe RS, Perkins DO, Gu H, Zipursky RB, Christensen BK, Lieberman JA. A longitudinal study of neurocognitive function in individuals at-risk for psychosis. Schizophr Res. 2006;88(1-3):26-35.
3. Niendam TA, Bearden CE, Johnson JK, et al. Neurocognitive performance and functional disability in the psychosis prodrome. Schizophr Res. 2006;84(1):100-111.
4. Spencer MD, Moorhead TW, McIntosh AM, et al. Grey matter correlates of early psychotic symptoms in adolescents at enhanced risk of psychosis: a voxel-based study. Neuroimage. 2007;35(3):1181-1191.
5. Hall J, Whalley HC, Job DE, et al. A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms. Nat Neurosci. 2006;9(12):1477-1478.
6. McGorry PD, Yung AR, Phillips LJ, et al. Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms. Arch Gen Psychiatry. 2002;59(10):921-928.  
7. McGlashan TH, Zipursky RB, Perkins D, et al. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry. 2006;163(5):790-799.
8. Morrison AP, French P, Walford L, et al. Cognitive therapy for the prevention of psychosis in people at ultra-high risk: randomised controlled trial. Br J Psychiatry. 2004;185:291-297.

Question-and-Answer Session

Q: What is the main reason for the high rate of treatment noncompliance in patients with psychosis? 

Dr. Buckley: One of the most prominent reasons is lack of insight, which is a razor-edged sword in first-episode patients. Even though treatment is quite effective and keeps them stable, patients have to gain insight to see the benefit of staying on their medicine. Helping a patient gain insight involves explaining the risk of relapse, which inevitably exposes the patient to the chronicity of the illness and its consequences, including suicide. Early in the illness people suffer depression, so we must consider the possibility of reactive depression when a patient wakes up to the enormity of his condition. While improving insight early on may increase medication compliance, it is also risky because of the demoralization and distress caused by the patient’s realization of his condition.

Q: To what extent do clinicians have a hard time recommending long-term medication, especially in a patient who has had just one episode of psychosis with good or complete recovery?

Dr. Buckley: That is a complex issue that takes on greater significance when considering the side effects, such as weight gain and diabetes, that relate to the length of time one takes a medication. Even though a first-episode patient has a higher degree of response, he is still at risk for some of these side effects, and clinicians are risk-averse. They must balance the risk of treating a chronic condition, even in the context of a patient who actually has “remitted” or “recovered,” with the importance of preventing or delaying future relapse.  There are competing concerns about the accrual of long-term medication side effects and long-term neurodegeneration.

Q: How do you identify prodromal illness and intervene?

Dr. Perkins: It is surprisingly hard to define when psychosis actually begins. The prodrome is not a linear event, and the symptoms can wax and wane. It is sometimes a challenge to know when these symptoms are severe enough to determine that a person is psychotic and requires treatment. When clinicians are confronted with a patient who may need an antipsychotic, the extent to which the patient’s symptoms interfere with their function plays a large role in the treatment decision.

The ultimate goal is to be able to prevent psychosis. The problem is knowing what treatment to use and whether or not treatments are beneficial in the very earliest stages. Antipsychotics have  been used in clinical trials so far, but it may be that neuroprotective agents or other kinds of treatments are more beneficial. For example, a small open study showed that that omega-3 fatty acids were potentially beneficial,¹ and another open study suggested glycine might hold benefits as well.²

Dr. Lieberman: When I was training, my supervisors said that young patients having a first episode of psychosis may need to get sick again before they learn treatment compliance, as though it was a process of self-education. It was assumed that, in the long run, this process would not harm the patients or limit their ability to respond to treatment, so long as they eventually appreciated its value. We now have substantial evidence that disease progression is driven by recurrences and duration of psychotic episodes.

Q: Do you think the neurodegeneration evidence that has emerged through research studies influences clinical practice?

Dr. Perkins: Yes. Clinicians, families, and patients seem to be impressed by the data, especially when they see evidence of the shrinking brain and the concern that it may be irreversible. I tell patients that once they stop their medication the illness will take its natural course, and we do not know how severe their particular illness will become. Once progression has occurred, we may be less able to restore function and improve symptoms. I ask them, “What kind of gambler are you? How much of a chance will you take that you will develop a more severe, disabling course of illness?”    

Dr. Buckley: Thompson’s³ study contains provocative information for both clinicians and family members, suggesting there is evidence of brain tissue loss. I think this is something that resonates with clinicians and family members.

Q: Is it now indicated that patients who have recovered from first-episode schizophrenia should take medication indefinitely?

Dr. Buckley: I do not think we have enough information to say that treatment will be indefinite, but I would be very cautious to take a patient off of medication once there is a clear diagnosis of schizophrenia, even if the first episode is followed by recovery. I think the stakes are too high with this condition. It is hard to justify indefinite treatment, and it is a very hard message to give a patient. Telling a patient they will never get off a medicine almost begs them to try to stop taking it, therefore I am reluctant to be so forceful. However, I feel equally uncomfortable with short-term measures, or taking patients off medication after a year or so.

Dr. Perkins: I recommend indefinite treatment for recovering first-episode patients. We do not currently have the tools to predict who is at risk for a more severe, progressive illness and who may have a milder course, but the stakes are pretty high. We can try to minimize side effects with low-dose medication. We have learned a great deal in the past decade, and in the ensuing years we may learn a great deal more about who is really at risk and what the best ways to prevent this illness are. For now, if it were my son or daughter, I would have them on a long-term antipsychotic.    

Dr. Lieberman: The guidelines for sustained, continued treatment would probably be 1 or 2 years. Afterward, it is still up to the clinician’s judgment and patient preference.
    

References

1. Amminger GP, Schafer MR.  Indicated prevention with omega-3 fatty acids in adolescents at ultra high risk for psychosis—rationale, methods, and 3-months outcome. Schizophr Res. 2006;86(suppl):S97.
2. Woods SW, Walsh B, Pearlson GD, et al. Glycine treatment of prodromal symptoms.  Schizophr Res. 2006;86(suppl):S7.
3. Thompson PM, Vidal C, Giedd JN, et al. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci U S A. 2001;98(20):11650-11655.