Schizophrenia

From the 4th Annual University of California Davis Conference: Evidence-Based Treatment Approaches to Psychotic Disorders, presented by the UC Davis School of Medicine

Educational Objectives

The goal of this program is to improve prevention and early treatment of psychosis, and treatment of cognitive im­pairment in individuals with schizophrenia. After hearing and assimilating this program, the clinician will be better able to:

1.   State why recognizing early signs of psychosis should be considered a public health issue.

2.   Discuss the effects of untreated initial psychosis on patients’ lives.

3.   Describe the Portland Identification and Early Prevention project and the efficacy of this biosocial model in identifying and treating early indications of psychosis.

4.   Assess neurobiologic functions behind impairment of cognitive control mechanisms in schizophrenia.

5.   Utilize cognitive training to improve functioning in patients with schizophrenia.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of in­terest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose. In their lectures, Drs. McFarlane and Carter discussed the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Drs. McFarlane and Carter were recorded at 4th Annual UC Davis Conference: Evidence-Based Treatment Approaches to Psychotic Disorders, held September 10, 2009, in Sacramento, CA, and sponsored by the University of California, Davis, School of Medicine. The Audio-Digest Foundation thanks the speakers and UC Davis School of Medicine for their cooper­ation in the production of this program.

Prevention of and Early Intervention for Psychosis

William R. McFarlane, MD, Professor of Psychiatry, University of Vermont College of Medicine, Burlington; Director, Center for Psychiatric Research, Maine Medical Center Research Institute, Portland, ME

“Staging” schizophrenia: schizophrenia can be staged in manner analogous to cancer staging; stage I (premorbid state)  —  some subtle markers that might be predictive; stage II (prodrome)  —  subtle and infrequent psychotic symptoms not yet meeting criteria for schizophrenia; stage III  —  first full-blown episode of psychosis; 75% chance of relapse and 25% chance of full remission; stage IV  —chronic schizophrenia with multiple episodes and deterio­rating course; only at this stage can schizophrenia be differentiated from bipolar disorder with psychotic mania; speaker suggests that early stages of schizophrenia should be public health issue (as with early stages of cancer and cardiovascular disease); early intervention could result in huge cost-savings to society

Loss of functioning in schizophrenia: positive and negative symptoms develop rapidly near time of first episode, leading to early disability; much can occur before individual becomes frankly psychotic; disorder most sensitive to treatment before first episode; after each episode, it takes twice as long for patient to reach remission as after previ­ous episode (ie, with time, schizophrenia becomes less responsive to treatment);

Can early intervention prevent development of schizophrenia? thought likely, based on numerous trials of indi­cated prevention; duration of untreated psychosis (DUP) highly predictive of short- and long-term outcomes

Effects of untreated initial psychosis: cascade of psychosocial effects  —  the longer psychosis lasts, the more trau­matic and stigmatizing it becomes; reduced neurocognitive and social function  —  caused by psychotic state; the longer psychosis lasts, the greater the risk patient will lose contact with family and friends, fail in school, or lose job; treatment rejection  —  the longer psychosis lasts, the more difficult it will be for clinician to establish good therapeutic relationship with patient

Benefits of early intervention: disturbing symptoms (eg, hallucinations, delusions) take prolonged period of un­treated psychosis to develop; early intervention may help prevent or ameliorate such disruptive and disabling symptoms; neurobiologic deficit processes that progress near time of first episode may be arrested or possibly re­versed

When should treatment for psychosis start? controversial; some think “absolutely reliable and valid” diagnosis must be made before starting treatment; others think enough known about early indicators of psychosis to begin treatment earlier; yet others trying to find optimal balance between definitive diagnosis and early intervention

Prevention trials: number of controlled trials completed (and others ongoing) internationally that look at effects of identifying and treating subtle early symptoms of psychosis that do not meet criteria for schizophrenia; studies used different evidence-based treatments for schizophrenia; controls either no treatment or standard treatment; results not incontrovertible, but clearly suggest that early intervention may make a difference

Portland Identification and Early Referral (PIER) project: biosocial model based on premise that course of psy­chotic illness, particularly schizophrenia, results from continual interaction of specific biologic and social pro­cesses; subtle social influences exacerbate and amplify biologic influences; research suggests that before actual onset of schizophrenia, individual has loss of brain tissue, particularly in parietal, frontal, and temporal cortices; tissue loss has subtle effects, including interference with social relationships and loss of problem-solving ability; individual often recognizes that “something [is] wrong,” but cannot specifically identify it; deficits amplified by psychosocial stressors as parents, siblings, teachers, peers, and others react, often negatively, to changes

Family-aided Assertive Community Treatment (FACT): treatment approach developed by speaker and colleagues to accompany antipsychotic treatment based on symptoms

Pilot study: FACT offered to all patients along with medication based on symptoms; assessments made by consen­sus of clinical staff (not independent); treatment lasted ³2 yr, sometimes with lengthy continuation

Randomized controlled trial: patients randomized to FACT or to family education and crisis intervention, with medications held constant; assessments independent, blinded, serial, and multidimensional; fixed 2-yr treat­ment period and assessment protocol

First step: professional and public education of as many individuals in community (eg, pediatricians, guidance counselors, school nurses, college health services, employers) as possible; goals  —  reduce stigma associated with mental illness; provide information about modern concepts of psychotic disorders; increase understanding of early stages of mental illness and prodromal symptoms

Clinical assessment: prodromal psychosis determined by 1) Schedule of Prodromal Syndrome (SOPS; evaluates for clustering of changes in behavior, thoughts, and emotions, with preservation of insight [eg, magical think­ing, fleeting apparitions, unusual fears, satanic preoccupations, reduced emotional responsiveness]); 2) signifi­cant deterioration in functioning; 3) social withdrawal

Intervention: rapid crisis-oriented initiation of treatment; psychoeducational multifamily groups; case manage­ment using “Assertive Community Treatment” methods; supported employment and education; cognitive as­sessments to inform support; low-dose atypical antipsychotic medications (aripiprazole most common) and (if indicated) mood stabilizers

Outcomes: still being analyzed, but data available for 148 patients after 1 yr of treatment; professional and public education  —  100% of public schools and colleges visited ³2 times; »7300 professionals in community trained; >70,000 bookmarks distributed; >1400 resource guides distributed; website (www.preventmentalillness.org) had >500,000 hits; awareness of program increased from 8% to 19%; overall efficiency ratio 69%; acceptance of treatment  —  declined by only 7% of screened individuals; only 15% dropped out within 3 mo; demographics of treated sample  —  53% male, 47% female; average age 16.5 yr; only 15% had substance abuse disorder; con­version to psychosis within 12 mo  —  no conversion in 77%; of those who converted, »10% had psychotic epi­sode that lasted >30 days (almost all noncompliant with treatment); »13% had psychotic episode that lasted £30 days (almost all compliant with treatment); first admissions for psychosis dropped significantly; multisite follow-up study now under way; accurate referrals coming from outside of mental health system; efficiency of early identification and sex distribution for prodromal and early psychotic episodes almost identical to Port­land study

Conclusions: very low conversion rates and functional improvement associated with early treatment; substantial pro­portion of incident population can be identified, and  development of psychosis prevented; psychiatrists’ practice expected to shift from late comprehensive approach used for established disorder to early treatment modalities

Cognitive Impairment in Schizophrenia

Cameron S. Carter, MD, Professor, Department of Psychiatry and Behavioral Sciences, and Director, University of Cali­fornia Davis Imaging Research Center, UC Davis, School of Medicine, Sacramento

Introduction: patients with schizophrenia have substantial cognitive impairment at onset of disorder and throughout lifespan; impaired cognition considered strong predictor of disability in schizophrenia; current treatments have lit­tle impact on cognitive disability, which ranges from impairment in attention and memory to disturbances in lan­guage (all  manifestations of impaired cognitive control)

Cognitive control: defined as mental processes that support goal-directed behavior, particularly when faced with dis­tractions or stimuli that conflict with task-appropriate responses; system in brain that regulates attention, mem­ory, language comprehension and production, and other functions; can be assessed with Stroop test (individuals with schizophrenia make more errors due to disorganization in prefrontal cortex); in functional magnetic reso­nance imaging (fMRI) study,  healthy controls showed much more activity in dorsolateral portion of prefrontal cortex when performing difficult task than those with schizophrenia

“Top down” control: in healthy subject, when dorsolateral prefrontal cortex becomes active, control network formed with parietal and premotor cortices; allows subject to produce correct responses; individuals with schizo­phrenia have low connectivity between prefrontal cortex and network, and perform tasks less proficiently

Mechanism of impairment: “bold” signal on fMRI (ie, measurement of bloodflow) related to neural activity in which large populations of neurons firing synchronously; data suggest that underlying oscillatory activity in cor­tex might be impaired in schizophrenia; oscillation of pyramidal neurons in prefrontal cortex observed on elec­troencephalography during task performance; regulated by inhibitory neurons which synchronize firing of adjacent neurons; disturbance in production of necessary neurotransmitter (g-aminobutyric acid [GABA]) ob­served in schizophrenia

Implications for treatment: can target toward increasing sensitivity of GABA receptors to improve function of lo­cal circuits, which in turn would produce better activation of frontal lobe and better cognitive performance; speaker performed small trial in which experimental benzodiazepine (selective GABA A a2 receptor agonist) ad­ministered to patients with schizophrenia; found improved cognitive performance and increased gamma activity in prefrontal cortex (corresponds to performance of demanding cognitive tasks); larger trial under way in which functional outcomes being evaluated; other classes of drugs also under study

Neuroplasticity: neural basis of learning known to be dependent on change in strength of connectivity between cells which become active simultaneously; connections can become tighter and stronger (long-term potentiation) or looser and weaker (long-term depression); this reorganization of neural networks that involves reengineering of synaptic connections believed to be basis of learning and memory; when memories retrieved, simultaneous activa­tion of larger networks becomes important; networks must oscillate in same manner required of neurons in prefron­tal cortex to maintain particular task set

Can neuroplastic changes be made through cognitive training alone? yes, but requires 1) highly intensive training schedules; 2) frequent and repetitive engagement of attention and reward systems; 3) carefully controlled and constrained learning tasks; 4) individualized adaptation of task difficulty; implicit learning and memory intact, and neural responses to repetitive practice normal in schizophrenia; led to hypothesis of beneficial effect of inten­sive cognitive training exercises

Vinogradov et al study (improving cognitive function in individuals with schizophrenia): training begins with sim­ple perceptual discrimination tasks which get progressively more difficult; memory load added later to train working memory (engages frontal and parietal regions of brain); patients with chronic disease randomized to 1 hr per day of computer-based training vs active control (1 hr per day of computer games); repeated over many weeks; patients received »50 hr of training in auditory module, 30 hr in visual module, and 20 hr in cognitive control module; results  —  posttraining data show significant improvement in treated group, but none in control group; gains seen at 6 mo persisted to 12 mo; patients in training group still cognitively impaired, but less than before training ( »0.5 SD below mean, rather than 1.0 SD)

Conclusions: entering new era in understanding of neurobiologic mechanisms that underlie successful cognitive re­mediation; applies to psychopharmacology and cognitive training

UC Davis research projects: Early Diagnosis and Preventive Treatment of Psychotic Illness (EDAPT)  —  multisite; effectiveness of cognitive rehabiliation of patients with first episode of psychosis during preceding year; cognitive rehabilitation in patients with “clinical high risk”  —  uses same tools as EDAPT study; pharmacologic trials  —modafinil and atomoxetine treatment of impaired cognition in schizophrenia; H3 antagonist treatment  —  increases dopamine in prefrontal cortex (may enhance cognitive performance); transcranial magnetic stimulation for im­paired cognition  —  used successfully to treat auditory hallucinations in schizophrenia

Suggested Reading

Addington D: Best practices: improving quality of care for patients with first-episode psychosis. Psychiatr Serv 60:1164, 2009; Becker TM et al: Prefrontal dysfunction in first-degree relatives of schizophrenia patients during a Stroop task. Neu­ropsychopharmacology 33:2619, 2008; Cho RY et al: Impairments in frontal cortical gamma synchrony and cognitive con­trol in schizophrenia. Proc Natl Acad Sci U S A. 103:19878, 2006; Cotton SM et al: Gender differences in premorbid, entry, treatment, and outcome characteristics in a treated epidemiological sample of 661 patients with first-episode psycho­sis. Schizophr Res 114:17, 2009; Faridi K et al:. Prevalence of psychotic and nonpsychotic disorders in relatives of patients with a first-episode psychosis. Schizophr Res 114:57, 2009; McFarlane WR et al: Employment outcomes in Family-aided Assertive Community Treatment. Am J Orthopsychiatry 70:203, 2000; McGorry P et al: Early intervention in psychosis: keeping faith with evidence-based health care. Psychol Med 24:1, 2009; Minzenberg MJ et al: Meta-analysis of 41 func­tional neuroimaging studies of executive function in schizophrenia. Arch Gen Psychiatry 66:811, 2009; Niendam TA et al: Exploring predictors of outcome in the psychosis prodrome: implications for early identification and intervention. Neuro­psychol Rev 19:280, 2009; Ravizza SM et al: The impact of context-processing deficits on task-switching performance in schizophrenia. Schizophr Res Sep 4, 2009; Tallon-Baudry C, Bertrand O: Oscillatory gamma activity in humans and its role in object representation. Trends Cogn Sci 3:151, 1999; Tranulis C et al: Early intervention in psychosis: A Case study on normal and pathological. Cult Med Psychiatry Aug 28, 2009. [Epub ahead of print]; Yoon JH et al: Association of dor­solateral prefrontal cortex dysfunction with disrupted coordinated brain activity in schizophrenia: relationship with im­paired cognition, behavioral disorganization, and global function. Am J Psychiatry 165:1006, 2008; Yoon JH et al: Diminished orientation-specific surround suppression of visual processing in schizophrenia. Schizophr Bull 35:1078, 2009.