does relapse in schizophrenia cause neurodegeneration? a ......– schizophrenia is the 6 th leading...

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DOES RELAPSE IN SCHIZOPHRENIA CAUSE NEURODEGENERATION? A SIMULCAST DEBATE & VIRTUAL FORUM TO EXPLORE THE EVIDENCEPeter Weiden, MDProfessor of Psychiatry UIC Medical Center Chicago, IL

Henry A. Nasrallah, MDSydney W. Souers Professor Chair Department of Neurology & PsychiatrySaint Louis University School of MedicineSaint Louis, MO MRC2.CORP.D.00015


The following presentation is sponsored by Otsuka America Pharmaceutical, Inc. and

Lundbeck, LLC.

Drs. Weiden and Nasrallah are paid consultants for Otsuka America Pharmaceutical, Inc.


© 2015 Otsuka America Pharmaceutical, Inc., Rockville, MD

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THE PUBLIC HEALTH BURDEN OF RELAPSE AND ACUTE PSYCHOTIC EPISODESPeter Weiden, MDProfessor of Psychiatry UIC Medical Center Chicago, IL



COPD, chronic obstructive pulmonary disease; YLD, years lost due to disability.1. The Global Burden of Disease: 2004 update. World Health Organization 2008. ISBN 978 92 4 156371 0.2. Patel V, et al. Lancet 2007;369:1302-1313. 3. The World Health Report 2001. Mental Health: New Understanding, New Hope. World Health Organization 2001. ISBN 92 4 156201 3.

• Globally, schizophrenia ranks 14th in the list of disabling conditions1

– Schizophrenia is the 6th leading cause of years lost to disability in low- and middle-income countries1

– 5 out of the 10 leading causes of disability-adjusted life years in people aged 15–44 years are mental disorders, including schizophrenia2

Schizophrenia is a Public Health Problem

5

Leading Global Causes of YLD, by sex1 Leading Causes of YLD, by age3

MALES FEMALES

Rank Cause YLD (millions)

Rank Cause YLD (millions)

1 Unipolar depressive disorders

24.3 1 Unipolar depressive disorders

41.0

2 Alcohol use disorders

19.9 2 Refractive errors 14.0

3 Hearing loss, adult onset

14.1 3 Hearing loss, adult onset

13.3

4 Refractive errors 13.8 4 Cataracts 9.9

5 Schizophrenia 8.3 5 Osteoarthritis 95

6 Cataracts 7.9 6 Schizophrenia 8.0

7 Bipolar disorder 7.3 7 Anaemia 7.4

8 COPD 6.9 8 Bipolar disorder 7.1



Start of acute therapy

Start of stabilization

Maintenance

1. Lehman AF, Lieberman JA, Dixon LB, et al; American Psychiatric Association; Steering Committee on Practice Guidelines. Am J Psychiatry. 2004;161(2 Suppl):1-56.

Phase of Illness Model for Long-term Treatment1

Sym

ptom

s

Time

6



1. Lader M. Int Clin Psychopharmacol. 1995;9 Suppl 5:5-9.2. Olivares JM, Sermon J, Hemels M, et al. Ann Gen Psychiatry. 2013;12:32.3. Andreasen NC, Liu D, Ziebell S, et al. Am J Psychiatry. 2013;170:609-615.4. Csernansky JG, Mahmoud R, Brenner R; Risperidone-USA-79 Study Group. N Engl J Med. 2002;346:16-22.5. Lehman AF, Lieberman JA, Dixon LB, et al; American Psychiatric Association; Steering Committee on Practice Guidelines. Am J Psychiatry. 2004;161(2 Suppl):1-56.

• Relapse implies at least one prior episode that was followed by improvement or response (return of disease after partial recovery)1,2

• Implies change from equilibrium “baseline”1

• Implies worsening of symptoms over and above expected symptom fluctuation as calibrated to the specific individual2–4

• Usually but not always represents recurrence of psychotic symptoms or significant worsening of positive symptoms2–4

• Implies a change in functional status that adversely affects relationships with others, social and role functioning, ability to care for self, or represents a safety risk to self or others2–4

• Relapse is part of phase of illness concept5

Defining Relapse in Schizophrenia

7



1. Weiden PJ and Oltson M. Schizophren Bull. 1995;21:419-429.2. Olivares JM, Sermon J, Hemels M, et al. Ann Gen Psychiatry. 2013;12:32.3. Buckley PF, Miller BJ, Lehrer DS, et al. Schizophr Bull. 2009;35:383-402.4. Sleep Health Foundation. SCHIZOPHRENIA AND SLEEP. Available at: http://www.sleephealthfoundation.org.au/files/pdfs/SchizophreniaandSleep.pdf. Accessed 11/17/2014.5. Arroll MA, Wilder L, Neil J. Nutr J. 2014;13:91. doi: 10.1186/1475-2891-13-91.6. Oh G, Petronis A. Schizophr Bull. 2008;34(6):1122-1129.

Many factors contribute…• Lack of efficacy of medication1

• Poor adherence2 (don’t take OUR drugs)• Drug or alcohol use2 (THEIR drugs!)• Comorbid medical problems3

• Psychosocial stressors2

• Environmental changes4-6

There may be single or multiple causes

Common Causes of Relapse

8

http://www.sleephealthfoundation.org.au/files/pdfs/SchizophreniaandSleep.pdf



• 82% of patients relapse within the first 5 years1

• Studies of relapse have yielded several observations:2– Longer treatment period does not reduce risk of relapse– Many patients relapse very soon after treatment discontinuation– Relapse event may be abrupt with few warning signs– Relapse symptom severity is similar to the initial episode– A subset of patients do not respond to the re-introduction

of treatment

Even First Episode Schizophrenia is Usually Phasic

9

1. Robinson D et al. Arch Gen Psychiatry.1999;56:241-247.2. Emsley R et al. BMC Psychiatry. 2013;13:50.

Event, time Relapse Rate (95% CI)First Relapse, 5 years 82% (71–93)Second Relapse, 5 years 78% (47–100)Third Relapse, 4 years 86% (62–100)



• Schizophrenia hospitalizations result in similar number of total hospitalization days as hospitalizations due to acute myocardial infarction

• These data do NOT include state hospitals, jails, prisons or VA inpatient settings, and therefore may be an underestimation

Estimated Number of Hospitalizations from Schizophrenia (2010)(compared to myocardial infarctions)

ICD CodeNumber of

Hospitalizations (thousands)

Average Length (days)

Total Hospital Days

Acute myocardial infarction1

410 595 5.4 3,224

Schizophrenic disorders1 295 266 10.6 2,822

1. Centers for Disease Control and Prevention National Hospital Discharge Survey. http://www.cdc.gov/nchs/nhds/nhds_tables.htm#number. Accessed on 18th November 2014.

10

http://www.cdc.gov/nchs/nhds/nhds_tables.htm%23number



CNS, central nervous system.

• There is no question that relapse is, at best, disruptive and, at worst, life-threatening – However, there is a dearth of data on the biology

of schizophrenia, particularly on the acute psychotic episode

– Little is known about the mechanisms involved and possible CNS consequences

• This debate will discuss the hypothesis that relapse is a driver of CNS neurodegeneration

The Question

11



DISEASE PROGRESSION AS A CONSEQUENCE OF RELAPSEHenry A. Nasrallah, MDSydney W. Souers Professor Chair Department of Neurology & PsychiatrySaint Louis University School of MedicineSaint Louis, MO



• Meta-analysis of 27 studies, 928 patients, 867 controls, 32 brain regions of interest

• Compared to controls, patients showed significantly greater decreases over time in:– whole brain volume– whole brain gray matter– frontal gray and white matter– parietal white matter– temporal white matter volume

• Compared to controls, patients showed a significantly greater increase over time in:– lateral ventricular volume

Has Neurodegeneration in SchizophreniaBeen Observed?

1. Olabi B et al. Biol Psychiatry. 2011;70:88-96.

13



Rate of Gray Matter Loss in Patients with Schizophrenia and Control Subjects

14

Copyright (2001) National Academy of Sciences, U.S.A.

1. Thompson PM et al. Proc Natl Acad Sci. 2001;98:11650-11655.




• First-episode schizophrenia (n=34); matched healthy controls (n=36)

• MRI obtained at inclusion, and after 1 year. Outcome measured at 2 years

• Total brain volume and cerebral grayvolume were significantly decreased, and lateral ventricle volume significantly increased in patients compared with controls

-4

-2

0

2

4

6

8

10

Total brainvolume

Cerebral grayvolume

Lateralventriclevolume

Cha

nge

in v

olum

e (%

)

Brain volume change after first-episode schizophrenia

Brain Volume Changes in First-episode Schizophrenia: a 1-year Follow-up Study

MRI, magnetic resonance imaging.1. Cahn et al. Arch Gen Psychiatry. 2002;59:1002-1010.

Decrease in global gray matter volume was significantly correlated with outcome and,

independent of that, with higher cumulative dosage of antipsychotic medication

******

***

***p≤0.001 versus healthy comparison subjects.

15



But what about neurodegeneration during relapse?



Neurodegeneration During Relapse: Mathalon

*p≤0.05; †p≤0.01.CSF, cerebrospinal fluid; MRI, magnetic resonance imaging.1. Mathalon DH et al. Arch Gen Psychiatry. 2001;58:148-157.

Pearson correlations of MRI slopes with percentage of time hospitalized

MRI Slope (cm3/y) Percentage of Time Hospitalized

CSF

Prefrontal 0.52*Frontal 0.48†

Anterior superior temporal 0.01

Posterior superior temporal 0.04

Lateral ventricles 0.27

Gray matter

Prefrontal -0.52*Frontal -0.17

Anterior superior temporal -0.31

Posterior superior temporal -0.32

17



*Post-hoc analysis. Other areas not reported.MRI, magnetic resonance imaging.1. van Haren NEM et al. Neuropsychopharmacology. 2007;32:2057-2066.

• Compared to controls, patients showed significantly greater decreases over time in gray matter density in the:– left superior frontal area– left superior temporal gyrus– right caudate nucleus– right thalamus

Neurodegeneration During Relapse: van Haren

Number, but not duration, of hospitalizations during the scan interval was significantly associated with a larger decrease in gray matter density in the left superior frontal gyrus*

18



Neurodegeneration During Relapse:Andreasen

Effect of relapse duration on brain volume

*Tissue decrease during interscan intervals due to relapse duration in cc/year.SE, standard error.1. Andreasen NC et al. Am J Psychiatry. 2013;170:609-615.

19

Brain Volume Measure β2* SE p

Cerebral

Total -1.55 0.61 0.01

White matter -0.95 0.54 0.07

Frontal lobe

Total -0.99 0.34 0.004

White matter -0.48 0.24 0.04

Temporal lobe

Total -0.14 0.11 0.23

White matter -0.17 0.08 0.03

Parietal lobe

Total -0.34 0.20 0.08

White matter -0.20 0.16 0.22



What are the neurotoxic processes occurring during psychotic episodes?



COX, cyclooxygenase; IFN, interferon; IL, interleukin; TNF, tumour necrosis factor.1. Meyer. Brain Behav Immun. 2011;25:1507-1518.2. Monji et al. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:115-121.

• There are many lines of evidence for immune dysregulation and neuroinflammation in schizophrenia1,2

• Microglia activation by various mechanisms directly contributes to neuronal degeneration by producing pro-inflammatory cytokines and free radicals, which inhibit neurogenesis, and are toxic to white matter1,2

• Elevated inflammatory cytokines in schizophrenia (TNF-α, IFN-γ, IL-6).2Microglia are the primary reservoirs of pro-inflammatory cytokines, which act as antigens in the CNS and play a major role in innate immunity1,2

• Some antipsychotic drugs (second generation) reduce inflammation and oxidative stress. N-Acetylcysteine has been used for its anti-oxidant effects1,2

• Adding anti-inflammatory agents to antipsychotic drugs potentiates response, e.g., minocycline, Cox-2 inhibitors, omega-3 fatty acids…

…Especially in first episode!1,2

Neuroinflammation in Schizophrenia

21



1. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th Edition. New York, NY: Cambridge University Press; 2013. 2. Tourjman V et al. Schizophr Res. 2013;151:43-47.

• The common notion is that the efficacy of antipsychotics is mediated by dopamine D2blockade1

• However, part of the efficacy of antipsychotics may be mediated by an anti-inflammatory mechanism2

Antipsychotics are Anti-inflammatory

22



ROS, reactive oxygen species.1. Ciobica et al. Psychiatr Danub. 2011;23:237-245.

• Oxidative stress is defined as an imbalance between toxic reactive species or ROS (free radicals) and antioxidant systems

• It is relevant to the pathophysiology of schizophrenia• Free radicals are counteracted by several

cytoprotective antioxidant enzymes that limit their damage such as:– Superoxide dismutase– Glutathione peroxidase

Oxidative Stress During Psychosis

23



4-HNE, 4-hydroxynonenal; CAT, catalase; GPX, glutathione peroxidase; MDA, malondialdehyde; SOD, superoxide dismutase; TAOP, total antioxidant property; TBARS, thiobarbituric acid reactive substances; TpERoX, total peroxide levels.1. Ciobica et al. Psychiatr Danub. 2011;23:237-245. 2. Pedrini et al. J Psychiatr Res. 2012;46:819-824.3. Dean et al. Curr Med Chem. 2009;16:2965-2976.4. Nasrallah H. Curr Psychiatry. 2013;12:7-8.5. Nandra KS and Agius M. Pyschiatr Danub. 2012;24(Suppl 1):S95-S99.

• Oxidative stress markers in schizophrenia studies include:1,2 SOD, GPX, MDA, TBARS, CAT, TAOP, TpERoX, 4-HNE, TRX

• Mitochondrial dysfunction has been reported in schizophrenia and may account for the low levels of the powerful antioxidant glutathione3,4

• Second-generation antipsychotics have been reported to normalise the abnormal free radical metabolism, but the first-generation antipsychotics like haloperidol increase oxidative stress and apoptosis4,5

Oxidative Stress During Psychosis (cont.)

24



Neurotoxic Processes in Schizophrenia

Feigenson et al. Neurosci Biobehav Rev. 2014;38:72–93. Flatow et al. Biol Psychiatry. 2013;74:400-409.

Genetic risk factors

Environmental risk factors

Oxidative stress

Altered myelination

Synaptic dysfunction

Chronic inflammation

Altered glutamate metabolism

Abnormal plasticity

Abnormal maturation of brain circuits

Disconnectivity

Abnormal neural coordination

25



1. Buckley PF et al. Schiz Res. 2007;94:1-11.

• A growing literature confirms that neurotrophinssuch as NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor) are decreasedin drug-naïve schizophrenia1

• Neurotrophins play a key role in neuroplasticity and neuroprotection against apoptosis (programmed cell death)

• Thus, it is reasonable to assume that the deficit of NGF and BDNF in schizophrenia is related to loss of brain tissue via apoptosis

Effects of Antipsychotics on Neurotrophic Factors in Schizophrenia

26



DISEASE PROGRESSION AS A CONSEQUENCE OF RELAPSE?Peter Weiden, MDProfessor of Psychiatry UIC Medical Center Chicago, IL



1. McGlashan TH. J Psychiatr Res. 1998;32:133-141.2. Zipursky RB, Reilly TJ, Murray RM. Schizophr Bull. 2013;39:1363-1372.3. Emsley R, Chiliza B, Asmal L. Schizophr Res. 2013;148:117-121.4. Emsley R, Chiliza B, Asmal L, Harvey BH. BMC Psychiatry. 2013;13:50.

• Deterioration has been a core feature of the description and process of schizophrenia since the time of Kraepelin1

– Helped to establish idea of schizophrenia as a progressive brain disease, which has contributed to the rationale for early intervention2

• In the early 1990s Richard Wyatt proposed that psychosis has an inherent biologically toxic effect (neurotoxic psychosis hypothesis)3

– Provided impetus for minimization of duration of untreated psychosis2

– If psychosis is neurotoxic, then acute psychotic exacerbations may lead to disease progression and impaired treatment response4

– As episodes of relapse are times of active psychosis, they have also been suggested to be associated with deterioration and disease progression4

The Neurodegenerative Hypothesis in Schizophrenia

28



1. Lieberman JA. Biol Psychiatry. 1999;46:729-739.2. Emsley R, Chiliza B, Asmal L. Schizophr Res. 2013;148:117-121.3. Arroll MA, Wilder L, Neil J. Nutr J. 2014;13:91. doi: 10.1186/1475-2891-13-91.4. Emsley R, Chiliza B, Asmal L, Harvey BH. BMC Psychiatry. 2013;13:50.

• Persons with schizophrenia undergo many changes over time– Patients experience varying degrees of behavioral and cognitive

deterioration1

• Lives of persons with schizophrenia are very different from those of healthy controls– Negative impact on relationships, employment, lifestyle, etc2

– Presence of comorbid conditions, effects on life expectancy, etc3

• Relapse can be associated with negative clinical and physiological changes4

– Occurring before, during, and immediately after relapse

Assuming Neurodegeneration Happens…Why Does it Happen?

29



• If relapse directly causes damage to the brain, then preventing relapse should prevent neurodegeneration

• If damage is related to secondary physical and psychological stresses, there are important clinical implications:– Address secondary issues as soon as possible (eg,

nutrition, sleep, exercise)– Minimize psychological trauma secondary to relapse – Minimize iatrogenic problems such as excessive use of high

dose antipsychotics, may be especially problematic during acute phase

Why Does Neurodegeneration Happen…Why the “WHY” Matters

30



1. Pajonk FG, Wobrock T, Gruber O, et al. Arch Gen Psychiatry. 2010;67:133-143.2. Arroll MA, Wilder L, Neil J. Nutr J. 2014 Sep 16;13:91. doi: 10.1186/1475-2891-13-91.3. Sleep Health Foundation. SCHIZOPHRENIA AND SLEEP. Available at: http://www.sleephealthfoundation.org.au/files/pdfs/SchizophreniaandSleep.pdf. Accessed

11/17/2014.4. Zunzunegui MV, Alvarado BE, Del Ser T, Otero A. J Gerontol B Psychol Sci Soc Sci. 2003;58(2):S93-S100.5. Lommen MJ, Restifo K. Community Ment Health J. 2009;45:485-496.6. David AS, Prince M. J Neurol Neurosurg Psychiatry. 2005;76 Suppl 1:i53-60.7. Rais M, Cahn W, Van Haren N, Schnack H, Caspers E, Hulshoff Pol H, Kahn R. Am J Psychiatry. 2008;165(4):490-496.

• Physiological/brain changes could potentially occur in response to:– Level of physical exercise1

– Aging1

– Inadequate nutrition2

– Disruptions in sleep-wake cycle3

– Level of social engagement4– Likelihood of Posttraumatic Stress Disorder (PTSD) events5

– Head trauma6

– Cannabis smoking7

Alternate Explanations for Physiological Differences Observed in Schizophrenia Patients

31

http://www.sleephealthfoundation.org.au/files/pdfs/SchizophreniaandSleep.pdf.%20Accessed%2011/17/2014



1. Zipursky RB, Reilly TJ, Murray RM. Schizophr Bull. 2013;39:1363-1372.2. Emsley R, Chiliza B, Asmal L. Schizophr Res. 2013;148:117-121.3. Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Arch Gen Psychiatry. 2011;68:128-137.

• Consistent with hypothesis: Evidence of progressive brain changes– MRI studies have demonstrated deficits in gray and white matter volumes, the

magnitude of which was greater for more chronically ill patients1

• Inconsistent with hypothesis:– A longitudinal study of first-episode schizophrenia patients followed over ~7 years

reported relapse duration, but not frequency, was related to changes in brain measures2

– While studies have indicated structural changes over time, cognitive impairment has been reported to be present at disease onset, but remains stable (at least over the early course of schizophrenia)2

– Additionally, there is evidence of an association between factors common to patients with schizophrenia and similar structural changes within the brain:1

• Effects of medications (including high-dose antipsychotic medications)3

• Cannabis smoking• Cigarette smoking• Alcohol• Stress (elevated glucocorticoid levels)

If Schizophrenia is a Progressive Disease Where Relapse Leads to Neurodegeneration…

32



1. McEwen BS. Dialogues Clin Neurosci. 2006;8:367-381.

• The brain is the key organ of stress– Determines threats and physiological/

behavioral responses to it– Regulates neuroendocrine,

autonomic, and immune systems• In normal responses, stress

initiates a response (elevated signals: cortisol, sympathetic activity, proinflammatory cytokines, etc) which is turned off after an appropriate interval– Repeated stressors can lead to a lack

of adaptation – Prolonged responses can occur when

shutdown is delayed– Inadequate responses can lead to

compensatory activity of other mediators

The Brain and Stress Responses

33

Normal Response to Stress

Time

Phys

iolo

gic

resp

onse

Stress

Recovery period

Prolonged Response to Stress

Time

Phys

iolo

gic

resp

onse

Repeated Stress

Time

Phys

iolo

gic

resp

onse

Normal responseUnable to adapt

Recovery period



1. McEwen BS. Dialogues Clin Neurosci. 2006;8:367-381.

• “Allostasis” refers to how the organism responds to daily events and maintains stability– “Allostatic overload” results from too

much stress or inefficient turning off of the stress response

• Chronic stress in animal models has been shown to cause atrophy of neurons in the hippocampus/prefrontal cortex and hypertrophy of neurons in the amygdala

Neuro-structural Remodeling in Response to Stress

34

– Clinical examples of the effects of chronic stress on the brain have been demonstrated in depression, Cushing’s disease, and post-traumatic stress disorder

• Alterations in hippocampus, amygdala, and prefrontal cortex

Brain regions involved in the stress response, and structural remodeling

that can result from stress.

Structural remodeling of the brain under stress

Prefrontal cortex

atrophy

Hippocampusatrophy

Amygdalahypertrophy and eventual

atrophy



1. Rais M, Cahn W, Van Haren N, Schnack H, Caspers E, Hulshoff Pol H, Kahn R. Am J Psychiatry. 2008;165:490-496.

• Background– Poor outcomes have been associated with cannabis use

• Longitudinal studies examining effect on brain changes have been limited

• Methods– Patients with recent-onset schizophrenia (n=51) and

matched healthy subjects (n=31) underwent MRI scans at baseline and after a 5-year follow-up

• Clinical outcome and amount of cumulative antipsychotic medication was also assessed

• 19 patients used cannabis; 32 did not

Brain Volume Loss Over Time in Cannabis-Using First-Episode Schizophrenia Patients

35



Image reprinted with permission from the American Journal of Psychiatry, (Copyright ©2008). American Psychiatric Association. All Rights Reserved.1. Rais M, Cahn W, Van Haren N, Schnack H, Caspers E, Hulshoff Pol H, Kahn R. Am J Psychiatry. 2008;165:490-496.

Effects of Substance Abuse on White Matter and Cognitive Deficits in Schizophrenia (cont’d)

36

• Results– Patients with schizophrenia

who used cannabis had more pronounced brain volume reductions vs those who did not use and healthy controls

• Lateral and third ventricle enlargement; gray matter loss

– Could not be attributed to differences in baseline characteristics, antipsychotic medication use, or poorer outcome



• In order to understand the neurobiologic causes and consequences of relapse, study methodology must be improved to include:– More frequent assessments (scans)– Better/consistent definition of relapse – Prompt reassessment after relapse – Broader measures of psychosocial and physiologic

environment in parallel with scanning

Room for Improvement: Methodology of Schizophrenia Studies

37



1. Andreasen NC, Liu D, Ziebell S, Vora A, Ho BC. Am J Psychiatry. 2013;170:609-615.

• Background– Recurrent relapses believed to play role in progressive brain tissue

loss, but relationship with MRI measures not rigorously assessed• Hypothesis: relapses after initial onset may have a “toxic” effect on the brain

– Used to support importance of adherence

• Methods– Iowa Longitudinal Study of first-episode schizophrenia patients

• Patients (n = 202) with adequate MRI data available from scans (N = 659) obtained at regular intervals over an average of 7 years

– Computed measures of relapse number and duration from clinical follow-ups (every 6 months) and related to structural MRI measures

– Brain tissue volume association with dose-years also assessed

• Results– 157/202 patients experienced ≥1 relapse (29 had none)– For those who relapsed, average number of relapses was 1.64;

mean duration was 1.34 years, and maximum was 7.09 years

Relapse Duration, Treatment Intensity, and Brain Tissue Loss in Schizophrenia

38



1. Andreasen NC, Liu D, Ziebell S, Vora A, Ho BC. Am J Psychiatry. 2013;170:609-615.

• Early phases characterized by multiple relapses of shorter duration– Over time, number decreased, but subset of patients experienced

prolonged relapses

• Relapse duration closely related to loss of brain tissue in multiple brain regions (particularly frontal lobes) and total cerebral volume

• Counting number of relapses had no predictive value• Both relapse duration and antipsychotic treatment intensity

contributed to brain tissue loss (effects relatively small)– Treatment effects more diffusely distributed vs relapse effects

most strongly associated with frontal lobe

Relapse Duration, Treatment Intensity, and Brain Tissue Loss in Schizophrenia (cont’d)

39



• Relapse can be associated with negative clinical and physiological changes– Physiological changes can occur in response to multiple

factors, many of which are pervasive in patients with schizophrenia

• Relapse in schizophrenia is often overlooked/under-researched due to its commonality, but more research and attention are required:– Need for improved relapse prevention strategies and

expanded scientific discourse about this topic

In Summary…

40


DISCUSSION


QUESTIONS


CLOSING



DOES RELAPSE IN SCHIZOPHRENIA CAUSE NEURODEGENERATION? A SIMULCAST DEBATE & VIRTUAL FORUM TO EXPLORE THE EVIDENCEPeter Weiden, MDProfessor of Psychiatry UIC Medical Center Chicago, IL

Henry A. Nasrallah, MDSydney W. Souers Professor Chair Department of Neurology & PsychiatrySaint Louis University School of MedicineSaint Louis, MO

does relapse in schizophrenia cause neurodegeneration? a ......– schizophrenia is the 6 th leading...

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