Cognitive impairment in schizoaffective disorder:greater or lesser impairment than schizophrenia or

bipolar disorder?

Carla TorrentBipolar Disorder ProgramHospital Clínic Barcelona

IRPB, Lisbon, 26th april 2015

Neurocognition and schizoaffectivedisorder (SAD)

One of the aims of research on neurocognition is tovalidate these diagnostic categories.

¢ The classical, kraepelinian classification of mental disordersmakes a distinction between dementia praecox and manic-depressive disorder.

¢ In clinical practice, some patients present a mixture ofschizophrenic and affective signs and symptoms.

¢ In more recent nosologic systems, a new diagnosticcategory: schizoaffective disorderØ A form of schizophrenia (SZ)Ø A form of bipolar disorder (BD)Ø An independent disorderØ A disorder intermediate between SZ and BD

Psychiatric disorders are associated withcomplex patterns of cognitive impairment

Adapted from Millan et al., Nature, 2012

• Attention

• Executive function

• Verbal learning and memory

• Speed of processing

• Social cognition

• Language

Genetic Epigenetic Developmental Environmental

Cognitive impairment by cognitive domains

Millanet al, 2012

Epidemiological, genetic, neuroimaging and neurocognitive studies show similaritiesbetween SZ and BD.

Cognitive impairment in SQZ and BD

¢ Prevalence 85-100%¢ Impairment across domains deficits 1-2

SD (verbal memory and processingspeed)

¢ Present at illness onset and remainrelatively stable over the course of theillness

¢ Do not change substantially withantipsychotic medications

¢ Account for much of the functionaldisability associated with the illness.

¢ Broad cognitive impairment is notattributable to reduced general intellect

¢ Prevalence 40-60%¢ Cognitive impairment during

remission¢ Impairments present early in the

course of illness¢ Do not change substantially with

available treatments¢ Bipolar I > Bipolar II¢ Higher number of manic episodes¢ Related to functional dysfunction¢ Increased in patients with history

of psychotic symptoms

Schizophrenia Bipolar disorder

Lewandowski et al, Psych Med, 2010

Cognitive development in subjects withschizophrenia, bipolar disorder and healthycontrols

A longitudinal study of cognitive functioning inschizophrenia

Dickerson et al, Schiz Res, 2014

N=132Mean age: 43.7 years

The results showed an absence ofcognitive decline for most measuresand modest gains in some measures

over a period of up to 10 years

Reichenberg et al, Am J Psychiatry, 2002

Premorbid intellectual, behavioral and languagefunctioning in schizophrenic, schizoaffective andnonpsychotic bipolar patients

SAD showed premorbid deficits on 3 of 4 intellectual measures, as well as on four of 5 behavioral measures.Future SAD scored worse than future BD on all four premorbid intellectual measures and on the reading andcomprehension tests.

Reichenberg et al, Schizophr Bull, 2009

Prevalence of NP normality ranged between:16% and 45% in schizophrenia,

20% and 33% in schizoaffective disorder,42% and 64% in bipolar disorder,and 42% and 77% in depression

Neuropsychological function and dysfunctionin schizophrenia and psychotic affectivedisorders

N=235

All groups demonstrated impairments inall cognitive domains. However, SZ

patients were more impaired than theother groups.

¢ Cognitive deficits in SAD do not differ significantlyfrom those of SZ.

¢ In the absence of comparisons with BD, noconclusions can be drawn with regard to SAD as aform of SZ or an intermediate disorder betweenBD and SZ.

¢ In some studies SZ and SAD patients were pooledtogether.

Studies comparing SAD with SZ

¢ In other studies, patients with psychotic disorders andthose with affective disorders presenting psychoticsymptoms were pooled together.Beatty et al, 1993; Bornstein et al, 1990; Evans et al, 1999; Glahn etal, 2006; Goldstein et al, 2005; Gooding et al, 2002; Jeste et al, 1996;Miller et al, 1996; Stip et al, 2005, Simonsen et al, 2009

¢ Other studies show that SAD perform better than SZon neuropsychological measuresHeinrichs et al, 2008; Stip et al, 2005; Szoke et al, 2008

Studies comparing SAD with SZ

Study Characteristics Findings

Evans et al, 1999 N=154 SZN=29 SADN=27 non psychotic mooddisorder

SAD and SZ more impaired that non psychoticmood disorder patients,No significant differences between SZ and SADPsychotic spectrum

Glahn et al, 2006 N=15 SZN=15 SADN=15 BD non psychotic

Lack of significant differences between the groupsPsychotic spectrum

Szoke et al, 2008 N=26 SADN=52 BP with psychosisN=51 BDN=65 controls

Executive functions: non significant differences in aexecutive measure (TMT)SZ<SAD<BP with psychosis<BD<C on theWCST perseverative errorsContinuum in psychosis

Reichenberg et al, 2009 N=94 SZN= 15 SADN=78 psychotic BDN=48 psychotic MD

Greater impairment in SZ and SAD incomparison to both psychotic mood disorders,no differences between SZ and SAD

Neuropsychological studies comparing SAD withBD

Cognitive deficits are common to the psychotic spectrum regardless of specificdiagnostic

N= 28 SAD

N= 32 BP

A worse cognitive outcome of SAD compared to BP patients in remissionStudentkowski et al., 2010

Schizoaffective patients showed more impairment thanbipolar patients on tests of attention, psychomotor speedand memory, but there were not significant differences on

measures of cognitive flexibility

N=34 SAD N=41 BD without psychosis N=35 healthy controls

¢ SAD showed greater impairment than controls and BDin verbal memory, executive functions and attentionalmeasures.

¢ BD performed similar to the controls except for verbalfluency.

¢ SAD carries more neurocognitive impairment thannonpsychotic BD and more occupational difficulties.

¢ Lithium and antipsychotics did not seem to influenceresults.

¢ History of psychosis was the best predictor of verbalmemory impairment.

Cognitive functioning in SAD and nonpsychotic BD

N=102 SZN=27 SADN=75 psychotic BDN=61 non psychotic BDN=280 heatlhy controls

N=545

Simonsen et al, 2011

Simonsen et al. Schizophr Res, 2011

¢ SZ, SAD, psychotic BD < nonpsychotic BD, HC¢ Nonpsychotic BD < HC (only on processing speed)¢ Psychotic BD < nonpsychotic BD (verbal fluency and

interference control).¢ Neurocognitive dysfunction in bipolar and SZ spectrum

disorders seems to be determined more by history ofpsychosis than by DSM-IV diagnostic category orsubtype.

¢ Neurocognition as an endophenotypic marker for thesedisorders.

Results

ü SAD schizomanic = 26

ü BD manic =51

(psychotic/ non-psychotic)

üAcute Schizophrenic =45

ü Controls=65

üWAIS-III / TAP

üPsychopathological assessment

(Young, PANSS)

üWechsler Memory Scale-III (WMS)

üAssessment Dysexecutive

Syndrome (BADS)

The aim of the study was to examine whether there is a pattern ofdecreasing cognitive impairment from SZ to SAD to BD.

Amann et al, 2011

Executive dysfunction and memory impairmentin schizoaffective disorder

Controls SADschizomanic

SchizophrenicBD manic

SADschizomanic

Controls BDmanic

Schizophrenic

Memory (WMS-III)

No differences between patient groups oncomposite score, verbal memory and

working memory.

Visual memory differences between SZ and HC.

Executive functions (BADS)

All 3 patient groups were moreimpaired in the BADS than controls.

Differences in Action program test:SZ < Bip= SAD

Amann et al, 2011

Executive dysfunction and memory impairmentin schizoaffective disorder

¢ Out of 10 tests, there was only one significant difference:SAD and BD patients peformed better than the SZpatients on the Action Program Test of the BADS, whichtests problem-solving skills.

¢ SZ, SAD and manic patients show a similar degree ofexecutive and memory deficits in the acute phase of theillness.

¢ No significant differences were found between psychotic(n=22) and nonpsychotic (n=29) bipolar patients.

¢ These findings do not support a categorical differentiationacross different psychotic categories with regard toneuropsychological deficits.

Executive dysfunction and memory impairmentin schizoaffective disorder

¢ Cognitive functioning in affectivepsychosis and schizoaffective disorder ismuch less studied compared withschizophrenia.

¢ 31 studies that compared theperformances of people with SZ(n=1979) with that of those withaffective psychosis or schizoaffectivedisorder (n=1314) were included.

¢ In 6 of 12 cognitive domains, peoplewith SZ performed worse than peoplewith schizoaffective disorder oraffective psychosis.

Bora et al, BJP 2009

Cognitive functioning in schizoaffectivedisorders

¢ Between-group differences were driven by a higherpercentage of males, more severe negativesymptoms and younger age at onset of illness in SZ.

¢ Neuropsychological data do not provide evidencefor categorical differences between SZ and othergroups.

¢ However, a subgroup of individuals with SZ withmore severe negative symptoms may be cognitivelymore impaired than those with affectivepsychosis/schizoaffective disorder.

Bora et al, BJP 2009

Cognitive functioning in schizoaffectivedisorders

Two different alternatives of the Kraepelinian dichotomy:¢ The most severe SZ and psychotic BD may lie on the

opposite ends of a continuum, with only a quantitativechange in the degree of cognitive dysfuntion along thecontinuum from SZ and psychotic mood disorders.

¢ Only people with SZ with more severe negative symptomsare more impaired in certain domains (‘deficit’ SZ):categorical distinction between a subgroup with pooroutcome SZ and other psychotic disorders includingpeople with SZ with a good prognosis.

Cognitive functioning in schizoaffectivedisorders

Bora et al, BJP 2009

Cross-diagnostic cognitive study

Hill et al. AJP, 2013

SZ: 293

SAD: 165

Psychotic BD: 227

Healthy Controls: 295

Robust neuropsychologicalimpairment are present in SZ

and psychotic BD. Theseverity of cognitive across

psychotic disorders wasconsistent with a continuum .

with SZ having greaterimpairment than SAD and

SAD greater than BD

¢ Available evidence strongly supports that a generalized deficit ispresent across psychotic disorders that differs in severity moreso than form.

¢ Cognitive performance in groups of psychotic patients may beinfluenced by the degree to which they are symptomatic at thetime of testing (8-12 weeks of remission before testing).

¢ SAD vs. BD: One possible reason for the divergent findings maybe the presence or absence of psychotic symptoms in BD.

¢ Findings suggest that SZ, SAD and BDP are on a neurobiologicalcontinuum.

Conclusions

¢ Cognitive testing as well as functional assessment may be usefulin clinical practice to determine the extent of difficulties,beyond diagnosis or subtypes.

¢ A more complex, mixed, dimensional-categorical model couldbetter explain the available data.

¢ Early detection and intervention of cognitive deficits areessential to reduce disability in SZ, SAD and BD (optimizingindividualized pharmacological treatment + CR). Cognitiveremediation has at least equivalent benefits in affective andschizoaffective disorder as demonstrated in schizophrenia.

Conclusions

Antoni Benabarre

Mar Bonnín

Francesc Colom

Mercè Comes

Marina Garriga

Jose M Goikolea

Iria Grande

Diego Hidalgo

Esther Jiménez

Anabel Martinez-Arán

Andrea Murru

Isabella Pacchiarotti

Rosa Palaus

Dina Popovic

María Reinares

Jose Sánchez-Moreno

Brisa Solé

Carla Torrent

Imma Torres

Marc Valentí

Èlia Valls

Cristina Varo

Eduard Vieta

Ackowledgements

Pro-cognitive drugs?ü Neurotrophic and neuroprotective effects of lithium, valproateand new antipsychotic drugs counteracting possibleneurodegenerative effects of the illness.

üAtypical antipsychotics may improve cognition increasingprefrontal dopaminergic transmission (procholinergic effects):some evidence in SZ, limited or null in BD.

üOther procholinergic agents may be useful (rivastigmine,galantamine, nicotinic agonists).

üPotential use of psychoestimulants (methylphenidate, modafinil)in comorbid ADHD patients.

üOngoing studies focused on dopaminergic agonists(pramipexole) and antiglutamatergic agents (memantine) as newpharmacological strategies.

Solé y cols, , Eur Neuropsychopharm, en prensa

Posibles tratamientos para las disfuncionescognitivas en depresión unipolar

Modafinil (TDAH y SQZ)MemantinaGalantaminaDonepeciloEscopolaminaVortioxetinaDesvenlafaxinaEritropoietina (EPO)LisdexamfetaminaOxitocina intranasal

Omega-3S-adenosil-metioninaRehabilitación cognitivaEjercicio físicoTécnicas no invasivas deestimulación cerebralKetaminaEsketaminaLaniceminaGlyx-13