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Improving Adherence in Patients with Schizophrenia

Professor Tarek A. OkashaM.D., M.S. (N&P), D.P.P., F.A.P.A., Dip. I.A.B.M.C.P.

Professor of PsychiatryDirector of the WPA Collaborating Center for Research and Training in PsychiatryInstitute of Psychiatry, Faculty of Medicine, Ain Shams University, Cairo, Egypt

President Egyptian Alzheimer SocietyEditor In-chief Middle East Current Psychiatry Journal

Major health problem

• Risk: 1% of the population.• All over the world.• Patients occupy 50-60% of all mental health

beds.• 2/3 of homeless people.

• Schizophrenia is a complex and disturbing disorder.

• A subject of intense scientific scrutiny for over a century, pursued from every histo-pathological, molecular, social, and psychological perspective

• The circles of investigation are both ever widening encompassing genetics, infections, toxins, immigration, social status, and intergenerational exposures—and ever narrowing, as the focus now zooms in on specific domains of dysfunction

Scope of Research

Malaspina D, 2013

Cognitive symptoms:attentionmemoryexecutive functions

(eg, abstraction)

Positive symptoms:delusionshallucinationsdisorganized speechcatatonia

Clinical Features of Schizophrenia and Impact on Over all Functions

Occupational

Interpersonal

Self-care

Social

Work

Negativesymptoms:affective flatteningalogiaavolitionanhedonia

Mood symptoms:dysphoriasuicidalityhelplessness

Mesocortical /prefrontal cortex

Symptoms & Brain Regions

(Conlry.R, 2007)

Positivesymptoms

Mesolimbic

Negativesymptoms

Nucleus accumbens reward circuits

Cognitivesymptoms

Dorsolateral prefrontal cortex

Dopamine

Aggressivesymptoms

AmygdalaOrbitofrontalcortex

AffectivesymptomsVentromedial

Prefrontalcortex

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Early & Late Brain Loss

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Staal et al., Am J Psychiatry 2001;158(7):1140-1142

Bad evolution> 15 years sick

hospitalization > 50%in the past 3 years

Good evolution15 years sick

hospitalization < 10%in the past 3 years

outpatient X 1 year

Normal

Grey Matter Loss: Bad Vs. Good Evolution

• Research reports a very intriguing finding for schizophrenia and psychosis using direct imaging of retinal micro-vessels in over 900 members of the Dunedin birth cohort at age 38.

• Probands with schizophrenia, and even those with only transient psychotic symptoms in childhood, had significantly wider venular calibers than other cohort members, including those with persistent depression.

• This new finding builds on a long history of inquiry into the association between micro-vessel abnormalities and the risk for schizophrenia

Malaspina D, 2013Norris AS et al, 1964

Vascular Abnormality

• The widened microvenules could arise from prenatal and early-life infections or hypoxia, or from other adversities, such as susceptibility genes that interact with infections, stress, or toxic exposures, including cigarette smoking.

• The next era in psychiatry must approach schizophrenia as a systemic disease that first presents as altered behavior rather than as a brain disease per se.

• We might feasibly learn more about the disease from its comorbidities than from enhanced measures of brain functioning.

Malaspina D, 2013

The widened microvenules

Mukherjee S et al, 1989

• People with schizophrenia have a more limited general cognitive resource than average and that this constrains the performance of a wide range of specific cognitive functions.

• Information processing )معالجة المعلومات( speed explains up to 25% of the variance in the general ability.

• Reduced processing speed may be one of the fundamental causes of general cognitive impairment in schizophrenia.

Information Processing

Joyce,2013, BJP

• Speed of processing is highly dependent on the integrity of myelinated axons.

• Measured by magnetic resonance diffusion tensor imaging.

• IQ correlated with an index of white matter integrity across 12 major white matter tracts.

• In schizophrenia white matter development is abnormal linking generalized cognitive impairment to a neuro-developmental risk factor.

Joyce,2013, BJP

IQ and white matter

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Cognitive Impairment and Negative Symptoms have Adverse Effects on

many Aspects of Daily Living• Excessive dopamine blockade is a common cause of

‘negative symptoms’

• Sedation due actions at Histamine H1 receptors may also contribute

• Anticholinergic properties of antipsychotic drugs or anticholinergic medications increase cognitive impairment

• Depression and hopelessness impact adversely on both

Green et al, 1997; Kane and Tamminga, 1998; Gallhofer et al, 2001; Krieger et al, 2001; Brekke et al, 2005

MATRICS• A battery of neurocognitive tests, the MATRICS

consensus Cognitive Battery, recommended by NIMH to the FDA and now viewed as an instrument with broad acceptance for clinical drug trials.

• MATRICS measures 7 cognitive functions:1. Speed of processing2. Attention and vigilance,3. Working memory4. Verbal learning5. Visual learning 6. Social cognition7. Reasoning and problem solving

MATRICS Consensus Cognitive Battery measures

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Typical course of schizophrenia illness and theopportunity for early effective intervention

Evidence is mounting for a lasting beneficial effect ofearly intervention programs2

3

E Kraepelin1 Years

1. Kraepelin. Manic-Depressive Insanity and Paranoia (trans. R.M.Barclay). Edinburgh: Livingstone.1919;2. Henry et al. J Clin Psychiatry 2010;71:716-728; 3. Lieberman. J Clin Psychiatry 1996;57( suppl 11):68-71

Comparisons between the clinical and social outcome of Schizophrenia during

three periods between 1900 and 1980

15 19

6249

14 55

50 41 60

SatisfactorySocial Outcome

Dead

Deteriorated

Recovered

%

0%

100%

% %

%

%% %

%%

% % %

%% %

%%

1900-1929 1930-1949 1950-1980OverallDeveloped Developing Shepherd et al (1989)

3333

68

43

57

20

33

29

%

Long-term Outcomes in Schizophrenia

Improve self-careReduce aggression

Reduce self-injury

‘Survive’ out of hospitalDe-institutionalisation

Reduce relapseMinimize positive symptoms

Increase ‘stable’ periodsMinimize negative symptoms

Pre-1960s

1960-70s

1980s

1990s

Focus on functionalityPotential for remission

2000+

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Definition of Remission

1

2

3

4

5

6

7

Absent

Minimal

Mild

Moderate

Moderate severe

Severe

Extreme

• On all 8 PANSS items– P1 Delusion– P2 Conceptual disorganization.– P3 Hallucinatory behaviour.– G9 Unusual thought content.– G5 Mannerism & Posturing.– N1 Blunt affect– N4 Social withdrawal.– N6 Lack of spontaneity.

At least6

monthsPANSS scale level of MILD or lessAndreasen, N.C. et al.(2005).

Consequences of relapse

Psychosocial1• Risk of self harm and harm

to others• Relapse may:

- Jeopardize interpersonalrelationships

- Interrupt employment oreducational status

- Diminish personal autonomy- Contribute to stigma

Biological2• Is psychosis neurotoxic?

1. Kane J Clin.Psychiatry 68 Suppl 2007;14:27-30;2. Wyatt Schizophr Bull 1991;17:325-351

Neurobiological findings intreatment-naïve, first-episode patients

1600p=0.001

1400

1200

1000

800

600

400

200

0

Patients (n=20)Controls (n=26)

p=0.05

p=0.01

Treatment-naïve,first-episodepatients have

reduced wholebrain, white

matter and greymatter volume,compared with

controls,significantly

related to lowerIQ

Whole brain White matter Grey matter

Rais et al. PsycholMed 2012; 42:1847-56

Relapses are associated with adeteriorating course of illness

• With each relapse, recovery can be slowed and course ofillness worsened1,2

- Loss of functional achievements; more difficult to re-establish previousgains; illness may become more resistant to treatment

Dutch 15-year prospective study25

20

15

10

5

01st episode (n=82)

of first-episode patients3

2nd episode (n=49) 3rd episode (n=27) 4th episode (n=15)Episode number

The probability of chronicity, in terms of continuing psychoticsymptoms, increases with each subsequent episode3

1. Kane. J Clin Psychiatry 2007;68(suppl 14):27-30; 2. Kane. CNS Spectr 2007;12:21-26;3. Wiersma et al. Schizophr Bull 1998;24:75-85

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Changes in brain volume correlate withcognitive functioning

• Correlations between medication-related change in white matter volume andreaction time performance on higher-order executive tasks

1600

1400

1200

1000

800

600

400

200r= -0.431, p=0.045

2500

2000

1500

1000

500

r= -0.465, p=0.029

Medication-relatedpreservation of

white mattercorrelates with

higher-ordercognitive

functioning

-2.00 -1.50 -1.00 -0.50 0.00 0.50 1.00 1.50Change in volume

The relationship betw een change in w hite mattervolume and reaction time on the Tw o-Back task

(a w orking memory task)

-2.00 -1.50 -1.00 -0.50 0.00 0.50 1.00 1.50Change in volume

The relationship betw een change in w hite mattervolume and reaction time on a Set-Shifting task

(a measure of mental f lexibility)

Risperidone long-acting injectable, n=11; Risperidone oral, n=13; healthy controls, n=14

Reproduced w ith permissionBartzokis et al. Schizophr Res 2011;132:35-41

What is the evidence for illnessprogression after relapse?

• Treatment response is better in first episode than inmulti-episode patients1

• 7-year follow-up study:2- 80% deteriorated– Degree of deterioration significantly correlated with the number of relapses

• 15-year follow-up study:3- Striking finding: one in six patients did not remit after each episode

• Preliminary study:4- Increased times to treatment response in succeeding episodes

1. Robinson et al. Arch Gen Psychiatry 1999;56:241-247; 2. Curson et al. Br J Psychiatry 1985;146:474-480;3. Wiersma et al. Schizophr Bull 1998;24:75-85; 4. Lieberman et al. Neuropsychopharmacology 1996;14(suppl 3):13S-21S

Relapse duration, treatment intensity andbrain tissue loss in schizophrenia

Prospective longitudinalstudy from 202 patients

Analysis of the effect ofrecurrent relapses andtreatment intensity onprogressive brain loss

after the onset ofschizophrenia

N=659 scans,obtained at regularintervals over an

average of 7 years

Greater relapse durationwas significantly

associated with tissueloss in some brain

regions

These include onegeneral measure,decrease in total

cerebral volume, aswell as more specific

measures; inparticular, frontallobe and white

matter are moreprominently affected

Treatment intensity wasshown to have a

relationship with brainvolume changes

Statisticallysignificant

relationships wereobserved in the total

cerebral volume,ventricle:brain ratio,total temporal and

frontal volumes andparietal white matter

Data suggests that extended periods of relapse may have a negativeeffect on brain integrity in patients with schizophrenia

Andreasen et al. Am J Psychiatry. 2013 Apr 5 [Epub ahead of print]

10090

Relapse rates after a firstschizophrenia

82

episode of

86

80

7060 545040

78

302010

02 years 5 years 5 years 4 years

First relapse Second relapse Third relapse

Prospective, longitudinal study of first-episode schizophrenia patients

n=104

Robinson D, et al. Arch Gen Psychiatry 1999;56:241-7

Antipsychotic discontinuation after a firsthospitalization for schizophrenia

• Nationwide cohort study conducted 2000-2007 in Finland (n=2588)

Patients0% 20% 40% 60% 80% 100%

Collected a prescription during the first30 days after discharge

Continued their initial treatment for 30days or longer

58.2

45.7

Tiihonen et al. Am J Psychiatry 2011;168:603-609

Uninterrupted therapy optimises outcomes

Kane JM. N Engl J Med 1996;334:34–41

Relapse after 1 year of continuous or intermittent maintenance therapy with conventional antipsychotics

0 10 20 30 40 50 60

Relapse rate (%)

Schooler et al., 1993

Pietzcker et al., 1993

Jolley et al., 1989, 1990

Herz et al., 1991

Carpenter et al., 1990

2032

1535

730

1029

3355

Oral medication

Continuous

Intermittent

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Medication compliance is poor inpatients with Schizophrenia

Coldham EL, et al. Acta Psychiatr Scand 2002;106:286–90

Nearly two-thirds of schizophrenia patients have compliance problems

39% Non- compliant

41% Compliant

20% Partially compliant

Stopping antipsychotic medication is themost powerful predictor of relapse

Survival analysis: risk of a first or second relapse when not takingmedication ~5 times greater than when taking it

6

5

4

3

2

1

0

n=104

4.89 4.57

First relapse Second relapse

Robinson D, et al. Arch Gen Psychiatry 1999;56:241-7

Poor adherence to oral antipsychoticmedication in schizophrenia

1009080706050403020100

Rated as Compliant

67.5

38.1

10.3

94.7

Pill Count Patient MEMS Cap Clinician

*Criterion: ”took all pills.”†Criteria: >70% of days (MEMS cap); score >4 on clinician rating scale.*Lam YWF et al. Poster presented at: Biennial Meeting of ICOSR; March 29 -April 2, 2003;Colorado Springs, Colorado.

†Byerly M et al. Poster presented at: Annual Meeting of APA; May 17-22, 2003; San Francisco, California.

*To determine the feasibility of using the Medication Event Monitoring System (MEMS) to estimate medication compliancein patients with schizophrenia or schizoaffective disorder.

1Linden M, et al. Schizophr Bull 2001;27(4):585–962Kozuki Y, et al. West J Nurs Res 2003;25(1):57–74

3Perkins DO. J Clin Psychiatry 2002;63:1121–84Lacro JP, et al. J Clin Psychiatry 2002;63:892–909

5Robinson D, et al. Schizophr Res 2002;57:209–19

Why are patients non-adherent?• Factors associated with non-adherence include:

- Poor insight 2,3

- Negative attitude 3

- Substance abuse 4

- Shorter illness duration 1,4

- Inadequate discharge planning/after care environment 4

- Poor therapeutic alliance 4

1Linden M, et al. Schizophr Bull 2001;27(4):585–962Kozuki Y, et al. West J Nurs Res 2003;25(1):57–74

3Perkins DO. J Clin Psychiatry 2002;63:1121–84Lacro JP, et al. J Clin Psychiatry 2002;63:892–909

5Robinson D, et al. Schizophr Res 2002;57:209–19

Why are patients non-adherent?

• Factors associated with non-adherence include:

- Youth 1

- Poor pre-morbid cognitive functioning 5

- Barriers to treatment (e.g. ease of access totreatment, degree of family or social support) 3

- Side effects 3,5

Therapeutic Goals in Schizophrenia

Regainfunctioning

Weiden.P.J, 2007

Improve quality of lifeSocial & vocational

functions

Maintain stability, effective relapse prevention minimize side effects, promote adherence

Symptoms Remission (rapid control of +ve symptoms)Prevention of non-adherencePreservation of cognitive function

Recovery

Kopolowicz, 2008

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Therapeutic Alliance

• Psycho-education for the patient• Psycho-education for the family• CBT for psychosis• Cognitive enhancement therapy (CET)

(cognitive remediation)• Social Skill Training• Rehabilitation

Treatment Guidelines

Conclusion• Currently we have more than 54 antipsychotics,

oral, drops, depot IM, disintegrated tablets, sublingual and Extended Release.

• FGA about 40 • SGA about 14• Treatment effectiveness and prognosis are

inextricably interwoven• The psychiatrists selection depends on efficacy

(Minimal difference), adverse effects profile, tolerance, plateau plasma level, ease of administration, and cost.

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