Stimulant Stimulant psychosis:systematic psychosis:systematic review: review:

• Catherine curranCatherine curran

• Neetha ByrappaNeetha Byrappa

• Andrew McBrideAndrew McBride

• British journal of psychiatryBritish journal of psychiatry• 2004/185,196-2042004/185,196-204

Sensitisation: When & Sensitisation: When & Who?..Who?..

• Guttmann & Sargant,1937Guttmann & Sargant,1937 Connell’s Monograph, Connell’s Monograph, 19581958

• 1980,Ellingwood & Kilbey: ‘a form of kindling = 1980,Ellingwood & Kilbey: ‘a form of kindling = sensitisation’ producing psychosis similar to sensitisation’ producing psychosis similar to schizophrenia in repeated low dose stimulants abuseschizophrenia in repeated low dose stimulants abuse

• 1991:amphetamine epidemic Japan1991:amphetamine epidemic Japan

• Animal experiments: 1976Animal experiments: 1976

• Antithesis: Brabbins and Poole,1996,debatable Antithesis: Brabbins and Poole,1996,debatable outcome of early Rx. outcome of early Rx.

• Cochrane review,2004 : Lack early intervention studiesCochrane review,2004 : Lack early intervention studies

Aim and hypothesisAim and hypothesis

• Evidence for theory of sensitisationEvidence for theory of sensitisation

• Stimulant psychosisStimulant psychosis

Toxic type response

Chronic persisting type response

MethodMethod

• Human Studies: experimental and Human Studies: experimental and observational.observational.– No case series, cross sectionalNo case series, cross sectional

• Searches: Medline, PsycLIT, EMBASE.Searches: Medline, PsycLIT, EMBASE.

• Time: earliest up to 2001Time: earliest up to 2001

• TERMS used: cocaine, crack, amphetamine, TERMS used: cocaine, crack, amphetamine, methylphenidate, psychoactive drugs, stimulant methylphenidate, psychoactive drugs, stimulant drugs, drug induced psychosis, schizophrenia, schizo drugs, drug induced psychosis, schizophrenia, schizo affective.affective.

– MeSH exploded, references checked.MeSH exploded, references checked.

Types of studiesTypes of studies

• Experimental: Experimental:

• ObservationalObservational– LongitudinalLongitudinal

– Case – ControlCase – Control

Inclusion criteria – Inclusion criteria – ExperimentalExperimental

• Participants were give stimulantsParticipants were give stimulants

• Monitored for psychosisMonitored for psychosis

• Controlled circumstances of Controlled circumstances of administrationadministration

• Standardised measurements used Standardised measurements used to measure the psychosisto measure the psychosis

Inclusion criteria - Inclusion criteria - LongitudinalLongitudinal

• Cohort of users followed up for definitive Cohort of users followed up for definitive period of timeperiod of time

• Stimulant users well delineated from Stimulant users well delineated from othersothers

Inclusion criteria - Case Inclusion criteria - Case ControlControl

• Stimulants with psychosis Vs Stimulants Stimulants with psychosis Vs Stimulants onlyonly

• Stimulants with psychosis VS psychosis Stimulants with psychosis VS psychosis onlyonly

• Stimulants Vs Non – StimulantsStimulants Vs Non – Stimulants

• Identified and differentiated from other Identified and differentiated from other substance users.substance users.

ResultsResults

• Total studies : 84Total studies : 84

• Initial agreement on studies:Initial agreement on studies: 89% experimental studies89% experimental studies 82% longitudinal studies82% longitudinal studies 75% case control studies75% case control studies

Final agreement: 43 studiesFinal agreement: 43 studies 32 – experimental32 – experimental 7 – longitudinal7 – longitudinal 4 – case control4 – case control

Experimental studiesExperimental studies 32 total32 total

28 – single oral or IV doses of dexamph or 28 – single oral or IV doses of dexamph or methylphenidate to schizophreniamethylphenidate to schizophrenia 9/28 – control group9/28 – control group

4 - two or more oral or IV doses of stimulants4 - two or more oral or IV doses of stimulants 1 / 4 – heterogeneous group1 / 4 – heterogeneous group 2 / 4 – substance users group2 / 4 – substance users group 1 / 4 – RCT, 520 number,oral dexamphs for 20 weeks1 / 4 – RCT, 520 number,oral dexamphs for 20 weeks

ALL studies used standardised scales mostly BPRSALL studies used standardised scales mostly BPRS

Single dose experimentalSingle dose experimental

Response was brief Response was brief

few hoursfew hours

Response not reflected in the rating Response not reflected in the rating scales used to measurescales used to measure

Two or more doses – Two or more doses – experimentalexperimental

Strakowski, 1997Strakowski, 1997greater second dose greater second dose response in ‘controls’response in ‘controls’ No changes in psychosis groupNo changes in psychosis group

Casey et al ,1961 Casey et al ,1961 dexamph as adjunct dexamph as adjunct in treatment of schizophrenia. in treatment of schizophrenia. NO BenefitNO Benefit

Worsening of hostile belligerency, paranoid Worsening of hostile belligerency, paranoid belligerency and thought disturbancesbelligerency and thought disturbances

Results of experimental Results of experimental studies..studies..

Statistical analysis – from 26 studiesStatistical analysis – from 26 studies

Differences in psychotic responses Differences in psychotic responses between controls,those with between controls,those with schizophrenia in remission and schizophrenia in remission and schizophrenia with positive schizophrenia with positive symptoms.symptoms.

Results of experimental Results of experimental studies..studies..

51.4%51.4% Schizophrenia Schizophrenia with positive with positive symptomssymptoms

Positive or Positive or negativeP<0.0negativeP<0.0001001

Rx or NoRx Rx or NoRx

P= 0.80P= 0.80

28.3%28.3% Schizophrenia Schizophrenia in remissionin remission

10.2%10.2% controlscontrols

??

The Longitudinal studiesThe Longitudinal studies

Only 7 studies met the inclusion Only 7 studies met the inclusion criteriacriteria

Most studies were commonly Most studies were commonly excluded because of the presence excluded because of the presence of other substances abuseof other substances abuse

The Longitudinal studiesThe Longitudinal studies

2 – prescribed stimulants in narcolepsy /ADHD2 – prescribed stimulants in narcolepsy /ADHD

2 – follow up studies of cocaine users2 – follow up studies of cocaine users

1 – amphetamines re users with h/o psychosis 1 – amphetamines re users with h/o psychosis follow up follow up

1 – presenting with psychosis + amphetamine 1 – presenting with psychosis + amphetamine abuse follow upabuse follow up

1 – 10 year follow up study, Kwapil-1996, substance 1 – 10 year follow up study, Kwapil-1996, substance users and controls who scored highly on ‘Chapman users and controls who scored highly on ‘Chapman questionnaire psychosis proneness scale’questionnaire psychosis proneness scale’

Results of longitudinal Results of longitudinal studiesstudies

PawluckPawluck

19951995

5years5years 2/11 2/11

Premorbid Premorbid difficulties +family difficulties +family historyhistory

Cherland & Cherland & FitzpatrickFitzpatrick

19991999

5 years 5 years 9/192-mood 9/192-mood incongruent incongruent psychosispsychosis

11/192- mood 11/192- mood congruent psychosiscongruent psychosis

3 cluster of 3 cluster of symptoms identifiedsymptoms identified

Results of longitudinal Results of longitudinal studiesstudies

Carroll et alCarroll et al

19931993

1 year1 year No evidenceNo evidence

Kwapil Kwapil

19961996

10 years10 years 8000 screened8000 screened

193 psychosis prone193 psychosis prone

Cocaine users-12Cocaine users-12

Amphs – 11Amphs – 11

Power SMALL Power SMALL

Substance use not Substance use not predictive of predictive of psychosispsychosis

Case control studies: Case control studies: Stimulant users with & Stimulant users with & without psychosiswithout psychosis 4 studies : cocaine users4 studies : cocaine users

Greater duration and amount of abuse in Greater duration and amount of abuse in admission groupadmission group

72% reported psychosis with increased use72% reported psychosis with increased use

1 / 4 study unable to determine direction or 1 / 4 study unable to determine direction or causalitycausality

Greater duration in sensitised group, Greater duration in sensitised group, sensitisation linked to other features of sensitisation linked to other features of psychosispsychosis

Case control studies : Case control studies : psychosis with and without psychosis with and without stimulant abusestimulant abuse Age of onset of schizophrenia lower in Age of onset of schizophrenia lower in

schizophrenia group. 2 studiesschizophrenia group. 2 studies

Frequent hospitalisation – 1 studyFrequent hospitalisation – 1 study

Reduced negative symptoms – 2 studiesReduced negative symptoms – 2 studies

Paranoid themes more common, less Paranoid themes more common, less intense first rank symptoms – 1 studyintense first rank symptoms – 1 study

Cocaine users more likely to be paranoidCocaine users more likely to be paranoid

Case control studies: Case control studies: stimulant users Vs other stimulant users Vs other drugsdrugs Dalamu – 1999: 461 amphetamine Vs Dalamu – 1999: 461 amphetamine Vs

425 cannabis425 cannabis Psychosis: amphetamine and cannabis > Psychosis: amphetamine and cannabis >

opiate : 30% Vs 6%opiate : 30% Vs 6%

Psychotic profile on MMPI at discharge Psychotic profile on MMPI at discharge greater in stimulant group, 1977 and greater in stimulant group, 1977 and low sample size and many groups.low sample size and many groups.

Change in psychotic ratingsChange in psychotic ratings

0

10

20

30

40

50

60

70

80

Amph- oralAmphs -IVmethylphenidate

Less dosing with IV

Change in psychotic Change in psychotic ratingsratings

010

203040

506070

amph -oral

amph-iv

methylphenidateoverall

Change in psychotic Change in psychotic ratingsratings

0

10

20

30

40

50

60

70

80

90

increase no change

remission

active psychosis

control

Overall change in Overall change in psychotic ratingspsychotic ratings

0

50

100

150

200

250

300

350

400

increase no increase

overall number

overallpercentage

SENSITISATION SENSITISATION ?? There is very limited evidence There is very limited evidence

suggesting the existence of suggesting the existence of sensitisationsensitisation

Strakowski,97Strakowski,9722ndnd dose more BPRS dose more BPRS scoresscores

Brady et al,91Brady et al,91with time lower with time lower doses doses psychosispsychosis

The effect of stimulantsThe effect of stimulants

Presence of positive symptoms is likely Presence of positive symptoms is likely to worsen with use of stimulantsto worsen with use of stimulants

Antipsychotics have limited evidence in Antipsychotics have limited evidence in preventing deteriorationpreventing deterioration

Large enough dose invariably produces Large enough dose invariably produces acute brief psychotic reactionacute brief psychotic reaction

Stimulants,Cannabis > Stimulants,Cannabis > opiates opiates ?? ?sensitisation?sensitisation

?other factors: hospitalisation for ?other factors: hospitalisation for detoxdetox Less severe withdrawal features of Less severe withdrawal features of

amphs/ cannabisamphs/ cannabis

Difference in admission ratesDifference in admission rates

Difficulties in follow up Difficulties in follow up studies….studies….

Widespread use of Widespread use of methamphetamine IV in 1 Japanese methamphetamine IV in 1 Japanese studystudy

Sample was possibly contaminated Sample was possibly contaminated by schizophrenic individuals using IV by schizophrenic individuals using IV abuse, because of chronic persistent abuse, because of chronic persistent psychosis effect results.psychosis effect results.

Antipsychotics use?Antipsychotics use?

Limited evidenceLimited evidence

1 small open label trial1 small open label trial

8 of the cohorts with chronic 8 of the cohorts with chronic psychosis with persistent use did psychosis with persistent use did not relapse because of 3 mg not relapse because of 3 mg haloperidol/dailyhaloperidol/daily

Animal studiesAnimal studies

Rats, Rhesus monkeysRats, Rhesus monkeys

Stimulant induced stereotype behaviours produced Stimulant induced stereotype behaviours produced and initiated - Initiation phase / sensitisation takes and initiated - Initiation phase / sensitisation takes place, controls can be blocked with low dose place, controls can be blocked with low dose antipsychotic medicationantipsychotic medication

Low dose stimulants given during the expression Low dose stimulants given during the expression phase phase the test animals produces enhanced the test animals produces enhanced psychosis responses with timepsychosis responses with time

Lieberman 1990,Castner &Goldman 1999, Meng 1998Lieberman 1990,Castner &Goldman 1999, Meng 1998

Human experimental Human experimental Unethical Unethical

Summary of evidence for Summary of evidence for sensitisationsensitisation

Sato et al – low dose haloperidol Sato et al – low dose haloperidol prevented relapse of psychosis even prevented relapse of psychosis even after relapsing into dexamph abuseafter relapsing into dexamph abuse

Animal studiesAnimal studies

Evidences against Evidences against sensitisationsensitisation

Seibyl – stimulant use started after Seibyl – stimulant use started after psychotic illnesspsychotic illness

Conclusions:Conclusions:

StimulantsStimulantsbrief psychotic reaction, few brief psychotic reaction, few hourshours

More problems to individuals with active More problems to individuals with active psychosis, with little benefits of antipsychotic psychosis, with little benefits of antipsychotic treatmenttreatment

Treatment should aim at: abstinence, Treatment should aim at: abstinence, medication till acute symptoms settle medication till acute symptoms settle

Regular low dose of anti psychotics in >than Regular low dose of anti psychotics in >than 1 episode of psychosis.1 episode of psychosis.

Hypothesis ?Hypothesis ?

Chronic psychosis following Chronic psychosis following amphetamine use has lower quality amphetamine use has lower quality of evidence in human studies.of evidence in human studies.

Only Supported by experimental Only Supported by experimental animal studiesanimal studies

Even though Poor quality Even though Poor quality evidence exists for evidence exists for sensitisation occurring in sensitisation occurring in humans, it is Important that humans, it is Important that people using stimulants people using stimulants should be assertively should be assertively managedmanaged