Questions.

1
Questions.

• What is the most difficult comorbidity
  (psychiatric substance misuse) to manage?
• In a patient with comorbid substance misuse, what
• Antipsychotic
• Antidepressant
• Mood stabiliser
• Pharmacological treatment for their substance
  misuse
• do you favour and why?

2
Treating patients with comorbid substance abuse.
Dr Anne Lingford-Hughes Reader in Biological
Psychiatry and Addiction, University of
Bristol Hon Consultant Bristol Specialist Drug
and Alcohol Service, AWP
3

• It has been proposed that the implicit hope of
  pharmacotherapy is to result in improvement in
  psychiatric symptoms that will
• help make the patient more accessible to
• psychosocial treatment for substance abuse,
• and
• reduce the patients vulnerability to relapse
  to substance abuse by diminishing symptoms such
  as psychosis, depression, or anxiety.
• (Weiss et al 1995).

4
Schizophrenia
5
Schizophrenia.

• prevalence of substance abuse in schizophrenia
• 47 (ECA study) 37 alcohol 23
  cannabis 13 stimulants/hallucinogens
• 3 times rate of general population
• Characteristics
• greater users of services - male
• earlier age of onset - depression
• more positive symptoms - suicide
• poor treatment response - homelessness
• once abstinent have a better prognosis than other
  frequently hospitalized schizophrenics

6
s
Hunt et al 2002
Hunt et al 2002
7
Theories on co-occurrence.

• Self-medication now is little support
• of psychiatric symptoms psychosis, dysphoria,
  negative symptoms
• of prescribed drug side effects motor side
  effects (extrapyramidal)
• of illicit drug effects
• Stress model
• Neurobiological vulnerability interacts with
  environmental stressor (substance misuse)
• Accumulative risk factor
• People with scz have risk factors for SUD e.g.
  poor cognitive, social, vocational function,
  poverty
• comorbid addiction vulnerability eg dysfunction
  in reward circuitry
• abuse substances because they find them rewarding
  and fail to anticipate or respond to the negative
  consequences

8
Self-medication negative reinforcement
Neuropathology of schizophrenia
Substance abuse vulnerability
Symptoms of schizophrenia
Primary Addiction Hypothesis positive
reinforcement
Neuropathology of schizophrenia
Substance abuse vulnerability
Symptoms of schizophrenia
extra reward valence
9
Antipsychotic medication for schizophrenia and
substance abuse.

• Typical antipsychotics
• Animal studies show increased self-administration
  of cocaine or amphetamine
• In schizophrenia
• may be more resistant
• may cause side effects increasing substance abuse
• patients with schizophrenia may be more
  susceptible to motor side effects
• less compliant

10
Am J Add, 2006

• Review of VA case notes
• Addiction severity index used to assess clinical
  change in patients with schizophrenia SUD.
• No change in ASI in those maintained on or
  switched to typical
• Decrease in ASI seen in those maintained on or
  switched to atypical (olanzapine, risperidone,
  quetiapine)
• However comparison to those maintained on
  typicals was not significant
• Therefore data do not suggest that atypicals (in
  absence of other SUD treatment) are effective in
  reducing comorbid substance misuse in
  schizophrenia

11
Atypicals little information, tolerability

• Olanzapine - mixed
• Reported to lead to complete remission of
  substance abuse in 70 of pts with schizophrenia
  / schizoaffective disorder switched from typical
  antipsychotic partial remission in 30.
• No difference to haloperidol in cocaine use, or
  in psychiatric outcome but lower craving with
  haloperidol 10mg
• In alcohol misuse, can reduce craving in lab
  setting

12

• Trend in data shows that patients with SUD ve
  history respond more poorly to antipsychotics
  than SUD ve _at_ 12 weeks PANSS.
• Suggestion that those AUD ve respond less well
  to olanzapine than AUD ve not seen with
  haloperidol
• SUDve are less likely to complete 12 weeks of
  haloperidol not seen with olanzapine.

13

• No data re substance misuse reported!

14
Other atypicals little information

• Risperidone
• Case reports - improved opiate and stimulant
  (cocaine) abuse
• 6 week open label vs typicals greater reduction
  in cravings relapse to cocaine misuse.
• Naturalistic study safe, tolerated, may reduce
  cocaine craving.
• Compared with clozapine, patients on risperidone
  were less likely to be abstinent from alcohol or
  cannabis (54 vs 13).

15
Atypicals continued

• Quetiapine
• An open-label, uncontrolled trial showed
  significant improvements in substance abuse,
  psychiatric symptoms, extrapyramidal symptoms,
  and cognition
• In switch from typicals, quetiapine associated
  with reduced drug craving stimulants but not
  use.
• Aripiprazole
• In pilot studies reported to decrease cravings
  for and use of alcohol and cocaine.

16
Clozapine.Case reports, retrospective surveys,
naturalistic studies.Most data available for an
atypical.

• alcohol, cocaine, hallucinogens, cannabis,
  nicotine
• 50 of patients treated with clozapine were still
  abstinent from alcohol 18 months after hospital
  discharge.
• 80 of patients treated with clozapine reduce
  their substance, including alcohol and nicotine,
  abuse.
• Useful also in relapse prevention (8 vs 40
  Brunette et al 2006)

17
Why clozapine ?

• reduced need to self-medicate psychiatric
  symptoms and side effects of medication
• antidepressant so improved negative symptoms
• greater insight into the negative consequences of
  their substance abuse and improved psychosocial
  functioning
• its pharmacology
• 5HT2C antagonism stimulation of this receptor
  may result in craving and drinking
• Weak D2 antagonism, potent antagonism of
  noradrenergic a2 receptor, increase in NA.

18
Schizophrenia.

• Summary
• Typical antipsychotics may not improve substance
  misuse and may even contribute to it
• Atypical antipsychotics appear to have a more
  favourable outcome though there are no controlled
  data to support this supposition.
• Clozapine has been reported to reduce substance
  misuse and improve psychosis but this data is
  still preliminary.

19
Bipolar disorder.
20
How to treat pharmacologically?

• Very little guidance mostly open trials, small.
• Are any medications treating BPD more effective
  than others in minimising substance misuse ?
• Monotherapy or as adjunct
• Anticonvulsants - valproate, quetiapine,
  lamotrigine, carbamazepine, gabapentin may be
  better than lithium
• Lithium carbonate was ineffective in decreasing
  alcohol consumption in a large multicenter VA
  trial of depressed alcoholics. (Dorus et al 89)
• Lithium may not be effective in bipolar variants
  such as dysphoric, mixed, or rapid cycling, which
  are over-represented in bipolar alcoholic
  patients

21
Role of anticonvulsants.

• Use medication to target substance misuse whilst
  maintaining existing BPD treatment.
• In substance dependence, anticonvulsants e.g.
  topiramate - alcohol, valproate cocaine,
  alcohol have been shown to reduce misuse
• Similarly with atypical antipsychotics

22
AmJPsych 2005

• 24 week, BPD I alcoholism
• All had Li, treatment as usual, alcohol detox,
  psychosocial interventions for SUD
• Valproate group had
• Fewer heavy drinking days related to valproate
  plasma levels improved GGT
• No difference in improvement of symptoms of mania
  or depression between groups

23
Bipolar disorder.

• Summary
• Given the lack of evidence, it is not possible to
  make specific recommendations regarding
  pharmacological approaches.
• Valproate may have greater acceptability than
  lithium due to less side effects
• May get poor compliance with lithium since warned
  not to drink alcohol
• Need more knowledge about the role of different
  mood stabilizers in improving substance misuse
  either directly or indirectly through improving
  their bipolar illness.

24
Depression.
25
Depression and drug withdrawal have a similar
neurobiology.
Markou, Koob
26
Rates of depression are higher in drug misuse and
vice versa.

• Most common combination of two disorders is
  affective disorders and substance dependence
• Which came first?
• Rates of lifetime depression
• 54 in opiate addicts (current rates for those in treatment, reason why present?
• 38 in alcohol dependence 80 c/o symptoms
• 32 in cocaine dependence
• 7 in community sample of general population
• Lifetime prevalence of drug (excluding alcohol,
  nicotine) misuse in mood disorders estimated to
  be 20.

27
JAMA, 2004
28
Effect of antidepressant medication on outcome of
depression Hamilton scale related to placebo
response.
29
Effect of antidepressant medication on outcome of
substance use related to depression effect
size but not sustained or robust.
30
Alcohol Depression a complex but common
relationship.

• 80 complain of 1
• depressive symptoms
• 30 major depressive
• disorder (lifetime)
• 42 at start
• 6 after 1 month had
• depressive disorder

• alcohol abuse/dependence
• alcoholic inpatients with depressive symptoms

no systematic pattern for major
depression depression alcohol abuse
31
No significant effect of SSRI antidepressant
(sertraline) on depressive symptoms
Significant effect of other antidepressant
(imipramine, desipramine, nefazodone) on
depressive symptoms
favours control favours treatment
Systematic review by Torrens et al 2005.
32
No significant effect of SSRI antidepressant
(sertraline) on reduction of alcohol consumption
No significant effect of other antidepressants
(imipramine, desipramine, nefazodone) on
reduction of alcohol consumption
favours control favours treatment
33
No significant effect of antidepressant on
alcohol consumption without comorbid depression
favours control favours treatment
SSRIs (top) or others (bottom desipramine,
nefazodone) Torrens et al 2005
34
Treatment SSRI antidepressants.

• Alcoholism NOT depressed
• sertraline/fluoxetine/fluvoxamine
• subtype specific
• Type 2 (male, FHve, antisocial
  personality/impulsive traits) do worse or
  equivalent compared to placebo
• Type 1 (both genders, FH-ve, anxious) benefit or
  equivalent compared to placebo

35
Depression in opiate addiction

• primary mood disorder is rare (10)
• use of cocaine depression
• methadone
• acts through m, k, d receptors
• k receptors associated with dysphoria
• buprenorphine
• partial agonist at m receptors
• antagonist at k receptors
• less propensity to cause depressive symptoms
• naltrexone
• non-specific antagonist
• may lead to depressive symptoms by antagonising
  mu receptors, but not clinically seen generally

36
No effect of antidepressant on depressive
symptoms minimal on opiate consumption.
All in methadone maintenance Others not included
in above meta-analysis fluoxetine, sertraline -
not effective imipramine mixed
results. Torrens et al 2005
37
Depression with opioid dependence.

• Summary.
• Like with alcohol dependence, antidepressants
  have limited efficacy in treating depression and
  opiate misuse
• TCAs are not recommended due to potentially
  serious interactions including cardiotoxicity and
  death in overdose.
• SSRIs may be less effective than mixed
  antidepressants
• Getting opiate addicts into treatment and on
  substitution treatment, buprenorphine or
  methadone, is likely to improve mood not clear
  if one has greater benefit.

38
No effect of antidepressant on cocaine
consumption in those without comorbid depression.
favours control favours treatment
SSRI- fluoxetine. Desipramine most of other
AD All studies did not support efficacy of
antidepressants for treating cocaine
dependence Torrens et al 2005
39
No effect of antidepressant on cocaine use
depressive symptoms in those with comorbid
depression
SSRI- fluoxetine (tend to be negative).
Desipramine most of other AD Some taking
methadone or buprenorphine No reduction in
cocaine use or depressive symptoms Torrens
et al 2005
40
Depression with cocaine dependence.

• Summary
• For all pharmacological studies, the importance
  of psychosocial interventions is emphasized and
  should be addressed since there is no robust
  evidence showing pharmacotherapy is effective.
• However
• Suggestion that more stimulating antidepressants
  are better than SSRIs
• venlafaxine one small study
• reduced depressive symptomatology
• reduced cocaine use

41
Treating substance misuse.
42
Use of substance directed pharmacotherapy.

• Opiate
• methadone / buprenorphine
• no problems reported
• Getting people stable on substitute medication
  generally improve their mental health.
• Naltrexone opiate antagonist (opioid analgesia)
• Alcohol
• Disulfiram
• Acamprosate
• No studies, no particular safety issues
• Improves abstinence
• Naltrexone
• Opiate antagonist reduces DA-ergic activity in
  pleasure reward system
• Reduces relapse rates

43
Disulfiram.

• Can precipitate anxiety, mania, psychosis,
  depression
• Presumed to do this by increasing brain dopamine
  levels and decreasing noradrenaline levels
  (dopamine beta-hydroxylase inhibitor)
• However data mainly from 70s and higher doses
  were used (1-2g now 200mg).
• More recent reports that it did not worsen
  symptoms (e.g Mueser et al 2003 Petrakis et al
  2006)

44
Biol Psych. 2005

• Major depression, PTSD, schizophrenia, GAD/panic,
  bipolar disorder.
• 12 weeks
• Medication had a modest advantage over placebo in
  improving drinking measures - continuous
  abstinence and fewer drinking days (but were high
  rates 70 abstinent from alcohol, motivated
  group)
• Naltrexone disulfiram
• No advantage of combination
• Disulfiram reduced craving

45
Psychotic vs non-psychotic spectrum disorder
(Petrakis et al 2006).

• Those with psychosis
• No difference in retention or compliance
• More heavy drinking days, less abstinence
• Did better with ntx or dis than placebo
• No change in psychotic symptoms
• No more side-effects/adverse reactions

46
Biol Psych. 2006

• 12week
• PTSD patients had better alcohol outcomes on ntx
  or dis or combination than on placebo.
• PTSD symptoms improved over time and not
  adversely affected by ntx or dis
• Those on dis improved more than those on ntx
• Maybe related to reduction in noradrenaline
• More side effects reported with combination

47
J Clin Psychopharm 2007

• 55 met DSM-IV criteria for major depression
• There was no relationship between the diagnosis
  of depression and medication treatment on alcohol
  use outcomes, psychiatric symptoms, or the
  reporting of side effects for these medications.
• those on disulfiram reported lower craving over
  time than those on naltrexone.
• Both are safe drugs to use (ntx did not increase
  depression)

48
Some key points .

• assessment diagnosis
• what are you treating?
• integrated treatment
• pharmacological
• psychotherapeutic
• interaction between these two approaches
• Not much robust evidence but consider
• clozapine schizophrenia
• alcoholism subtypes SSRIs
• opiate substitute therapy
• naltrexone/disulfiram for alcohol misuse

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www.bap.org.uk
50
Questions.

• In a patient with comorbid substance misuse, what
• Antipsychotic
• Antidepressant
• Mood stabiliser
• Pharmacological treatment for their substance
  misuse
• do you favour and why?

51

• Desirable characteristics of dual diagnosis
  service
• Integrated
• Step-wise
• Comprehensive
• Individualised
• What works?
• Group-counselling
• Residential rehab for comorbid patients
• Contingency management
• (Drake, 2007)