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Dual Diagnosis

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Dual Diagnosis Powered By Docstoc
					 The neurobiology of substance
 misuse and its relationship to
        dual diagnosis.
       Dr Anne Lingford-Hughes

Reader in Biological Psychiatry and Addiction,
            University of Bristol
               Hon Consultant
Bristol Area Specialist Alcohol Service, AWP
PLEASURE
           Drugs of abuse increase dopamine
              concentration in the nucleus
  DA :    accumbens of the mesolimbic system
cocaine,
amphetamine,
alcohol,
opiates,
nicotine,
cannabinoids,
                         NAC
MDMA

DA independent
alcohol,
opiates,
nicotine,
? benzodiazepines
 The dopamine reinforcement pathway:
 where substances of misuse interact.
                                                   • stimulants
           VTA                                         +
                                                      PFC
      GABA           DA                  Nucleus
                                 +       accumbens           glut

• opiates (mu)
• alcohol (via opiate mu)
                            • stimulants: direct action on
• nicotine                  DA neurons blocking uptake
• cannabis (CB1)            (cocaine) and/or stimulating
All inhibit GABA neuron     release (amphetamine)
leading to increased DA-    • nicotine
ergic neuronal firing.      • opiates
                            • ?alcohol
Increases in brain
dopamine are associated
with reinforcing effects
of psychostimulants in
humans.




            Volkow et al 1999
  Dopamine release & ‘pleasure’ from
     substances of abuse in man.
• In healthy volunteers           • In dependent subjects
  – psychostimulants                – Cocaine
    [methylphenidate,                  • Volkow et al, Schlaepfer
    amphetamine]                         et al
     • Volkow, Laruelle, Brier,     – Nicotine
       Drevets, Leyton                 • Barrett et al, Brody et al
  – alcohol                         – NOT heroin
     • Boileau et al                   • Daglish et al

  • And in other paradigms:
     • playing a video game, feeding, expecting
     a DA agonist in Parkinson’s disease,
But in dependence …

• For substances of
abuse – cocaine,
methamphetamine,
alcohol - reduced
DRD2 levels have been
found
• do not recover with
abstinence

• Cause or
consequence ?

Volkow et al
Little change with abstinence in dopamine D2
              receptors levels:


                                       cocaine



  Control     1 month     4 months




                                       alcohol

  Control     < 6 weeks   1-4 months
                                              Predictors of vulnerability?
                                            Subjects with low DRD2receptors
                                            report methylphenidate as pleasant
Dopamine D2 receptors levels



                                            and those with high receptors as
                                            unpleasant


                                               Dopamine D2 receptors
                               Unpleasant




                                Pleasant
                                                                       Volkow et al 1999
             Dopamine
• The dopamine system is therefore key
  in mediating reward
• Dopamine lies at the heart of
  substance use, abuse and addiction
• Psychiatric disorders that dopamine is
  implicated in include
  – Schizophrenia
  – Psychosis
  – Depression
            Reward & DA.
• Similarities in motivational dysfunction in
  schizophrenia and in individuals with
  substance misuse – less sensitive to reward
  and punishment.

• Anhedonia and other negative affective
  symptoms may be caused by disruption in
  DA-ergic functioning leading to lower
  sensitivity.
   – disruptions of frontostriatal and
     corticolimbic networks
 Iowa Gambling Task : decision making process.
 As the task progresses, controls shift their
 preference to ‘good’ decks (C,D) away from ‘bad’
 decks (A,B) – unlike patients with schizophrenia or
 substance dependence (alcohol + stimulants)



           control                   control




                      SCZ
                                               SUD


Bechara et al, Shurman et al
       Dysfunction of ventral striatal
     reward prediction in schizophrenia
    During anticipation of monetary gain or loss, activation
   seen in ventral striatum of healthy controls and is NOT
   seen in unmedicated SCZ; related to negative symptoms.


Gain – neutral




Loss - neutral


Juckel et al 2006
 Is there a common underlying DA-ergic
     dysfunction in schizophrenia and
            substance abuse?

Substance abuse            Schizophrenia
• Reduced DA release       • DA ‘hyperactivity’
  and DRD2 binding           may not occur in the
  levels                     ventral striatum
• DRD2 levels              • DRD2 blockade by
  negatively correlate       antipsychotics
  with alcohol craving       reducing function
  These reductions in DA function may contribute
    to the deficits in ventral striatal activation
 during the anticipation of reward and punishment.
       Self-medication : negative reinforcement

                 Neuropathology of
                 schizophrenia

    Symptoms of                  Substance abuse
    schizophrenia                vulnerability

Primary Addiction Hypothesis : positive reinforcement
                 Neuropathology of
                 schizophrenia


     Symptoms of                 Substance abuse
     schizophrenia               vulnerability
                               ‘extra reward valence’
  Prefrontal cortex
                                    glutamate




                        Thalamus



Ventral
striatum

           dopamine
VTA                   Hippocampal
                      formation
  Prefrontal cortex
                                    glutamate




                        Thalamus



Ventral    ++++++++
striatum

           dopamine
VTA                   Hippocampal
                      formation
 Motivational responses to natural and drug
   rewards in rats with neonatal ventral
  hippocampal lesions: an animal model of
       dual diagnosis schizophrenia.




Animals with neonatal ventral hippocampal lesions
press the lever more for cocaine than control
animals.                         Chambers & Self, 2002
       Depression

Dopamine also plays a key role.
Depression and drug withdrawal
  have a similar neurobiology.




                         Markou, Koob
          Nicotine & Depression.
                            • ~50% depressed
                              patients smoke
                            • Number of cigarettes
                              smoked /day is
                              associated with
                              lifetime prevalence of
                              major depression.
                            • Antidepressants can
                              reduce smoking
• Which comes first?
   • Nicotine ameliorates symptoms of depression
   • Nicotine dependence leads to changes in the brain
   which result in depressive symptoms – particularly
   emerging in withdrawal.
         Nicotine’s biology


• Increase in DA is important for pleasurable
  and reinforcing effects
• Nicotine modulates dopamine, serotonin,
  noradrenaline, ACH, GABA, glutamate
• Role for opioid and cannabinoid systems
  since nicotine is not dependence producing
  or rewarding in mice lacking mu opioid
  receptors or CB1 receptors
  – Role for antagonists: naltrexone or rimonabant
   Brain
monoamine
oxidase A
  and B
inhibition
(~40%) in
cigarette
 smokers




 Fowler et al 1996
            Nicotine & schizophrenia.



• Higher rates of smoking (~90%),
  extract more nicotine during smoking
• Nicotine improves cognitive functioning
  – Attention, working memory, reaction
    times
• Nicotine withdrawal worsens cognitive
  deficits.
Specific drugs of abuse

        Cannabis
         Alcohol
              Cannabis.
• Active psychoactive constituent
  – ∆9tetrahydrocannabinol
• Other constituent
  – cannabidiol - ?antipsychotic
• Receptors
  – CB1 – brain, neuronal
  – CB2 – immune cells
• Endocannabinoids
  – Anandamide
  – 2 Arachidonyl-glycerol (2-AG)
                  Endocannabinoids are Retrograde Modulators
                         of Neurotransmitter Release
                                    Pre synaptic
                                                            neurone
                                                                                                    e.g. GABA,
                                                                                                    glutamate
                                                                                                    dopamine,
                                            Ca++
                                     1
                                CB




                                                                                               HO    N H
                                    HO     N H
                                                                                                      O
                                            O
                                                                                                           ? Transporter

                                                                                               HO    N H

                                                                                                       O


    anandamide
                                    HO     N H

                                            O
                                                                                          Arachidonate
                                                                                          Ethanolamine

Wilson & Nicoll Nature 2001;410:588-592   Kreitzer & Regehr Neuron 2001;29:717-727   Ohno-Shosaku et al Neuron 2001;29:729-738
     Cannabis & schizophrenia
• Neurobiological links
  – Higher CSF levels of anandamide in SCZ
  – DA transporter levels in THC (-) SCZ are
    lower than controls, but THC (+) are
    equivalent
  – CB1 receptor levels higher in some parts of
    the brain e.g. prefrontal cortex in SCZ
  – i.v. ∆9-THC in patients leads to increased
    positive symptoms in SCZ, worsens memory
  – Genetic
     • CB1 receptor and hebephrenic SCZ
     • Val158Met COMT (but with psychosis)
Alcohol.
      Alcohol : modulates GABA-
   benzodiazepine receptor function.

Acutely : alcohol
increases GABA-ergic
function leading to
- reduced anxiety, ataxia,
slurred speech, sedation,
disinhibition, reduced
levels of consciousness.

Chronically :
GABA-ergic function is
reduced: tolerance
   The GABAA receptor & alcohol
        GABA          GABA+alcohol       GABA+alcohol
            Cl-           Cl-                Cl-

        γ    α
                  β
    β        α




   No alcohol         Acute alcohol      Chronic alcohol
α1−6, β1−3, γ1−3               tolerance
                                ? subunit switch
 Reduced BDZR                                         Give midazolam:
levels in alcohol                                  No difference in BDZR
  dependence                                       occupancy but reduced
                                                      total sleep time
                                                   40.00



                                                   35.00



                                                   30.00




                         total sleep time [mins]
                                                   25.00



                                                   20.00



                                                   15.00
                                                                             *
                                                   10.00



                                                    5.00



                                                    0.00

                                                           Control   Alcohol dependent
                                                                     1




 We have shown reduced sensitivity to the
sleep inducing effects of benzodiazepine in
                 alcoholism Lingford-Hughes et al 2005
                                    Does this
                                    underpin
                                    the
                                    comorbidity
                                    between
                                    alcohol
                                    misuse and
                                    anxiety?


Healthy control   Panic disorder   Malizia et al 1998
          Alcohol and the
  excitatory glutamatergic system.




Alcohol acts as an NMDA receptor antagonist
          Ca2+ flux     excitation
  The NMDA receptor & alcohol
• to overcome alcohol antagonising NMDA
receptor function
    • NMDA receptors are upregulated

• effects :
    •long term potentiation (process involved in
    memory) in the hippocampus is attenuated
    by alcohol
    • hyper-excitable state in withdrawal
        • seizures, DTs
         Alcohol withdrawal
• increased activity in
   – NMDA receptor                    Ca2+ flux
   – L-subtype of Ca2+ channel
   – noradrenergic activity       hyper-excitability
                                     cell death
• decreased
   – GABA-ergic activity
   – Mg2+ inhibitory system (NMDA receptor)
   – DAergic activity
         Hippocampal damage during
             alcohol withdrawal
              Role of the NMDA receptor system

 Dead
          Control        Alcohol Withdrawal




 Alive




courtesy of Prendergast & Littleton
         Hippocampal damage during
             alcohol withdrawal
              Role of the NMDA receptor system

 Dead                                         Alcohol Withdrawal
          Control        Alcohol Withdrawal   + Acamprosate (200 mM)




 Alive

                                             cell death also
                                           reduced with other
                                          NMDA antagonists, but
courtesy of Prendergast & Littleton
                                              not diazepam
           Alcohol withdrawal
• Multiple cycles of ethanol withdrawal
  significantly increased sensitivity to seizures
  – Diazepam suppressed withdrawal symptoms but
    did not alter seizure susceptibility Mhatre et al 2001


• Ethanol withdrawal is associated with
  increases in glutamate in the brain
  – Acamprosate blocks this
• Repeated ethanol withdrawal leads to greater
  levels of glutamate & increased mortality
  – Acamprosate blocks this           Dahchour & De Witte 2003
    Treatment.

 What is being treated?

   Psychiatric disorder
Substance misuse disorder
www.bap.org.uk
  Treatment of comorbid depression
• Overall, antidepressants may improve mood but not
  necessarily alcohol /drug behaviour in depressed
  dependent patients.
• Alcohol
   – SSRIs appear effective in improving drinking behaviour and
     depression only in severely depressed patients.
   – SSRIs should be avoided in type 2 alcoholism
• Cocaine
   – Desipramine and fluoxetine show no significant advantage
     over placebo in cocaine dependence alone or in cocaine
     misusing methadone maintained opioids addicts
• Nicotine
   – Limited studies but should offer NRT and/or bupropion


• TCAs are not recommended due to potentially serious
  interactions between TCAs and substance; overdose
   Schizophrenia with substance misuse
            and dependence:

• Given the dearth of information, it is difficult to
  draw up recommendations
• Typical antipsychotics do not seem to improve
  substance misuse and may even contribute to it, so
  we recommend that their use be avoided where
  possible
• Atypical antipsychotics appear to have a more
  favourable outcome though there are no controlled
  data to support this supposition (except nicotine)
• Clozapine has been reported to reduce substance
  misuse and improve psychosis but this data is still
  preliminary
Summary.
 The neurobiology of substance misuse
 and its relationship to dual diagnosis.
• Knowledge about neurobiology of substance
  misuse is increasing
  – able to compare with psychiatric disorders and
    predict the potential consequences of
    substance misuse
• Dopamine is a key neurotransmitter
  involved in substance misuse and many
  psychiatric disorders
  – Too much and too little
  – Modifiers: opioid, cannabinoid, glutamate – all
    potential therapeutic targets.

				
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