Unit 4 Amphetamines: dependence, depression, withdrawal, and psychosis

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• Unit 4Amphetamines dependence, depression,
  withdrawal, and psychosis
• Developed by
• Dr Adam R Winstock
• MRCP MRCPsych FAChAM

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Amphetamine type stimulants (ATS)

• Types
• Amphetamine sulphate, dexamphetamine,
  methylphenidate and methamphetamine.
• The most common of illicitly used amphetamines in
  Australia are the potent methamphetamine base
  (ice, crystal) and less potent powder (speed)
• Dealing unit
• 0.1gm (point) - 1gm or eight ball (3.5gm 1/8
  oz)
• Cost
• 50 - 60 / 0.1g, 300-400/gm for methamphetamine
• 100 - 200/gm for speed
• Route of administration
• Swallowed, snorted, injected or smoked
  (methamphetamine only) The latter two routes can
  be associated with higher rates of dependence,
  complications and morbidity

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Amphetamines
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Prevalence
1 in 10 users seek treatment- why?
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Treatment aims for stimulant users

• Harm reduction
• Prevent development of dependence
• Early intervention
• Detoxification and withdrawal attenuation
• Maintenance/ substitute prescribing
• Relapse prevention
• Advocate for other service provision e.g. mental
  health

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How stimulants work

• Cocaine
• ? acute transient blockade of the dopamine
  transporter (DAT)
• ? indirect sympathomimetic effect
• ? increased DA in VTA (n.accumbens) highjacks
  the reward pathway
• ? Inhibition of the DAT causes acute elevation of
  DA levels pleasure burst
• Amphetamine
• ? both direct release and reuptake inhibition of
  monoamines
• ? DA NA and 5HT release-variable receptor
  activation profiles
• MDMA
• ? release of 5HT (and DA) with subsequent
  depletion

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Up - down Dopamine and 5HT/NA
Intoxication
Schizophrenia panic/anxiety paranoia/mania halluci
nations psychosis agitation/aggression
ANTIPSYCHOTICS DA

DA
Depression Comedown Withdrawal
ANTI-Ds 5HT/NA/DA
Withdrawal
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Assessment summary

• Amount used, frequency, duration of use and
  recent changes in pattern of use
• Route of use
• Pattern and duration of any withdrawal/
  intoxication related symptoms that may mimic
  psychiatric disorders (depression/ psychosis)
• Past episodes of hospitalisations for mental/
  physical health
• Consequences of use
• Past abstinence periods, treatment and relapse
• Other substance use

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Psychiatric history and stimulant use

• First use- age, route, effects, pre-existing
  psychiatric diagnosis or childhood history
  Conduct Disorder/ ADHD/ depression
• Map low mood and withdrawal symptoms with use
  patterns
• Map binge use patterns and days without sleep
• Identify past episodes of hallucinations,
  delusions, violence, hospitalisation, self harm
• Look for ADHD- paradoxical effects calming/
  confidence, predisposing depression (less
  commonly anxiety disorders)
• Identify other substance use especially
  benzodiazepines, opioids and alcohol

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Differentiating intoxication effects from
personality/ pre existing psychopathology

• Identifying temporal relationship between use,
  symptoms and other life events
• Ask about specific experiences, their duration,
  intensity, functional impact, outcome
• Assess the patients insight and attribution
• Ask about family history of amphetamine and other
  drug use/ mental illness in immediate and
  extended family
• Ask about previous assessments, admissions and
  course of medication (including response)
• Focus on client concerns and feedback assessment

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Dependence

• High dose users especially those who inject are
  at risk of developing dependence
• May not be a daily use pattern
• Binge pattern common use 3 - 5 days then crash
• There is often a concurrent dependence of abuse
  of other sedative or stimulant drugs, especially
  alcohol and benzodiazepines
• High risk factor for developing psychotic
  episodes

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The blur of pre morbid depression, comedown,
withdrawal and drug induced depression
Both depression and stimulant withdrawal share a
common neurobiological mechanism- reduced levels
of monoamines

• Come
• down

Withdrawal
Pre morbid depression/ drug induced
Pre morbid depression
2 - 4 weeks
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What underlies the depressive symptoms
associated with stimulant use?

• Comedown
• acute neurotransmitter and precursor mono amine
  depletion- assisted most by medicated withdrawal
• Recovery
• repletion of source amino acids (anorexia) and
  recovery of rate limiting enzyme
• Withdrawal
• hypodopaminergic state reversal of more
  persistent neuroadaptive change

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Stimulant withdrawal vs Depression
NOTE PAST HISTORY, FAMILY HISTORY, ADHD, FUNCTION
OF DRUG USE
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Withdrawal management

• Not a lot of evidence to support current use of
  withdrawal medications
• Message stop using and eat and sleep
• Controlled dispensing of Benzodiazepines
• low dose lt 7 days
• Analgesics
• Anti-spasmodic medications
• Antidepressants have no significant role in
  managing withdrawal (in those without pre
  existing depression)
• Good diet full of mono amine precursors (?)

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Chronic state of hypodopaminergic activity and
craving (Volkow 2002)

• Reductions in D2 receptors and in dopamine
  release
• Dopamine is thought to play a central role in
  reward and motivational pathways
• Low levels of DA activity may lead to dysphoria,
  anhedonia, apathy, craving and relapse
• D3 receptors are involved in cue conditioned
  responses
• Opiate and CB1 receptors also involved

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The importance of differentiating depression from
withdrawal

• There is a gradual resolution (over 2 - 4 wk) of
  stimulant withdrawal associated depressive
  symptoms
• If first presentation, a cross-sectional
  assessment of mood symptoms needs to be related
  to what part of the drug use cycle the patient is
  in
• Where depressive symptoms are entirely due to
  use, resolution of symptoms with abstinence acts
  as motivator for continued abstinence (no need
  for anti-depressants)
• Identifying and treating pre existing/ persistent
  depressive disorder following withdrawal is
  important as being depressed is associated with
  enhanced initial response to stimulant drugs
• Depression predicts poorer outcomes in cocaine
  dependence
• Where there is a confident pre existing history
  of depression, anti depressants may be commenced
  after abstinence has begun

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Do anti depressants work in depressed stimulant
users?

• Anti depressants only effective in reducing
  stimulant use and depression in clinically
  depressed patients
• Evidence for efficacy of desipramine, imipramine,
  buproprion, and fluoxetine, citalopram in
  treating depressed stimulant users (when they are
  abstinent)
• Successful treatment of depression associated
  with reduction in stimulant use
• Most studies suggest more severely depressed show
  positive response to anti depressant treatment
• (Yes)

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Risks of prescribing to current amphetamine users

• Problems in attribution
• If I take this medication I can carry on using
  and my depression may get better
• Stimulant use is not responsible for my
  depression
• Uncertain diagnosis
• Medication may reduce intrinsic motivation
• If the patient commences anti depressant and
  stops using and feels better in a month, what is
  the cause?
• Potential for adverse interactions
• Probable poor response
• poor compliance
• mono amine depletion
• interference in neuroadaptive changes associated
  with positive response to anti depressants ?
  therapeutic nihilism
• 
  
• .

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When to prescribe anti depressants?

• Advantages of waiting to prescribe once patient
  has completed withdrawal
• Improved accuracy of diagnosis (possibly however
  this may delay treatment in someone with
  pre-existing depression)
• Clearer idea of aetiology, better understanding
  by patient and clinician
• No potential for adverse interactions- may
  support abstinence
• When to prescribe anti depressants?
• Usually 2 - 4 weeks after cessation of use,
  following reassessment of mood
• Abstinent supported for both use and depression
  by CBT- refer to psychologist may be
  appropriate.
• Anti depressants may be started earlier in those
  with history of treatment responsive depression
• 
  

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Psychological approaches in stimulant users

• CBT is the most highly evidence-based
  intervention for stimulant use disorders
• Benefit may be seen in some patients from a
  single brief intervention
• Some may require longer duration of treatment
• Interventions including relapse prevention may be
  given as 11 or in a group setting

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Ecstasy (MDMA)

• Route
• Usually swallowed, may also be snorted, injected
  or taken rectally
• Onset and duration of action
• The effects come on after 30 minutes and peak at
  2 - 4 hours
• Effects may last for up to 12 hours
• Many users report feeling lethargic and
  depressed in the 2 - 3 days following use
• Mechanism of action
• MDMA acts an indirect 5HT agonist and also
  blocks DA reuptake
• Sought-after effects
• Energy, mood elevation, euphoria, empathy,
  increase alertness, self-confidence and motor
  activity while reducing inhibitions, fatigue and
  appetite

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Psychiatric problems reported in association with
MDMA use

• depression
• anxiety
• panic
• social phobia
• bulimia
• sleep disorders
• paranoia
• cognitive disorders
• prolonged de-personalisation/ de-realisation
• suicide
• psychotic episodes
• flashbacks
• increased impulsivity

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Depression and MDMA (e)

• As with amphetamine use, after taking MDMA there
  is a period of acute 5HT depletion due to acute
  vesicular monoamine depletion (Tuesday blues)
• De novo/ exacerbated Mixed reports on mixing
  SSRIs and e (probably depends on chronicity)
• Short term SSRIs may not block effect of e but
  risks 5HT syndrome
• Long term SSRIs may block e effect (it may
  reduce reinforcement)
• Best not to mix
• Best wait 2 - 4 weeks after last e use before
  commencing SSRIs/ TCA (to avoid interaction and
  increase diagnostic accuracy)
• DO NOT USE MAOIs

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Summary of Amphetamine type stimulants (ATS)

• The neurobiological basis of depression and
  stimulant withdrawal have a lot in common
• Withdrawal is uncomplicated and management is
  supportive, symptomatic and aimed at attaining a
  break from easy access/ expectation
• The withdrawal period should be completed before
  confident diagnosis of depression can be made and
  anti depressants confidently started
• Depression should be treated in stimulant users,
  since untreated it may trigger relapses.

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Psychosis history

• Characterised as a paranoid psychosis, the
  syndrome was first described by Young and
  Scoville in 1938, six years after the
  introduction of amphetamine (Benzedrine) as a
  decongestant and narcoleptic
• In 1958, Connell published his classic study of
  amphetamine psychosis in 42 patients (27M, 15F)
  which represented the first large sample that
  described this syndrome

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Diagnostic issues

• Neither ICD-10/ DSM-IV provide specific
  psychopathological criteria for Substance Induced
  Psychosis (SIP)
• Diagnosis based on temporal relationship with
  substance use
• There is some association with chronicity
• Those with schizophrenia/bipolar have highest
  rates of co morbid substance use disorder
• Early treatment may alter disease process
• NB. There is limited research and follow up
  studies

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Psychotic/paranoid/panic symptoms an
understandable response to dose related
sympathomimetic activity
Panic/ anxiety Paranoid ideation Hallucinations De
lusions Sympathetic arousal

• Agitation
• Irritability
• Impulsivity
• Impaired judgment
• Grandiosity
• Compulsive behaviours

• Euphoria
• Alertness
• Self confidence
• Self esteem
• Social disinhibition

DOSE
Psychopathological severity

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Behavioural risks

• Stereotypical behaviours
• skin picking
• pulling things together and putting them back
  together
• hoarding
• Injecting
• Driving
• Violence
• Alcohol and other drug use
• Sex
• Spending

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Substance induced psychotic disorders

• Usually caused by stimulant drugs (but also by
  hallucinogens and rarely cannabis)
• Most drugs can exacerbate/ precipitate psychotic
  symptoms in those with pre-existing or
  significant constitutional vulnerability to
  psychosis
• Increased incidence is associated with stimulant
  drugs with longer half life (thus methamphetamine
  gt cocaine)
• Epidemics noted in Japan, Europe, USA
• Possibly a direct toxic effect

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Pattern of use and the risk of stimulant induced
psychosis

• Dependent users most at risk
• IV and smoke route
• Change to more potent route
• Previous episodes
• Other drug use
• Males more at risk
• Some association with duration and level of use
• Binge use and sleep deprivation

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Stimulant induced psychosis

• Related in part to dose and route (younger age at
  first use and more drug used)
• May be more common in those with premorbid
  schizoid/ schizoid-type personality disorder
• Spectrum from restless fearful ? paranoid
  psychotic
• Often psychopathologically indistinguishable from
  schizophrenia
• Paranoid ideation and hallucinatory experiences
  aggression violence prominent
• Psychopathology often grandiose/ persecutory
• Hallucinations visual/ auditory/ tactile/
  gustatory
• Preservation of orientation
• Absence of thought disorder

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Assessment

• Q. Have amphetamines been used with last 7 days?
• Check
• Route (IV use carries high risk of dependence)
• Time of last use
• Recent change in use, pattern or route
• Change/ increase in use
• Recent sleep deprivation
• Other drug use
• Specific examination for intravenous drug use
  sites
• Ask patient regarding attribution of symptoms
• do you think your problems are related to
  amphetamine use? (Medical problems may suggest
  an organic cause)
• Complete basic observations including hydration
  status

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Clinical signs of intoxication
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Stimulant induced psychosis

• Hallucinations auditory, tactile and visual
• Paranoia persecutory delusions and associated
  hostility
• Thought disorder
• Over excitement/ being withdrawn
• Hyper stimulation
• Fear/ lability/ aggression
• And a history of drug use
• It is OK to say I do not know what is wrong with
  this patientbut let us keep them safe as start
• A deferred diagnosis is better than an assumed
  one!

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Duration and management

• Examine for clinical signs suggestive of
  stimulant use (often present 2 - 4 days after
  last use)
• Confirm substance use urine/ hair anaylsis
• Observation/ symptomatic relief - sedation
• Anti psychotics should not routinely be used as
  first line management and their regular use
  should be avoided until a more accurate diagnosis
  is possible
• Management is difficult - set, setting, care out
  of crisis
• Most cases of SIP resolve in a few days to 2 wks
  (1- 15 persist for more than a month)

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Symptomatology and clinical progression of use
and psychosis

• Follow up essential to prevent misdiagnosis and
  allow Motivational Interviewing/relapse
  prevention to retain engagement with service
• Can be relapsing condition like schizophrenia
• Episodes may be precipitated by stimulant/other
  substance use or stress
• Behavioural sensitisation and reverse
  tolerance
• Sensitisation vs pre-existing vulnerability or
  precipitation
• Neurotoxicity
• Vulnerability mediated through genetic variation

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Clinical progression
Behavioural sensitisation
Chronic SIP
SIP
S
S
Schizophrenia spectrum
Other dx
Episode
N
S
Schizophrenia bi polar
S
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Assessment - ongoing

• Age of onset of different syndromes
• Family history
• Temporal association between substance use and
  the psychiatric disorder
• Impact of treatment/abstinence on the course of
  both conditions
• Precise documented phenomenology will assist
  accurate diagnosis
• Psychopathological relapse triggers
• Retrospective patient info problem (recall bias,
  cognitive impairment)
• Collateral informants

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Brief Intervention

• Psychosocial interventions should be considered
  when appropriate
• Motivational Interviewing (MI) may be
  appropriate for users who have difficulty
  perceiving methamphetamine-related problems or
  who are not motivated to attend treatment
• Assess for suitability for Cognitive Behaviour
  Therapy (CBT)

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Follow Up

• There is a distinct likelihood that these
  patients will present again, therefore a
  discharge summary including a treatment plan is
  vital
• This should be available to all those likely to
  be involved in the patients care such as GPs,
  drug and alcohol services and mental health
  services
• Include in the documentation
• what was effective in the management of the
  patient
• the pattern of presentation and recovery
• It is recognised that this information is vital
  for the management of these people

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Summary

• When uncertain, it is better to have assessed and
  deferred diagnosis than to have made a spurious
  one
• Where possible, let the condition follow its
  natural clinical course with as little
  pharmacological intervention as possible (outside
  sedation)
• Defer diagnosis for gt 2 weeks following drug use
• Follow up- monitor mood and drug use
• Consider Motivational Interviewing/ Relapse
  Prevention/ Cognitive Behavioural Therapy
• Establish collaborative management between mental
  health and drug health services
• Remember right treatment at the right time for
  the right disease

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End of Slide Show
The Can Do Initiative Managing Mental Health
and Substance Use in General Practice
Overview Session A Definitions prevalence
Session B Assessment history taking Session
C Common explanations Unit 1 Alcohol Unit
2 Benzodiazepines Unit 3 Cannabis Unit 4
Amphetamines Unit 5 Opioids and pain Unit 6
Pregnancy