Download Pharmacotherapy of amphetamine-type stimulant dependence: An

Stimulants seminar
shahid sadoughi university of
medical sciences
Esfand 1393
M Yassini MD
M Yassini MD.yazd medical sciences university.
[email protected]
1
 Drug
and Alcohol Review (September 2013),
32, 449–460
 Comprehensive textbook of psychiatry2009
Kaplan and sadock
 Neurobiology of Addiction
Koob, Michel Le Moal
 Synopsis of psychiatry 2015
Kaplan and sadock
M Yassini MD.yazd medical sciences university.
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 This
review describes the rationale and
targets for pharmacotherapies for abuse or
dependence on ATS
 reviews the extant evidence for select
agents
 discusses emerging pharmacogenetic data
 proposes directions for future work
M Yassini MD.yazd medical sciences university.
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 alter
the neurobiology of reinforcement or
reward from the drug
 attenuate the negative reinforcing effects of
withdrawal from and craving for the drug
 Ameliorate comorbid psychiatric
vulnerabilities that co-occur and that can
interfere with recovery.
M Yassini MD.yazd medical sciences university.
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 increases
-
-
extracellular levels of monoamines
both by
blocking presynaptic reuptake
Stimulating the release of catecholamines
through the disruption of vesicular storage
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 mediated
by neurotransmitter systems
including dopamine, serotonin and
norepinephrine
 dopaminergic system a favoured target for
pharmacotherapy
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 Initial
positive and rewarding subjective
effects of methamphetamine dull in quality
with repeated use of the drug, signalling
development of a series of neuroadaptations
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 Koob
and Le Moal [16] characterise this
process as the increasing recruitment of antireward processes, including
- hypoactivity in the dopaminergic system
- alterations in hypothalamic–pituitary–adrenal
axis functioning
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 Agonists
 antagonists
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 block
the action of the agonist to attenuate
or eliminate the positive reinforcing effects
of acute methamphetamine intoxication.
 compete with endogenous monoamines but
have no intrinsic activity at the receptor site
 Naltrexone in other addiction
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 bind
to and trigger responses from receptors
involved in the addiction process, often
mimicking the action of monoamines
involved in the reinforcement, withdrawal
symptoms and motivational aspects of
methamphetamine or amphetamine use
 promote early abstinence by providing a
modest level of subjective effects but may
have their greatest impact in minimizing
withdrawal and negative affective symptoms.
M Yassini MD.yazd medical sciences university.
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M Yassini MD.yazd medical sciences university.
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 an
opioid receptor antagonist
 opioid receptors partially modulate
dopaminergic effects and may act as a
relevant pharmacological target.
 encouraging but await confirmation in
several clinical trials that are currently
underway
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 Risperidone
in small samples of
methamphetamine-dependent adults showed
acceptability and decreases in weekly
methamphetamine use
 quetiapine and risperidone equally reduced
bipolar symptoms and drug cravings, with
reductions in cravings associating with
reductions in stimulant use
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 However,
in non-dependent volunteers in the
human laboratory, neither haloperidol nor
risperidone attenuated the euphorigenic
effects of methamphetamine
 dampening rationale for further evaluation of
dopamine antagonists.
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 iatrogenic
effect
 Exacerbation of drug use
 Attenuate psychotic symptoms
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M Yassini MD.yazd medical sciences university.
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 produce
behavioral and neurobiological
effects that are comparable or identical with
the drug of addiction
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 Increase
extracellular levels of dopamine
through a carrier mediated exchange at
presynaptic vesicles.
 In a small unblinded randomised trial,
Shearer demonstrated initial safety and
feasibility of dexamphetamine replacement
therapy (60 mg/day) for injecting
amphetamine dependent individuals.
 The study was underpowered to detect
treatment differences, but no serious
adverse events were observed
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Additional support for an agonist approach is
provided by Tiihonen
 20-week, randomised, double-blind, placebocontrolled trial of aripiprazole, methylphenidate
or placebo among participants dependent upon
injection use of amphetamine
 participants assigned to the 54 mg/day slowrelease methylphenidate condition (n = 17) had
significantly fewer amphetamine-positive urine
samples than placebo treated patients (n = 19;
odds ratio = 3.77; 95% confidence interval 1.55,
9.18).

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 nonamphetamine-type
stimulant with wakepromoting properties and cognitiveenhancing effects
 increases dopamine availability in nucleus
accumbens
 Despite disappointing findings, some
enthusiasm still exists for modafinil in its
current form or one of its enantiomers, Rmodafinil, as a treatment for
psychostimulant dependence
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 Although
not considered an agonist,
bupropion functions as a mild stimulant and
antidepressant.
 Bupropion is a non-selective inhibitor of the
dopamine and norepinephrine transporters
 also acts as an antagonist at nicotinic
acetylcholine receptors
 Bupropion increases dopamine transmission
in both the nucleus accumbens and the
prefrontal cortex
 encouraging but await confirmation
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 dopamine-enhancing
medications have
demonstrated the most consistent effects on
reducing methamphetamine use when
evaluated in placebo controlled randomized
trials.
 One of the challenges to continued work
using this strategy is that pure agonists have
abuse liability, which elicits concerns that
limit impact
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 marketed
serotonin-specific reuptake
inhibitors may be ineffective for treating
methamphetamine dependence.
 compounds in development that have
selective activity at specific serotonergic
receptors may be efficacious approaches.
 Indeed, one such medication, mirtazapine,
has demonstrated some promise
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 is
a pharmacologically distinctive
antidepressant with sedative and anxiolytic
properties that enhances both noradrenergic
and serotonergic activity.
 Its actions on the serotonergic system are
different from those of selective serotonin
reuptake inhibitors, including enhanced
transmission of 5-HT1A receptors and
blockade of 5-HT2 and 5-HT3
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 interacts
with dopaminergic processes, and
its activation exerts an inhibitory effect on
the reward system.
 This feature suggests that GABA agents may
have some efficacy in attenuating the
reinforcing effects of stimulants.
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 Increases
brain GABA
 Attenuate cocaine, nicotine, heroine, alcohol
and amphetamine induced increases in
extracellular nucleus accumbens dopamine
as well as drug seeking behaviors associated
with this biochemical changes in animals
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 Gabapentine
has no effects on
methamphetamine use, treatment retention
or drug craving.
 topiramate appeared to facilitate abstinence
during the second half of the trial
 Baclofen, tiagabine have shown some
promise In preclinical studies and early
clinical studies
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 Some
positive results in early treatment with
minimally drug dependent patients
 Little or no use inducing abstinence in
moderate or severe cases
 Desipramine as most effective
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 One
study found 300mg a day of dilantine
reduced cocaine use
 This study requires furthur replication
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 Cocaine
binding antibodies
Reduce the reinforcing effects of cocaine in
animal models
 Catalytic antibodies
Accelerate the hydrolysis of cocaine
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 Inhibitor
of dopamine beta dehydroxylate
enzyme
 Increases level of dopamine by slowing the
breakdown of synaptic dopamine
 Increase cocaine levels several fold
 Co administration of cocaine and disulfiram
make more negative response including
anxiety, restlessness and paranoia so
decreases cocaine use
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 Numerous
pharmacotherapies have been
assessed in randomized, placebo-controlled
trials but most have failed to demonstrate
efficacy
 Dependence on long-acting stimulants
represent a complex disease of staged
neuroplasticity involving multiple brain
systems
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 dopaminergic
system—the principle focus in
addiction medication research—is dependent
on competent functioning of the GABA
system and cholinergic interneurons
 Determining optimal pharmacological targets
is difficult
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 Although
the preponderance of findings from
clinical trials have been negative, not all
results have been disappointing.
 Agonist replacement therapies show some
promise.
 Concerns, however, have been raised
regarding public health implications of
widespread implementation of this strategy.
 Additionally, agonist therapies will likely
require significant behavioural support and
oversight in order to deliver robust public
health benefits
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 NIDA
has completed a second, confirmatory
trial of bupropion, and if results are similar
to existing studies, support would exist for
use of the medication as a pharmacotherapy.
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 Shoptaw
and Heinzerling are assessing
ibudilast, a phosphodiesterase inhibitor that
may attenuate the cascade of
methamphetamine-induced glial activation
and release of cytokines upon initial
abstinence.
 A Phase I trial is being completed
 Phase II trial of the compound not finished
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 demonstrated
promise in a preliminary study
 being assessed in a larger trial
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a partial agonist at alpha-4, beta-2 nicotinic
acetylcholine receptors is being examined as a
pharmacotherapy following promising pilot data
and encouraging results with both cocaine and
alcohol
 evidence suggests involvement of the cholinergic
system in the neurochemical effects of
methamphetamine use the reinstatement of
methamphetamine MA-seeking in animal models
 reduced subjective effects of methamphetamine
in a human laboratory study

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 Promising
preclinical and human laboratory
studies with cocaine have stimulated interest
in N-acetylcysteine as a pharmacotherapy for
methamphetamine dependence, though a
Phase II trial is years away.
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 NIDA
has recently signalled an interest in a
dopamine D3 receptor for cocaine
dependence
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 Two
randomized controlled trials will
evaluate buspirone as a relapse prevention
treatment among cocaine-dependent
patients being discharged from inpatient
treatment facilities
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 After
over 20 years of concerted effort to
develop a broadly effective medication for
MA dependence, no candidate has emerged.
 This highlights the need for new research
methodologies, better integration between
basic and clinical sciences and improved
collaboration between government, industry
and academic researchers.
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M Yassini MD.yazd medical sciences university.
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