BREAKING BAD: WHAT TO DO WHEN YOUR PATIENT IS USING METHAMPHETAMINE - - PowerPoint PPT Presentation

BREAKING BAD: WHAT TO DO WHEN YOUR PATIENT IS USING METHAMPHETAMINE

Learning Objectives

• Explore patient cases that involve a variety of

mental illnesses occurring in the context of previous or current methamphetamine use

• Implement strategies to improve differential

diagnosis and treatment for patients who have a history of methamphetamine use

Prevalence of Methamphetamine (MA) Use

• In 2018, among people aged 12 or older in the United

States:

• Approximately 1.9 million people (0.7% of the population)

used MA in the past year

• An estimated 1.1 million people (0.4% of the population)

had a MA use disorder

• Around 27 million people worldwide (0.5% of the adult

population), are estimated to have used amphetamines, including amphetamine, methamphetamine, and pharmaceutical stimulants, in the past year

Substance Abuse and Mental Health Services Administration 2019; World Drug Report 2020.

Psychiatric Developments of MA Abuse

Ballester J et al. Expert Rev Clin Pharmacol 2017;10(3):305-14; Javadian S et al. Prim Care Companion CNS Disord 2016;18(6):10.4088/PCC.16m02002; Härtel-Petri R et al. Pharmacopsychiatry 2017;50(3):96-104; Hellem

• TL. J Subst Abuse Treat 2016;71:16-22; Luo SX, Levin FR. Curr Psychiatry Rep 2017;19(3):14; Warden D et al.

Psychiatry Res 2016;246:136-41; Zhong N et al. Prog Neuropsychopharmacol Biol Psychiatry 2016;69:31-7.

10 20 30 40 50 60 70 80 90 100

Proportion of Meth Users (%)

*Hypobulia is a lowered ability to make decisions or act

MA Use in the Time of COVID-19

• MA causes pulmonary damage, pulmonary hypertension, and

cardiomyopathy, which increase risk for COVID-19 infection and associated complications

• MA users are at greater risk of overdose, especially in rural areas
• Less MA availability (border control)
• More availability of MA contaminated with fentanyl
• More likely to use alone (social distancing)
• Reduced access to health care and recovery services

Volkow ND. Ann Intern Med 2020;173(1):61-2; Ostrach B et al. J Rural Health 2020;1-4.

Meth-Gators

https://www.nbcnews.com/news/us-news/tennessee-police-warn-locals-not-flush-drugs-fear-meth-gators-n1030291

CASE 1

U S

ntr ntreated eated ymptoms mptoms

Attention Deficit Hyperactivity Disorder (ADHD) and Substance Abuse Disorder (SUD)

• Comorbidity of ADHD and SUD:
• 23.1% of patients with SUD have comorbid ADHD
• Lifetime prevalence of ADHD in methamphetamine users is 20.8%
• Lifetime prevalence of ADHD in non-users is 6.2%
• Treatment of childhood ADHD with a stimulant:
• Has not been shown to increase risk of later SUD
• May actually DECREASE risk of later SUD
• Individuals with a history of MA abuse may have increased

tolerance to stimulant medications and may require higher doses

Cook J et al. Aust N Z J Psychiatry 2017;51(9):876-85; Bordoloi M et al. Curr Dev Disord Rep 2019;6:224-7; Quinn PD et al. Am J Psychiatry 2017;174(9):877-85.

Malingering?

• Falsely or grossly exaggerated medical complaints with the goal of

receiving a prescription

• As many as 20% of nonmedical stimulant users misrepresent their

symptoms to obtain a prescription

• Tend to endorse more symptoms of hyperactivity and restlessness
• Often give intentionally poor performances on cognitive tests,

especially those assessing attention

• Important to confirm diagnosis of ADHD
• Nonmedical use and diversion of stimulants is commonly low

compared with other prescription medications, such as benzodiazepines or opioids

Clemow DB, Walker DJ. Postgrad Med 2014;126(5):64-81; Martinez-Raga J et al. Ther Adv Drug Saf 2017;8(3):87-99.

The Rewards of Dopamine

• Subjective rewards are due to stimulants increasing synaptic dopamine (DA)

levels in the mesocorticolimbic system

• Mesocortical circuit includes ventral tegmental area (VTA) projections to nucleus

accumbens and prefrontal cortex

Ashok AH et al. JAMA Psychiatry 2017;74(5):511-9; Ballester J et al. Expert Rev Clin Pharmacol 2017;10(3):305-14; Levy F. Ther Adv Psychopharmacol 2016;6(6):382-3; Volkow ND, Swanson JM. Am J Psychiatry 2003;160(11):1909-18.

Dopaminergic Synapses

Stahl SM. Stahl’s essential psychopharmacology 2015.

Vesicular monoamine transporter-2 (VMAT2) Vesicle containing dopamine Dopamine Dopamine D2 receptors Dopamine transporter (DAT)

Dopaminergic Effects of Methylphenidate

Methylphenidate inhibits DAT as an allosteric modulator (does not bind to the same spot as dopamine)

Stahl SM. Stahl’s essential psychopharmacology 2015.

Increased synaptic dopamine

Dopaminergic Effects of Amphetamine (Amph)

Stahl SM. Stahl’s essential psychopharmacology 2015; Ashok AH et al. JAMA Psychiatry 2017;74(5):511-9; Heal DJ et al. J Psychopharm 2013;27(6):479-96.

Amph competitively inhibits VMAT2 Increased synaptic dopamine Amph reverses the direction of DAT, leading to increased dopamine in synapse Amph competitively inhibits DAT Dopamine displaced from synaptic vesicles builds up in cytosol

Choose Your Poison

• Amphetamine (Amph)
• Competitively inhibits dopamine transporter (DAT)
• Increases DAT-mediated reverse transport of DA from cytoplasm to synapse
• Binds to vesicular monoamine transporter (VMAT2), inhibiting uptake of monoamines

into synaptic vesicles

• Inhibits monoamine oxidase (MOA), the enzyme responsible for monoamine breakdown
• Methamphetamine (MA)
• Same basic mechanism of action as Amph but…
• More addictive than Amph due to greater central nervous system (CNS) penetration and

longer duration of action

• Euphoria is experienced within 5 minutes and lasts for 8–12 hours
• Cocaine
• Slower CNS uptake and faster clearance than MA
• Acts primarily by blocking DAT
• Euphoria lasts for 20–30 minutes

Ashok AH et al. JAMA Psychiatry 2017;74(5):511-9; Ballester J et al. Expert Rev Clin Pharmacol 2017;10(3):305-14; Heal DJ et al. J Psychopharm 2013;27(6):479-96; Morais APD et al. CNS Neurosci Ther 2018;24(2):85-97; Thanos PK et al. Beh Brain Res 2017;320:282-90.

Prescription Stimulants vs. Illicit Stimulants

• Stimulant “high” depends on how much dopamine is increased AND how fast that

increase occurs

• Prescribed stimulants:
• Have been successfully used to treat ADHD in patients with MA or cocaine addiction
• Do not increase risk of substance-related events, even in patients with a history of illicit

stimulant use disorders

• Methylphenidate and d-amphetamine:
• Have a much slower striatal uptake compared to MA or cocaine
• When abused, are most often injected
• Formulations (extended release, bead technology, osmotic pump, tamper-proof capsules) lower

risk of abuse potential based on likability studies

• Lisdexamfetamine:
• Prodrug of d-amphetamine
• Injecting or snorting does not increase drug-positive effects because pharmacokinetic curve is

exactly the same

Levy F. Ther Adv Psychopharmacol 2016;6(6):382-3; Luo SX, Levin FR. Curr Psychiatry Rep 2017;19(3):14; Heal DJ et al. J Psychopharm 2013;27(6):479-96; Quinn PD et al. Am J Psychiatry 2017;174(9):877-85; Volkow ND, Swanson JM. Am J Psychiatry 2003;160(11):1909-18.

Non-Stimulants

• No direct influence on dopaminergic areas linked to stimulant

abuse

• Guanfacine and clonidine
• Influence norepinephrine levels by acting as alpha 2 adrenergic

receptor agonists

• Atomoxetine
• Norepinephrine transporter inhibitor
• Less effective for ADHD compared to stimulants?

Clemow DB, Walker DJ. Postgrad Med 2014;126(5):64-81; Martinez-Raga J et al. Ther Adv Drug Saf 2017;8(3):87-99; Cortese S et al. Lancet Psychiatry 2018;5(9):727-38.

Abuse Potential of Common ADHD Treatments

Treatments Abuse potential Stimulants Amphetamine (XR) High Methylphenidate (XR) High Lisdexamfetamine Low Non-stimulants Atomoxetine None Guanfacine (XR) None Clonidine (XR) Low

Bold indicates FDA approval for treatment of adult ADHD; XR=extended release.

Stahl SM. The prescriber’s guide. 6th ed. Cambridge University Press 2017.

Untreated Symptoms Summary

• MA may be misused to ameliorate untreated psychiatric

symptoms associated with ADHD

• Stimulant “high” depends on how much dopamine is

increased and how fast that increase occurs

• Prescribed stimulants may be used to treat ADHD in patients

with MA addiction; do not increase risk of substance-related events

• Methylphenidate and d-amphetamine have a much slower

striatal uptake compared to MA

• Lisdexamfetamine has very low abuse potential

CASE 2

Ta Dy

rdi rdive ve ski skinesi nesia

Methamphetamine (MA) is Associated with Dysregulated Dopamine and Fine Motor Function

• Meta-analyses indicate:
• Lower whole striatum, caudate,

and putamen dopamine D2/D3 receptor availability and dopamine transporter (DAT) availability in MA users versus non-users

• Deficits in fine motor function in

adults with a history of MA abuse or dependence versus non-users

Proebstl L et al. Eur Psychiatry 2019;59:15-24; Ashok AH et al. JAMA Psychiatry 2017;74(5):511-9; Scott JC et al. Neuropsychol Rev 2007;17(3):275-97; Volkow ND et al. Am J Psychiatry 2001;158(3):377-82. Fine motor deficits may be associated with striatal DAT availability in detoxified MA abusers (n=15)

Extrapyramidal Side Effects (EPSE) in Psychotic Disorder With Comorbid Methamphetamine (MA) Use Disorder

Adults with psychotic disorder and MA use disorder have greater odds for EPSE

4.01 x Odds

Adults with psychotic disorder and MA dependence are more likely to have EPSE

5.48 x Odds

Results from secondary analysis of data from three primary studies of adults with comorbid psychotic disorders who were taking antipsychotic medication (N=102). MA use disorder (abuse or dependence) was present in 25.5% of participants.

Temmingh HS et al. J Dual Diagn 2020;16(2):201-17.

*p<0.05

History of Methamphetamine Use Is Associated With a Parkinson’s Disease (PD) Risk Factor

Substantia nigra (SN) echogenicity was compared in adults with a history of chronic methamphetamine (METH) use (n=59) and controls (n=59) using transcranial sonography.

Rumpf JJ et al. Mov Disord 2017;32(12):1784-8; Berg D et al. Arch Neurol 2011;68(7)932-7; Berg D et al. Mov Disord 2013;28(2):216-9; van de Loo S et al. J Neurol Neurosurg Psychiatry 2010;81(10):1087-92.

Risk factor for PD

Potential Association Between Methamphetamine (MA) Use and the Development of Parkinson’s Disease (PD)

• 76% increased risk of developing PD over 16-year follow-up in

adults with MA use disorder (n=40,472) compared to a matched population-proxy appendicitis group (n=207,831)

• Elevated risk not observed in individuals with cocaine use disorder

Retrospective population-based cohort study

• 2.8 times greater risk of PD among chronic MA users (n=4,935)

versus matched controls (n=24,675)

• Elevated risk not observed in individuals with chronic cocaine use

Retrospective cohort study

• Prolonged amphetamine exposure was 8.04 times more frequent

in patients with PD than their spouses (N=480)

• Prolonged exposure to amphetamines occurred an average of 27

years before PD diagnosis

Survey study

Callaghan RC et al. Drug Alcohol Depend 2012;120(1-3):35-40; Curtin K et al. Drug Alcohol Depend 2015;146:30-8; Garwood ER et al. Neurotoxicity 2006;27(6):1003-6; Lappin JM et al. Drug Alcohol Depend 2018;187:134-40.

Modulatory Factors of the Association Between Methamphetamine (MA) and Parkinson’s Disease (PD)

• Age of MA onset and cessation
• Lag time between exposure to

MA and onset of PD (recovery from neurotoxic effects of MA?)

• Dose and duration of exposure

effects

• Smoking nicotine (reduces risk
• f PD)

Drug Use Factors

• Male gender
• Hispanic ethnicity
• Exposure to other neurotoxins
• Comorbid physical illness (e.g.,

HIV)

• Comorbid psychiatric illness

and their treatments

Individual-Level Factors

Lappin JM et al. Drug Alcohol Depend 2018;187:134-40.

Tardive Dyskinesia Summary

• MA use has negative impact on gross and fine motor function

that is associated with reduction in DAT availability

• Adults with psychotic disorder and MA use disorder or MA

dependence taking antipsychotics have greater risk of extrapyramidal side effects

• History of MA use is associated with a risk factor for

Parkinson’s disease (i.e., substantia nigra echogenicity)

• Risk of Parkinson’s disease may be elevated in individuals

with a history of MA use disorder or chronic MA use

• Risk may be modulated by individual and drug use factors

CASE 3

N Th

• vel
• vel

erapy erapy

Stimulant Agonist Therapies for Treating Methamphetamine (MA) Dependence

Studies on lisdexamfetamine, a prodrug of dexamphetamine, are ongoing

Dexamphetamine*

• Reduction in MA dependence

symptoms in post-hoc analysis

• Greater reduction in MA withdrawal

severity (secondary outcome)

• Greater reduction in MA cravings

(secondary outcome)

Methylphenidate+

• Fewer self-reported MA use

episodes (secondary outcome)

• Reduction in craving
• Fewer positive urine drug screens
• Reduced depressive symptoms

Stimulant agonist therapies (i.e., Medication Assisted Treatment) show promise for treating MA dependence, particularly regarding withdrawal and craving symptoms, in small clinical trials

*Sustained-release oral formulation

+Sustained/extended-release oral formulation

Siefried KJ et al. CNS Drugs 2020;34(4):337-65; Longo M et al. Addiction 2010;105(1):146-54; Galloway GP et al. Clin Pharmacol Ther 2011;89(2):276-82; Ling W et al. Addiction 2014;109(9):1489-500; Rezaei F et al. Daru 2015;23(1):2.

Aripiprazole Does Not Reduce Methamphetamine (MA) Use Compared to Placebo

Data from randomized controlled trial to test efficacy in decreasing use in MA-dependent adults (n=90) Abstinence from MA, medication adherence, and sexual risk behaviors also did not differ by treatment

Coffin PO et al. Addiction 2013;108(4):751-61.

Aripiprazole Does Not Increase Methamphetamine (MA) Abstinence Compared to Placebo

Data from double-blind study where MA-dependent subjects with a history of psychosis were randomly assigned to aripiprazole (5-10 mg/day; n=19) or placebo (n=18) for 8 weeks.

Sulaiman AH et al. Int J Psychiatry Clin Pract 2013;17(2):131-8. 10 20 30 40 50 60 70 80 90 100

Screen Baseline Day 7 Day 14 Day 28 Day 42 Day 56 Percent

Methamphetamine Positive Urine Screens

Placebo Aripiprazole Treatment with aripiprazole significantly reduced self-reported craving for MA compared to placebo (p=0.015)

Aripiprazole Reduces Methamphetamine (MA) Craving

1 2 3 4 5 6 7

Baseline Days 1-7 Days 10-16 Days 19-25 Visual Analogue Scale Score

Methamphetamine Craving

Data from patients with MA dependence and MA-associated psychosis (n=42) randomized to aripiprazole (initial dose 5–10 mg/day followed by flexible doses of 4–6 mg/day) or risperidone from Day 3 to Day 25 of inpatient hospital stay.

Wang G et al. J Subst Abuse Treat 2016;62:84-8.

*

*p<0.001

Long-Acting Injectable (LAI) Risperidone Treatment Associated With Reductions in MA Use

Data from an open-label trial of LAI risperidone treatment (4 bi-weekly 25 mg intramuscular injections) for MA dependence (during the past year and used MA within 30 days; n=22) following 7-day open-label run- in with oral risperidone (>2 mg/day) that was maintained during the first 3 weeks after initial injection.

Study Week

• 1

1 2 3 4 5 6 7 8

Daily oral dose Injection Injection Injection Injection

Estimated Mean MA Use Per Week Meredith CW et al. J Addict Med 2009;3(2):55-65.

• No serious adverse events
• Five subjects experienced mild

akathisia at one or two visits

• Increased prolactin, total

cholesterol, low-density lipoprotein cholesterol, and body mass index at Week 8 versus Week -1

MA Dependence Treatment Efficacy

Treatment Methamphetamine Outcomes Use Dependence a Craving a Withdrawal a Abstinence b Dexamphetamine

• ↓ (post-hoc)

↓ (2o outcome) ↓ (2o outcome)

• Methylphenidate

↓ (2o outcome) a

• ↓
• ↑ (2o outcome)

Aripiprazole

• ↓ (no PBO control)
• LAI risperidone

↓ (open-label) a, b

• 2o=secondary; PBO=placebo; LAI=long-acting injectable. a Determined from self report; b Determined from urine toxicology.

NOTE: All outcomes from small clinical trials (n≤110)

Novel Therapy Summary

• No strong clinical evidence of MA dependence

treatment efficacy; support from secondary endpoints and post-hoc analysis of data from small trials only

• Stimulant agonist therapies (i.e., dexamphetamine,

methylphenidate) may reduce MA craving and withdrawal symptoms, but not MA use

• Aripiprazole may reduce MA craving, but not MA use or

abstinence

• LAI risperidone may reduce MA use

CASE 4

Ac Co

tual tual ndi nditi tion

• n

Co-occurrence of MA Abuse and Bipolar Disorder

• Lifetime prevalence for stimulant dependence is 2.8% in bipolar

type I and 5.6% in bipolar type 2 disorder

• Among recently hospitalized patients with bipolar disorder, more

men than women use MA

• No difference in bipolar disorder patients with or without MA use in

the following:

• Age
• Duration of bipolar illness
• Number of hospitalizations
• Young Mania Rating Scale global score
• Hamilton Depression Rating Scale global score

Chengappa KN et al. Bipolar Disord 2000;2(3 Pt 1):191-5; Gouran Ourimi E et al. Med J Islam Repub Iran 2016;30:421.

Antipsychotic Treatment in Co-Occurring Bipolar Disorder and Stimulant Dependence

Results from randomized double-blind trial testing efficacy of quetiapine (n=42) and risperidone (n=38) in outpatients with bipolar disorder (I or II) and cocaine (63%) or methamphetamine (37%) dependence Decreased drug cravings were related to less frequent drug use (p=0.03)

Nejtek VA et al. J Clin Psychiatry 2008;69(8):1257-66.

*

*p<0.005, effect of study week

Drug Craving

*

Positive Effect of Citicoline on Depression Symptoms and Treatment Retention

Findings from randomized double-blind study of 48 patients with unipolar or bipolar depression and MA dependence (MA use within 14 days) treated with citicoline (up to 2000 mg/day) or placebo for 12 weeks. Greater Treatment Retention in Citicoline Group

2 4 6 8 10 12 14

Citicoline Placebo Change in Depression Severity Post-treatment—Baseline

Greater Reduction in Depression Severity with Citicoline

*

*p=0.05

Brown ES, Gabrielson B. J Affect Disord 2012;143(1-3):257-60.

Adjunctive Modafinil for Bipolar Depression Comorbid With Methamphetamine Abuse: A Case Study

• 38-year-old female diagnosed with bipolar

mixed type

• Reported almost daily MA use starting at age

30 to help maintain her hyperactivity and reduce her dysphoria, depression, and fatigue

• MA use made underlying withdrawal

depression worse, with frequent suicidal gestures

• Divalproex and quetiapine with adjunctive

dextroamphetamine, methylphenidate, and dexmethylphenidate were unsuccessful for treating depression

• Reduced fatigue and depressive symptoms

without induction of manic symptoms

• Decreased MA cravings; achieved

abstinence after 6 months Modafinil 600 mg/day + quetiapine 800 mg/day + divalproex 1,000 mg/day

Camacho A et al. Am J Addict 2010;19(2):190-1.

MA Use Disorder May Precipitate Ultra-Rapid Cycling Bipolar Disorder: A Case Study

• Man in mid-40s began MA use around 30

years old, with several 1- to 2-month periods in which he injected MA 1–2 times a week

• Received selective serotonin reuptake

inhibitors to treat depression and anxiety following an assault

• Hospitalized for two occasions of ultra-

rapid cycling mood states (mood states lasted 3–7 days each) that were precipitated following injections of a high- dose (1000 mg) of high purity (>90%) MA

• No psychotic symptoms

Ikawa H et al. SAGE Open Med Case Rep 2019;7:2050313X19827739.

Decreased mood symptoms, but he predominantly remained in moderately depressive state Lithium carbonate (600–800 mg/day) and aripiprazole (12 mg/day)

Actual Condition Summary

• MA use and dependence may co-occur with bipolar disorder,

which may complicate treatment

• Quetiapine and risperidone have demonstrated efficacy in

reducing MA craving in a small clinical trial (no placebo control)

• Adjunctive modafinil may reduce depression, MA craving, and

help achieve MA abstinence (case study)

• Citicoline has demonstrated efficacy in reducing depression

symptoms in a small clinical trial

• High-dose, high-potency MA may precipitate ultra-rapid

cycling bipolar disorder in chronic users (case study)

CASE 5

Pa P

ti tient ent sy sychosi hosis

MA Use Is Associated With Psychosis

• Chronic MA use is associated with extensive neurodegeneration, cognitive

impairment, and psychosis

• Repeated and high dosing of MA can result in psychosis that may persist for

months

• MA sensitization: Latency to precipitate psychosis in relapse state is shorter

than latency to initial psychosis from first MA use

• Underlying mechanism may be dopamine (DA) supersensitivity
• Presynaptic DA depletion due to long-term intermittent DA release or terminal

damage following repeated exposure to MA induces hypodopaminergic state

• The hypodopaminergic state then induces DA supersensitivity that leads to the

immediate recurrence of a psychotic state upon re-exposure to MA

Shin EJ et al. Arch Pharm Res 2017;40(4):403-28.

Treating MA-Induced Psychosis With Aripiprazole

Sulaiman AH et al. Int J Psychiatry Clin Pract 2013;17(2):131-8.

Results from a randomized, double-blind study testing efficacy of 8 weeks of risperidone (5–10 mg/day; n=19) versus placebo (n=18) treatment of psychosis in patients with MA dependence.

Treatment Outcome Direction of Effect Study retention Aripiprazole > Placebo MA-free days (urine testing) Aripiprazole = Placebo Decrease in psychotic symptom severity (PANSS) Aripiprazole > Placebo Decrease in illness severity (CGI-S) Aripiprazole > Placebo Decrease in MA cravings (BSCS) Aripiprazole > Placebo Akathisia (BARS) Aripiprazole = Placebo Extrapyramidal symptoms (AIMS) Aripiprazole = Placebo Parkinsonism symptoms (SAS) Aripiprazole = Placebo

AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Rating Scale; BSCS=Brief Substance Craving Scale; CGI-S=Clinical Global Impression-Severity; PANSS=Positive and Negative Syndrome Scale; SAS=Simpson-Angus

• Scale. Bold indicates significant finding at p<0.05.

Similar Efficacy of Quetiapine and Haloperidol for the Treatment of MA-Induced Psychosis

Verachai V et al. Psychopharmacology (Berl) 2014;231(16):3099-108.

Findings from a randomized, double-blind study comparing the efficacy of 4 weeks of quetiapine (>100 mg/day; n=36) and haloperidol (>2mg/day; n=44) on the treatment of MA-induced psychosis.

*p<0.001 effect of time

* *

Paliperidone Extended-Release (ER) Tablets for the Treatment of MA Use and Psychotic Relapse

Data from a randomized, double-blind exploratory study testing efficacy of 84 days of paliperidone ER (3 mg/day; n=40) or placebo (n=40) treatment for methamphetamine (MA) use in MA-dependent patients who were discharged from MA detoxification and had remitted psychotic symptoms 7 days prior.

10 20 30 40 50

Paliperidone ER Placebo Positive and Negative Syndrome Scale Total Score

Psychotic Symptom Severity

Baseline Day 84

*

1 2 3 4 5 6

Paliperidone ER Placebo MA Craving Score

Methamphetamine Craving

Baseline Day 84

* Participants in Paliperidone ER group had significantly lower risk of psychosis recurrence (HR=0.15, p=0.003) Paliperidone ER did not differ from placebo group in longest MA abstinence determined from urine (p=0.24)

*p<0.006

Wang G et al. Front Psychiatry 2019;10:656.

Similar Efficacy of Paliperidone Extended-Release (ER) and Risperidone for MA-Induced Psychosis Treatment

Data from a randomized, assessor-blinded study testing efficacy of 25 days of paliperidone ER (3–9 mg/day; n=60) versus risperidone (3–6 mg/day; n=60) treatment for MA-induced psychosis.

Wang G et al. Front Psychiatry 2020;11:237.

No significant group differences in illness severity, MA craving, or akathisia (p>0.05) Risperidone > Paliperidone ER

• Increase in parkinsonism

symptoms over time (group x time: p<0.01)

• Incidence of hypermyotonia,

salivation, and dizziness adverse events (p<0.05)

*p<0.01 effect of time

10 20 30 40 50 60 70 80 90 Baseline Time 1 (Days 1-7) Time 2 (Days 10-16) Time 3 (Days (19-25)

Positive and Negative Syndrome Scale Total Score

Psychosis Severity

Paliperidone ER Risperidone

* *

MA-Induced Psychosis Treatment Efficacy

Treatment Psychotic Symptom Severity a MA Use b MA Craving a Aripiprazole

↓ (2o outcome)

• ↓ (2o outcome)

Haloperidol

↓ (No PBO control)

• Quetiapine

↓ (No PBO control)

• Paliperidone ER

↓ (No PBO control)

• ↓

Risperidone

↓ (No PBO control)

• 2o=secondary; ER=extended release; PBO=placebo. a Determined from self report; b Determined from

urine toxicology.

NOTE: All outcomes from small clinical trials (n≤120)

Treating MA-Induced Resistant Psychosis With Clozapine: A Case Report

CASE 1

• 34-year-old man hospitalized 12 times due to MA-

induced psychosis

• Antipsychotic treatments (i.e., olanzapine,

risperidone, thiothixene) effective for 1–2 weeks

• nly
• Despite MA withdrawal, psychosis remained:

paranoid delusion and command auditory hallucinations

• 6 sessions of electroconvulsive therapy did not

resolve psychosis

• Clozapine (25 mg daily, titrated to 150 mg daily)
• Psychosis resolved in 2 weeks
• At 8-month follow-up, clozapine use continued, no

relapse of psychotic symptoms was noted, and early full remission from MA was achieved

Seddigh R et al. Case Rep Psychiatry 2014;2014:845145.

CASE 2

• 29-year-old man hospitalized for MA-induced

psychosis

• Symptoms continued despite MA withdrawal:

persecutory delusion, reference delusion, somatic hallucinations, and olfactory hallucinations

• Prescribed clonazepam for aggression during

hospitalization

• Antipsychotic treatments did not resolve psychosis

(i.e., olanzapine, risperidone, quetiapine, haloperidol)

• Clozapine (100 mg daily); clonazepam (2 mg daily)

discontinued 1 week after clozapine administration

• At 9-month follow-up, clozapine use continued, no

relapse of psychotic symptoms was noted, and early full remission from MA was achieved

Drug-Induced Parkinsonism Following Haloperidol Decanoate in Chronic MA User: A Case Study

• 32-year-old male with severe MA dependence (>2 years; 3–4 times per week smoking and IV)
• Command auditory hallucinations, intent to harm self, self-mutilating behavior
• Remained psychotic following high dose of oral haloperidol (15 mg BID), despite ceasing MA use for

several days

• Prescribed Haldol decanoate (100 mg IM, followed by additional 50 mg IM dose a week later) and oral

benztropine, and stabilized

• After discharge, he resumed daily IV meth use for at least 5 consecutive days
• Bilateral hand tremors, excessive salivation, tongue protrusion, trouble swallowing, knee and ankle

stiffness, truncal rigidity, and spastic gait with a tendency to lose balance after a few steps led to emergency department visit

• Patient stabilized after oral diphenhydramine (100 mg BID) was added to preexisting Haldol decanoate

and he was discharged

Matthew BJ, Gedzior JS. Int J Psychiatry Med 2015;50(4):405-11.

Patient Psychosis Summary

• MA-induced psychosis may be caused by dopamine supersensitivity

that is responsive to antipsychotic treatment

• Haloperidol, aripiprazole, quetiapine, risperidone, and paliperidone

have demonstrated efficacy in treating psychotic symptom severity in small clinical trials

• Aripiprazole and paliperidone have demonstrated efficacy in reducing

MA craving in small clinical trials

• No strong clinical evidence that antipsychotics reduce MA use
• In treatment-resistant MA-induced psychosis, clozapine may be

efficacious (case report)

• LAI haloperidol may cause drug-induced parkinsonism (case study)

Overall Summary

• Evidence from small clinical trials indicates there are several

medications that may reduce MA craving and withdrawal symptoms, but none that reduce MA use

• Secondary analyses indicate methylphenidate may reduce MA use

episodes

• Lisdexamfetamine trials are ongoing
• Special considerations when treating patients with comorbid

ADHD, bipolar disorder, or schizophrenia

• Stimulant treatment for ADHD does not worsen MA use outcomes
• Atypical antipsychotic treatment for MA-induced psychosis may

reduce MA craving

• Chronic MA use may increase risk for Parkinson’s disease

Posttest Question 1

Michael is a 26-year-old man who states that he has been using methamphetamines since he was 17 years old in order to self-medicate for diagnosed, but insufficiently treated, ADHD. His medical records show that he was indeed diagnosed with ADHD at age 10. At the time, his parents did not want him placed on a stimulant due to concerns over developing a substance use disorder. He therefore received adequate trials of non-stimulants (including atomoxetine, guanfacine, and clonidine) as a youth with minimal improvement in ADHD

• symptoms. He now comes to you asking for help in treating his ADHD symptoms.

Of the following treatments, which would be the best course of action?

• A. Re-trial of atomoxetine
• B. Initiate XR amphetamine
• C. Initiate XR methylphenidate
• D. Initiate lisdexamfetamine
• E. None of the above

Posttest Question 2

Chris is a 56-year-old Hispanic male who abused methamphetamine throughout his 30s and most of his 40s. He developed methamphetamine dependence, for which he is in remission. Except for smoking nicotine, he does not use any other

• substances. Which of the following individual or drug use factors is purported to

decrease his risk for developing Parkinson’s disease? A. His gender B. His ethnicity C. Smoking nicotine D. The duration of his methamphetamine abuse

Posttest Question 3

Rebecca is a 32-year-old woman with methamphetamine use disorder who is seeking treatment. Based on clinical trial data, which medication has strong evidence for reducing methamphetamine use? A. Dexamphetamine B. Methylphenidate C. Aripiprazole D. Risperidone E. None of the above

Posttest Question 4

Albert is a 42-year-old man who was recently admitted for inpatient psychiatric care following severe symptoms of psychosis, including auditory hallucinations, paranoid delusions, and agitation. His symptoms are likely due to chronic methamphetamine abuse and a recent 3-day methamphetamine binge episode. In addition to treating his psychosis, which of the following medications may reduce his methamphetamine craving, based on clinical trial evidence? A. Paliperidone B. Quetiapine C. Brexpiprazole D. Clozapine