An Antipsychotic?

The ABCDs of Overcoming Roadblocks to recovery in First episode psychosis

Matcheri S Keshavan MD MAPNET, Beth Israel Deaconess Medical Center, Massachusetts Mental Health Center and Harvard Medical School

MH 64023; 60902; 92440, Commonwealth Research Center and a FEPTAC grant by DMH. No other relevant disclosures STAGES OF RECOVERY

Worse

Stage 1: Symptom stabilization

Better

Stage 2: Functional Stage 3: recovery Acceptance, Integration Worse

Weeks Months Years Key points

• What are the outcome trajectories in schizophrenia? • How can we predict outcome? – Non-malleable – Malleable • How we can overcome these obstacles? • Summary and next steps The Kraepelinian pessimism of Dementia praecox And Bleulerian optimism The patient may never achieve restitutio ad integrum

Bleuler 1911

The sooner patients can be restored to an earlier life and the less They are allowed to withdraw into the world of their own ideas, The sooner do they become socially functional

Bleuler 1908 Outcome in schizophrenia is variable Single Episode, full remission

40% Episodic, without Inter-episode deficits

Episodic, w/inter-episode 30% deficits Chronic, Persistent/ 30% Ciompi, Bleuler, Jablenski declining Outcome can be improved by appropriate intervention at any phase of illness The “snowballing effect” in the course of schizophrenia

Premorbid deficits

Negative family and societal response Prodromal Psychotic/ negative sx Ist psychotic episode Sec negative Stresses of adolescence Untreated Sx “Neurotoxicity” Fear, denial, Stigma, Substance abuse Relapse Med side effects, Substance abuse Poor insight Cognitive impairment

Noncompliance Predictors of outcome • Outcome trajectories in schizophrenia • How can we Predict outcome? – Non-malleable – Malleable • Adherence • Brain and cognition • Cannabis and other substance misuse • Delay in Treatment (DUP) • Can we influence outcome of psychotic disorders? • Summary and next steps Gender: no differences in outcome Race : African Americans may

SEX*"timept1"; LS Means have poorer outcome Wilks lambda=.98706, F(10, 1752)=1.1443, p=.32487 70 RACE*"timept1"; LS Means Wilks lambda=.97829, F(10, 1600)=1.7658, p=.06201 65 Effective hypothesis decomposition Vertical bars denote 0.95 confidence intervals 60 70

65 55 172 males and 60 50 100 females 55

GAS 45 50

40 GAS 45

35 40

30 35 SEX 1 30 25 SEX BASELINE WK04 WK26 YR1 YR2 YR4 RACE 2 25 timept1 BASELINE WK04 WK26 YR1 YR2 YR4 1 RACE timept1 2

A diagnosis of schizophrenia predicts a poorer outcome

DIAGMAX*"timept1"; LS Means Wilks lambda=.95356, F(15, 2501.5)=2.8974, p=.00015 Effective hypothesis decomposition Vertical bars denote 0.95 confidence intervals 80

Pittsburgh 70 First episode 65 60 Non-Schiz psychoses n=95 Longitudinal 55 GAS 50 Study 45 Schiz psychoses n=175 40

30 DIAGMAX 25 BASELINE WK04 WK26 YR1 YR2 YR4 1 DIAGMAX Non-malleable predictors timept1 2 Reversible predictors: Early Adherence Predicts Subsequent Adherence During Follow-up in First Episode 1. Adherence to treatment Psychoses

120 p= .000025 .000155 .0024 .0005 100

20 Compliance rating Compliance

Follow-up 6 months 12 months 24 months 48 months Good (>80%) adherence at 4 weeks) Keshavan et al Poor (<80%) adherence at 4 weeks) unpublished Impaired neurocognition Reversible predictors: strongly points to brain dysfunction early in 2. Brain and cognition schizophrenia

Neuropsychological performance in early schizophrenia, psychotic and non-psychotic depression nd healthy comparison subjects (Hill, Keshavan et al AJP 2004) Frontotemporal gray matter loss predicts poor outcome in schizophrenia

Prasad et al Prog Neuropharmacol Biol Psychiatry 2005

Wojtalik JA1, Smith MJ2, Keshavan MS3, Eack SM1,4. A Systematic and Meta-analytic Review of Neural Correlates of Functional Outcome in Schizophrenia. Schizophr Bull. 2017 Wood et al 2006 Reversible predictors:3. Cannabis and other drugs of misuse.

Cannabis abuse predicts relapse and Brain dysfunction non-adherence mediates this effect Schoeler, et al Poor medication adherence and risk of relapse associated with continued cannabis use in patients with first-episode psychosis: (n=397) a prospective analysis Lancet Psychiatry. 2017

Schiz Res 2009 Intermittent and persistent users have lower rates of remission in FEP

On-off users Continuous users

N=301) Weibel et al Schiz Bulletin 2017 Frequency of conversion from SIP to schizophrenia is Highest with cannabis abuse

Alderson and Lawrie Psychological Medicine 2017 Prolonged Illness duration predicts poor outcome in first episode psychoses Keshavan et al Schizophrenia Bulletin 2003

35 Partial r=-.39; p=.001

ILLNESS DURATION FROM PRODROME (SQRT WKS) ILLNESS DURATION FROM PRODROME -5 4 6 8 10 12 14 16 18 STRAUSS CARPENTER OUTCOME SCORE AT 1 YEAR

Reversible predictors:

4. Delay in treatment

Neuroreport 2009 Summary: Roadblocks to recovery

Delay in treatment

c c Brain and

Cannabis and other drugs cognitive c Poor

dysfunction recovery c

Adherence, lacking Determinants of outcome • Outcome trajectories in schizophrenia • Predictors of outcome – Non-malleable – Malleable • How can we overcome these reversible roadblocks? • Summary Model of Care

Recognition & Assessment Screening Case manager, psychiatrist

Psychosocial Research Management Staff Coordinated . work Symptoms, side Specialty Care effects, quality of life, genetic, . school etc.)

. Neuropsychologist relationships TREATMENT

Medical Management Psychotherapy Individual Family Cognitive Group intervs. Family Education remediation Intervention Modules Approaches to enhance adherence

• Patient who refuses meds • Improve therapeutic alliance; rapid acting meds; involuntary meds as last resort • Patient non-adherent because • Dosage adjustment; consider meds not working medication switch, clozapine

• Patient non-adherent because • Dosage adjustment; consider of side effects medication switch; monitor & educate re. Side effects

• Patient does not show up for • Improve hospital to clinic first appointment continuity; make care more accessible and patient friendly

• Patient who frequently • Cues to remember; memory aids misses/forgets meds/appts such as pillboxes and alarm watches; phone call reminders; Long acting injections, digital pills • Patient who believes he/she • Compliance therapy; continuing does not need meds psychoeducation; cognitive remediation CET is effective in chronic schizophrenia .. as well as early course schizophrenia

Hogarty.. et al Arch Gen Psy 2004; Eack…Keshavan J Psychiatric Services 2009 Psychosocial treatments can Harness brain plasticity early in those at risk to protect against gray matter loss, and to build “reserve”

Eack et al Arch Gen Psychiatry 2010 Treatments for comorbid cannabis abuse

Psychoeducation

Cognitive-behavioral therapy

Contingency management

Motivational enhancement therapy

Cognitive enhancement therapy

No pharmacologic agents approved Early detection improves long term outcome in psychotic disorders

Hegelstad et al 2012 Am J psychiatry Conclusions • Outcome trajectories are variable, and increasingly optimistic in schizophrenia

• Predictors of outcome can be non-malleable but many are reversible. Brain structure and function mediate outcome, and are plastic, potentially reversible

• Outcome of psychotic disorders is likely to be favorably impacted by early integrated intervention. Each of the reversible roadblocks (Adherence, Brain reserve, Cannabis and treatment Delay) can be overcome, and leads to improved outcomes

• Symptomatic and functional recovery are not enough, and the goal has to include full personal recovery and integration Marijuana Legalization

David L. Hoffman, M.D., M.F.A. Medical Director, Metro Boston Area Massachusetts Dept. of Mental Health Objectives By the conclusion of this presentation, participants will be knowledgeable about: • The legal history of federal marijuana laws and regulations • The current status of regulations regarding medical and recreational marijuana in Massachusetts • Current Federal position regarding marijuana • Experience of states that have legalized marijuana • Challenges related to driving under the influence of marijuana • Significant issues involving the DMH service system created by the new medical and recreational marijuana regulations Disclosures

• I have no conflict of interest or commercial involvement in any products discussed in this presentation. U.S. Regulatory History of Marijuana - 1

• Widespread unregulated medicinal use until early 20th century. • 1st U.S restriction in Washington, D.C. in 1906 • In 1911 Massachusetts restricted sale of marijuana, requiring a prescription and classifying it as a habit-forming substance. • The Uniform State Narcotic Act (1925-1932) encouraged all states to regulate cannabis use. • Federal Bureau of Narcotics established in 1930. • 1937 Marihuana Tax Act prohibited all types of hemp production in U.S. and made marijuana illegal except for medical or industrial use. U.S. Regulatory History of Marijuana - 2

• 1970 - Controlled Substances Act, the federal drug policy under which the manufacture, importation, possession, use and distribution of certain substances, including marijuana, is regulated. • 1973 – Drug Enforcement Agency (DEA) established. The DEA is a Department of Justice federal law enforcement agency tasked with combating drug smuggling and use in the U.S. Schedules of Controlled Substances

• Placing a drug or other substance in a certain Schedule or removing it from a certain Schedule is primarily based on 21 USC §§ 801 • Every schedule otherwise requires finding and specifying the "potential for abuse" before a substance can be placed in that schedule.

• 21 USC § 801a - Congressional findings and declarations: psychotropic substances-

• (3) In implementing the Convention on Psychotropic Substances, the Congress intends that, consistent with the obligations of the United States under the Convention, control of psychotropic substances in the United States should be accomplished within the framework of the procedures and criteria for classification of substances provided in the Comprehensive Drug Abuse Prevention and Control Act of 1970. This will insure that:

• (A) the availability of psychotropic substances to manufacturers, distributors, dispensers, and researchers for useful and legitimate medical and scientific purposes will not be unduly restricted Schedule I

• Schedule I substances are those that have the following findings: • The drug or other substance has a high potential for abuse. • The drug or other substance has no currently accepted medical use in treatment in the United States. • There is a lack of accepted safety for use of the drug or other substance under medical supervision. • No prescriptions may be written for Schedule I substances, and such substances are subject to production quotas by the DEA.

• Some examples of Schedule I drugs are:

• heroin, lysergic acid diethylamide (LSD), marijuana (cannabis), 3,4- methylenedioxymethamphetamine (ecstasy), methaqualone, and peyote Marijuana as a Schedule I Drug

• On August 14, 1970, the Assistant Secretary of Health, Dr. Roger O. Egeberg wrote a letter recommending the plant, marijuana, be classified as a schedule 1 substance, and it has remained that way ever since. Dr. Egeberg wrote: "Since there is still a considerable void in our knowledge of the plant and effects of the active drug contained in it, our recommendation is that marijuana be retained within schedule 1 at least until the completion of certain studies now underway to resolve the issue.”

• Schedule I status has severely limited the ability to perform research regarding the clinical properties of marijuana in the U.S.

• “Ole Miss” - The University of Mississippi was selected in 1968 as the United States' first, and only, legal marijuana farm since the drug became illegal in 1937 under the Marijuana Tax Act. Gonzales v. Raich

• Gonzales v. Raich (previously Ashcroft v. Raich), (2005), was a decision by the Supreme Court ruling that under the Commerce Clause of the Constitution, Congress may criminalize the production and use of homegrown cannabis even where states approve its use for medicinal purposes.

• California voters passed Proposition 215 in 1996, legalizing the medical use of marijuana. The U.S. Federal Government has limited the use of marijuana since the 1937 Marijuana Tax Act came into effect. Defendant Angel Raich used homegrown medical marijuana, which was legal under California law, but illegal under federal law. On August 15, 2002, Butte County Sheriff’s Department officers and agents from the federal Drug Enforcement Agency (DEA) destroyed all six of California resident Diane Monson's marijuana plants. Current Legal Status of Marijuana

As of now, 9 states and Washington, D.C., have legalized the recreational use of marijuana. Only 4 states have no provision for access to marijuana for medical purposes. 205 million Americans live in a state where MJ is legal for either recreational or medical use. 65 million Americans live in a state where adults can legally consume MJ for any reason.

States where marijuana is decriminalized but not legalized:

•Connecticut •Delaware •Illinois •Maryland •Minnesota •Mississippi •Missouri •Nebraska •New Hampshire •New York •North Carolina •Ohio •Rhode Island Federal response to State Legalization of Marijuana Use - 1

• On August 27, 2013, Attorney General Eric Holder informed the governors of Washington and Colorado that the Department of Justice would allow the states to create a regime that would regulate and implement the ballot initiatives that legalized the use of marijuana for adults. • Deputy Attorney General James Cole also issued a three-and-a-half page memo to U.S. attorneys across the country. "The Department's guidance in this memorandum rests on its expectation that states and local governments that have enacted laws authorizing marijuana-related conduct will implement strong and effective regulatory and enforcement systems that will address the threat those state laws could pose to public safety, public health and other law enforcement interests. A system adequate to that task must not only contain robust controls and procedures on paper; it must also be effective in practice." Cole Memorandum

• The Cole Memorandum was a United States Department of Justice memorandum issued August 29, 2013 by United States Deputy Attorney General James M. Cole during the presidency of Barack Obama. The memorandum, sent to all United States Attorneys, governed federal prosecution of offenses related to marijuana. The memo stated that given its limited resources, the Justice Department would not enforce federal marijuana prohibition in states that "legalized marijuana in some form and ... implemented strong and effective regulatory and enforcement systems to control the cultivation, distribution, sale, and possession of marijuana," except where a lack of federal enforcement would undermine federal priorities (such as preventing violence in marijuana cultivation and distribution, preventing cannabis impaired driving, and preventing marijuana revenues from going to gangs and cartels). Rohrabacher–Farr amendment

The Rohrabacher–Farr amendment prohibits the Justice Department from spending funds to interfere with the implementation of state medical cannabis laws. It passed the House in May 2014 after six previously failed attempts. The passage of the amendment was the first time either chamber of Congress had voted to protect medical cannabis patients, and is viewed as a historic victory for cannabis reform advocates at the federal level. The amendment does not change the legal status of cannabis however, and must be renewed each fiscal year in order to remain in effect. No Change in Schedule 1 Status

• To the disappointment of many researchers, politicians, and patients, there was no attempt during the Obama administration to have cannabis removed from Schedule 1 to a different level which would have permitted a significant expansion in research regarding the harmful effects as well as the potential therapeutic effects of THC, CBD and the numerous other cannabinoids in marijuana. Jeff Sessions Position re MJ

• Attorney General Jeff Sessions announced on January 4, 2018 that he was rescinding an Obama-era policy that had paved the way for legalized marijuana to flourish in states across the country • Sessions said future prosecutions would be up to individual U.S. attorneys. However, the announcement appeared intended to discourage marijuana-related business by being deliberately vague about future federal enforcement efforts. • The new approach will probably increase confusion about the legal risk of marijuana-related activity in states that have passed legislation allowing people to grow, buy or use pot. • Boston U.S. Attorney, Andrew Lelling said he would not rule out targeted prosecution of the legal marijuana industry in Massachusetts. • Consequently, as of now no commercial banks in Massachusetts have agreed to work with recreational marijuana producers or distributors. "Black Americans are nearly four times more likely to get busted for marijuana possession than white Americans." (Nationwide, 3.73 times more likely.) 29 Communities of Disproportionate Impact

• In an effort to address the historical inequities in the prosecution of marijuana possession and distribution offenses, the Massachusetts Marijuana Control Commission has created provisions that encourage the participation of communities disproportionately affects by these past policies to become involved in the legal marijuana industry in the Commonwealth. • 29 Communities of Disproportionate Impact Abington Holyoke Revere Amherst Lowell Southbridge Boston Lynn Spencer Braintree Mansfield Springfield Brockton Monson Taunton Chelsea New Bedford Walpole Fall River North Adams Wareham Fitchburg Pittsfield West Springfield Greenfield Quincy Worcester Haverhill Randolph Is CBD Legal? MJ Legalization in MA • Decriminalization - On November 4, 2008, voters passed a ballot that decriminalized the possession of small amounts (less than 1 ounce) of marijuana. MJ Legalization in MA- Medical Marijuana • On November 6, 2012, 63% of Massachusetts voters approved Question 3, the Massachusetts Medical Marijuana Initiative. The law took effect on January 1, 2013, eliminating criminal and civil penalties for the possessions and use of up to a 60-day supply of marijuana for patients possessing a state issued registration card. MJ Legalization in MA- Recreational (non-medical) cannabis • In the November 8, 2016 election, Massachusetts voters passed a ballot initiative making recreational cannabis legal in the state. Governor Charles Baker signed legislation on 30 December 2016 extending the start date for recreational pot sales by six months, to July 2018. MJ Legalization in MA- Taxation • In July 2018, retail selling of marijuana is due to start in the state and the tax rate calls for a 10.75 percent excise tax on the marijuana, a 6.25 percent state sales tax, and up to a 3 percent local option tax for a total between 17-20 percent tax on purchases, depending on whether the locality has enacted the local option tax, which is a relatively low rate compared to other states. MA Marijuana Tax Revenue • Preliminary estimates predict that the Commonwealth could net $44-82M in additional tax revenue following full implementation of the recreational marijuana law. MA Cannabis Control Commission

• The mission of the Cannabis Control Commission is to honor the will of the voters of Massachusetts by safely, equitably and effectively implementing and administering the laws enabling access to medical and adult use marijuana in the Commonwealth. Steven J. Hoffman - Chairman Can Towns Ban MJ Sales?

• At least 189 of the state’s 351 municipalities have barred retail marijuana stores and, in most cases, cultivation facilities and other cannabis operations as well. • Fifty-nine of the local bans on marijuana businesses are indefinite. The remaining 130 are temporary moratoriums designed to buy local officials time to set up marijuana zoning rules. Many expire on July 1, and the rest are due to end later this year. • In municipalities where voters supported the 2016 ballot measure, implementing a ban requires a communitywide vote. In cities and towns where voters opposed legalization, elected bodies such as town councils or boards of selectmen can impose a ban without polling residents. Dispensaries Must Set Aside Product For Registered Patients

Registered marijuana patients in Massachusetts have had access to legal marijuana products at licensed dispensaries since 2015. Many of those patients fear there will be a stampede on July 1, when several of those dispensaries seek to also offer adult-use marijuana to anyone over the age of 21. The patients successfully convinced the Cannabis Control Commission to require that those dispensaries set aside 35% of their product, or a six-month average of their medical marijuana sales, for registered patients. Registered patients will also, at least for the time being, not have to stand in line with the general public to purchase what many consider their necessary medicine. FAQs • Can I grow my own marijuana in my home? – Yes. The law allows an individual over 21 years of age to grow up to six plants in their home.

• Can I smoke or consume adult use marijuana/ marijuana edibles at work? – Yes. An employer may restrict the consumption of marijuana in the workplace. FAQs • Can I drive with marijuana in my car? – Like alcohol, you may not have an open container of adult-use marijuana/marijuana products in the passenger area of your car while on the road or at a place where the public has access. An “open container” includes a package with its seal broken or a package from which the contents have been partially removed. The “passenger area” does not include a trunk or a locked glove compartment. The 2017 Act does not change the existing penalties for operating a car if you are impaired by the use of marijuana or marijuana products. You are strictly prohibited from consuming marijuana while operating a car. For specific information, see MGL c.90 § 24. MA Case Law re MJ & Driving • Comm. v. Gerhardt, 477 Mass. 775 (2017) – “There is a yet on scientific agreement on whether, and, if so, to what extent, [field sobriety] tests are indicative of marijuana intoxication...Neither a police officer not a lay witness who has not been qualified as an expert may offer an opinion as to whether a driver was under the influence of marijuana.” A police officer may testify, however, about his or her observations, including observations of the defendant’s performance on requested behaviors. • This decision includes a new Model Jury Instruction Regarding Roadside Assessments for Use in Prosecutions for Operating Under the Influence of Marijuana. MJ Drug Testing in the Workplace • >50% of US companies drug test their employees. • Federal laws re MJ can limit employer discretion re testing. • 4.2% of workers nationally test positive for drugs. • Positive tests for MJ are increasing nationally (~10-50%). • As with driving, there is no objective test criteria for actual impairment in job performance in individuals who test positive for MJ. • Some employers with discretion re mandatory testing are treating MJ the same way they treat alcohol use. • Other companies limit testing to employees engaged in more potentially risky tasks such as driving and operating machinery. The Colorado Experience

• Legalized Recreational MJ in 2012 by voter referendum – Colorado Amendment 64. • Visitors and tourists in Colorado can use and purchase marijuana, but face prosecution if found in possession in any adjacent state. Denver airport has banned all possession of marijuana but admits it has not charged a single person with possession nor has the airport seized any marijuana since the ban went into effect. • Colorado had legalized medical marijuana in 2000. • Colorado had decriminalized marijuana in 1975. Effect on Consumption Rate • Use by 12-17 year olds in Colorado declined from 12.5% to 9% in the 2 years following legalization. • Significant increase in positive marijuana tests in drivers in both fatal and non-fatal automobile accidents (~2x increase). Colorado MJ & Driving Law FAQs • Q: Is there a legal limit for marijuana impairment while operating a vehicle? • A: Colorado law specifies that drivers with five nanograms of active tetrahydrocannabinol (THC) in their whole blood can be prosecuted for driving under the influence (DUI). However, no matter the level of THC, law enforcement officers base arrests on observed impairment. • Q: What if I use marijuana medicinally? • A: If a substance has impaired your ability to operate a motor vehicle it is illegal for you to be driving, even if that substance is prescribed or legally acquired. 300+% Increase in Pediatric ER Visits • From 2005 to 2015, significant increase in cannabis- related ER visits among 13-21 year olds despite no overall increase in marijuana use in that age group. • 66% of patients presented with symptoms of mental illness • Over 50% of patients presented with a positive toxic screen for at least one other drug in addition to marijuana. • ~30% required hospital admission. • The high potency of current cannabis products is seen as a likely cause of this trend. Dosing Issues with Edible Marijuana Products • Strong Association between Edible Use and Overconsumption • Pharmacokinetic issues, including variable consumption and delayed peak effect (at 2-4 hours) are major factors. • Dosage labeling of edible products not always accurate, and packaging often contains high dosages (e.g., THC bars containing 100 mg. when the effective dose is 10-20 mg. and dividing the bar is not easily performed with accuracy). Symptoms of THC Intoxication

• Cognitive impairment • Motor impairment • Extreme sedation • Anxiety • Panic attacks • Agitation • Psychotic symptoms

States with medical marijuana laws see fewer opiate deaths.

According to a 2014 study in JAMA Internal Medicine, states with medical marijuana laws between 1999 and 2010 saw, on average, about 25% fewer opiate overdose deaths than states without such laws. Furthermore, the effect of a medical marijuana law appeared to grow over time — more lives were saved each additional year after the laws' implementation, suggesting an effect from more people taking advantage of the programs. Access to medical marijuana dispensaries is associated with less prescription painkiller abuse, and fewer overdose deaths.

A 2015 working paper published by the National Bureau of Economic Research found that the presence of medical marijuana dispensaries in a state was linked to a 15 to 35 percent decrease in admissions to substance abuse treatment centers, along with a similar decline in overdose deaths. Legalization Effect on Black Market

• In States where recreational MJ is illegal, the black market of course accounts for 100% of sales. • In Colorado, the black market sales have decreased to ~25%. • In Washington & Oregon, black market sales have only decreased to ~50% Market Forces of Legalization

• In states which have legalized recreational marijuana, the price has rapidly decreased by anywhere from 25-60% • In states where recreational marijuana is still illegal, the prices have also decreased somewhat, but not is dramatically. • The fairly high tax rate on legal marijuana does not appear to have affected this trend. • The high start-up costs for legal producers has driven many small growers out of the business. • There is evidence that organized crime is involved in producing marijuana in states where its cultivation is legal and then distributing it in other states. Issues for DMH

• Use in Hospitals • Use in DMH-funded Residences – Does DMH or Vendor Develop Policies? – Storage and Dispensing Issues • Prescriber Response to Requests for Use Certification

…and many more we haven’t thought of yet… What we Know about the Complex Relationships between Cannabis and Psychosis

Deepak Cyril D’Souza Professor of Psychiatry, Yale University School of Medicine Director, Schizophrenia Neuropharmacology Research Group at Yale (SNRGY) Disclosures

• NIDA, NCATS, NIAAA, NIMH, • VA R&D, • BBF(formerly NARSAD), • Insys – CBD

D’Souza 6/29/2018 Moreau: Cannabis Psychosis, 1845

“...psychotic reactions… lasting but a few hours, but occasionally as long as a week…the reaction seemed dose-related and …included paranoid ideation, illusions, HASHISH hallucinations, delusions, AND MENTAL ALIENATION depersonalization, confusion, restlessness and excitement...”

D’Souza 6/29/2018 Physical, Mental, and Moral Effects of Marijuana: The Indian Hemp Drugs Commission Report (1894)

In respect to the alleged mental effects of the drugs, the Commission have come to the conclusion that the moderate use of hemp drugs produces no injurious effects on the mind. It may indeed be accepted that in the case of specially marked neurotic diathesis, even the moderate use may produce mental injury. For the slightest mental stimulation or excitement may have that effect in such cases. But putting aside these quite exceptional cases, the moderate use of these drugs produces no mental injury. It is otherwise with the excessive use. Excessive use indicates and intensifies mental instability (1:264).

D’Souza 6/29/2018 A Brief Resume of the Types of Insanity commonly met with in India, with a Full Description of " Indian Hemp Insanity " peculiar to the Country.

……………………………..Among the toxic psychoses, that due to hemp is the commonest. The psychosis is almost confined to the male sex and usually occurs between the ages of 20 and 40. Hemp is used in the forms of ganja, bhang and charas (Ganja is the dried plant which has flowered and from which the resin has not been removed. Bhang is the larger leaves and capsules with the stalks. Charas is the resinous matter collected separately. Ganja and charas are chiefly used for smoking, bhang is usually taken as a decoction.). It is a very general custom to consume bhang on social festive occasions and its consumption is also in some places connected with religious rites. The effect of a moderate dose is to produce drowsiness, a dream state with a rapid flow of ideas, often of a sexual nature, and ultimately sleep. In larger doses there occur excitement, delusions, hallucinations, activity with a tendency to violence, ecstacy and deep sleep followed by forgetfulness of all but the initial symptoms. This is of importance from the medico-legal point of view. Three types of hemp insanity are met with: acute mania, chronic mania and dementia. The prognosis where the taking of the drug can be stopped is good. In acute cases nearly 90 per cent, and in chronic cases 40 per cent, recover. The drug can be stopped at once as no abstinence symptoms occur and for the rest symptomatic treatment only is required. Dhunjibhoy 1930 D’Souza 6/29/2018 Cannabis, cannabinoids and the brain cannabinoid system.

D’Souza 6/29/2018 Marijuana/Cannabis

D’Souza 6/29/2018 Plant-Derived Cannabinoids (>100) (Phytocannabinoids)

 D9-tetrahydrocannabinol-type (9)

 D8-tetrahydrocannabinol-type (2) OH  Cannabidiol-type (7)

 Cannabigerol-type (7)

 Cannabichromene-type (5) O C5H11 9  Cannabicyclol-type (3) D -THC

 Cannabielsoin-type (5)

 Cannabitriol-type (9) OH  Miscellaneous-type (14)

 Cannabinol-type (7)

 Cannabinodiol-type (2) OH C5H11 Cannabidiol D’Souza 6/29/2018 Human CB1 Receptor Extracellular N-terminal

Human CB2 Receptor

Extracellular N-terminal F TRP Transient receptor potential TRPV1 Intracellular TRPA1 C-terminal Y

Intracellular C-terminal Orphan GPCR (GPR55 GPR119)

D’Souza 6/29/2018 Herkenham et al. (1990), Proc. Natl. Acad. Sci. U.S.A. 87:1932-6

Cortex Cerebellum

HippTH CPu

GP HP

SNr

CB HP

TH =Thalamus, HP = Hippocampus, CB= Cerebellum Miles Herkenham, NIMH Cannabinoid Receptors (CB1R) In Human Brain

High density in brain areas concerned with memory, cognition, motor coordination and reward

D’Souza 6/29/2018 Exogenous and endogenous agonists

N OH H

N CH3 OH Anandamide आनंद = Anand = bliss Endorphins

O C H O 5 11 O HO D9-THC OH Morphine OH O OH

2-Arachidonoylglycerol (2-AG)

D’Souza 6/29/2018 Cannabis Potency Has Increased Over the Last 2 Decades (1995–2014) in the U.S

∆9-THC content ~12% in 2014

~4% in 1995

Average Δ9-tetrahydrocannabinol (THC) concentration of Drug Enforcement Administration specimens by year, 1995–2014.

ElSohly et al., 2016 Biological Psychiatry, Volume 79, Issue 7, 2016, 613–619 D’Souza 6/29/2018 The ratio of THC:CBD has increased over the Last 2 Decades (1995–2014) in the U.S

THC ↑ CBD may be protective CBD↓

ElSohly et al., 2016 Biological Psychiatry, Volume 79, Issue 7, 2016, 613–619 D’Souza 6/29/2018 D. Cyril D’Souza Affinity of Cannabinoids present in Spice for CB1 and CB2 receptors

Compound Type CB1 Ki (nM) CB2 Ki (nM) Delta-9-THC Classic Cannabinoid 41 36 ± 10 HU-210 Classic Cannabinoid 0.061 0.17 AM-694 Benzoylindone 0.08 1.4 RCS-4* Benzoylindone unknown unknown WIN-48,098 Benzoylindone 3155 ? CP-47,497 Cyclohexylphenol 2.2 ± 0.5 none detected JWH-018 Naphtoylindole 9 ± 5 2.9 ± 2.7 JWH-019 Naphtoylindole 9.8 ± 2 5.55 ± 2 JWH-073 Naphtoylindole 8.9 ± 1.8 38 ± 24 JWH-081 Naphtoylindole 1.2 12.4 ± 2.3 JWH-122 Naphtoylindole 0.7 ± 0.5 1.2 ± 1.2 JWH-210 Naphtoylindole 0.5 0.7 AM-2201 Naphtoylindole 1 2.6 JWH-203 Penylacetylindole 8 ± 1 7 ± 1.3 JWH-250 Penylacetylindole 11 ± 2 33 ± 2 RCS-8** Penylacetylindole unknown unknown *JWH-018 analog; **JWH-250 analog (Aung et al. 2000; D'Ambra et al. 1992; Howlett et al. 2002; Huffman and Padgett 2005; Huffman et al. 2005a; Huffman et al. 2005b; Melvin et al. 1993)

D’Souza 6/29/2018 Cannabinoids and Psychosis

D’Souza 6/29/2018 Psychotic Psychotic Symptoms Perceptual alterations Disorder (hallucinations,illusions) delusions, paranoia, Cognitive ideas of references, disorganized speech Symptoms and behavior, catatonia

Functional Deficits

D’Souza 6/29/2018 3 distinct relationships between cannabinoids and psychosis outcomes

D’Souza 6/29/2018 D. Cyril D’Souza Relationship #1

Intoxication Acute Transient Psychosis

Hours Days Weeks Months Years

Exposure

D’Souza 6/29/2018 Cannabinoids & Acute Transient Psychosis: The Evidence

• Nonexperimental:

– Anecdotal reports

– Surveys

– Case series

– “medicinal” cannabinoids

– Spice & K2

• Experimental

D’Souza 6/29/2018 Medicinal Cannabinoids

• Dronabinol (THC) • “loss of control”, • Nabilone • thought disturbances, • Levonantradol • feelings of unreality, • apprehension, fear and paranoia, • anxiety and panic, • dissociation and depersonalization, • difficulty concentrating, • hallucinations, • other perceptual alterations, • amnesia .

D’Souza 6/29/2018 Human Laboratory Studies with Intravenous THC

• Standardized delivery •> 1000 THC infusions • Uniform dose •Multiple doses:

• Clear dose-response • Multiple rates of infusion • Careful subject selection • Subjects: • Within subjects design – Healthy controls (with little • Exclude the effects of other drugs exposure), • Range of outcome measures – Cannabis users, • Clear temporal relationship – Schizophrenia – Family hx of SCZ

D’Souza 6/29/2018 Δ-9-THC Induced Psychotic-like Symptoms In Healthy Subjects in the Laboratory

Positive Symptoms

S.E.M.) ±

7 PANSS Positive Symptoms (Mean (Mean SymptomsPositive PANSS

6 -60 10 80 200 THC Infusion

Time (Minutes)

Placebo (Vehicle) 2.5 mg THC 5 mg THC

(D’Souza et al., Neuropsychopharmacology 2004) Clinician Rated CADSS (Mean ±S.E.M.) 0 1 2 3 4 5 6 7 8 - 60 THCInfusion Δ Clinician - 10 9 - THC Induced Perceptual Perceptual Induced THC Alterations - Rated 80 In Healthy Subjects Subjects In Healthy Placebo(Vehicle) Time Time (Minutes) 200 2.5 mg THC Subject Rated CADSS (Mean ±S.E.M.) 10 15 20 25 0 5 - 60 (D’Souza al., et THCInfusion 5 mg 5 mg THC Subject 10 - Neuropsychopharmacology Rated 80 2004) 200 Δ-9-THC Impaired Short Term Memory Immediate recall delayed recall Maximum Score Maximum Score 12 12

11 11

10 10

9 9

8 8

7 7

6 6

5 5

4 4 # Correct Words Words Recalled Correct #

3 3 # Correct Words RecalledCorrectWords #

2 2

1 1 Minimum Score Minimum Score 0 Trial #1 Trial #2 Trial #3 Delayed Free Delayed Cued Delayed Recognition Recall Recall Recall

Placebo (Vehicle) 2.5 mg THC 5 mg THC Time Perception Altered Under the Influence of THC

TIME ESTIMATION TIME PRODUCTION Δ-9-THC Impaired Time Perception

Actual Time Perceived Time Effects on P300 Event Related Potential (ERP)

Dog bark

Standard S S S Target S S S S Target S S S S Novel

P3b P3a Amplitude (μV) 12 - 4 0 4 8 0 100 Attention Allocation and ContextUpdating N1 THC 0.030 mg/kg THC 0.015 mg/kg Placebo (ms) Time 200 300 Δ P3b - 400 9 - 500 THC ReducedP 600 Placebo 3 - 3µV b Amplitude: mg/kg THC mg/kg 0.015 (D’Souza al., 2012) et 9µV mg/kg THC mg/kg 0.03 Gamma Oscillations

• Gamma-band (40 Hz) EEG activity important for numerous cognitive/perceptual operations including conscious awareness, object recognition, motion perception, and perceptual binding.

• Abnormal in SZ. Auditory Steady State Response

• EEG activity synchronizes with the frequency and phase of a periodic sensory stimulus. This entrainment response = steady state response

• By varying the frequency of the stimulus, one can test the capacity of neural circuits to support oscillations at specific frequencies (e.g. 40 Hz gamma). Dependent measure: power across time

40 Hz Input EEG Output 50

30 Time Time

20 Frequency (Hz) Frequency Time Time Δ-9-THC Reduces γ driving (ASSR)

Cortes-Briones & D’Souza., (2015) THC Increases Cortical Noise (Lempel-Ziv complexity)

0.44 *

0.43 *

0.42 *

0.41

Ziv complexity Ziv - 0.4

Lempel 0.39

0.38 Placebo 0.015mg/kg 0.03mg/kg

Drug *p<0.001

Cortes-Briones & D’Souza., Biological Psychiatry (2015) Psychosis-Like Effects of THC and Noise are Strongly Correlated

3 3

2 2

1 1

0 0

-1 scores) -1

-2 β=0.685 -2 β=0.754

-3 (z symptoms Disorganization -3

Positive symptoms scores) (z symptoms Positive -3 -1 1 3 -3 -1 1 3 Lempel-Ziv complexity (z scores) Lempel-Ziv complexity (z scores)

(Cortes et al., 2005) Positive symptoms Perceptual Alterations Negative symptoms Verbal Memory deficits Spatial Working Memory deficits Executive Function deficits Attentional deficits P300 deficits Ɣ oscillations Noise Acute Effects in SZ? PANSS Positive Symptoms (Mean ±S.E.M.) 10 12 14 16 18 20 6 8 Δ - 60 - 9 - THC Exacerbated THC Infusion Positive SymptomsPositive 10 80 Schizophrenia Patients Placebo(Vehicle) Positive &SymptomsIn Negative Time Time (Minutes) 200 2.5 mg THC

PANSS Negative Symptom (Mean ±S.E.M.) 11 13 15 17 19 5 7 9 - 60 5 mg 5 mg THC THC Infusion (D’Souza al., et Biological Psychiatry 2005) Negative SymptomsNegative 10 80 200 More SCZ Pts had clinically significant increases in Positive symptoms induced by Δ-9-THC

Controls Patients

Placebo 0% 0%

2.5 mg 35% 80%

5 mg 50% 75%

> 3 point increase on the PANSS Positive Symptoms Scale # Correct Words Recalled 10 11 12 0 1 2 3 4 5 6 7 8 9 Trial Trial #1 Schizophrenia patients moreSensitive to the healthy Trial Trial # memory effectsimpairing of THC 2 Placebo(Vehicle) Trial Trial #3 Trial Trial #1 2.5 mg THC 5 mg 5 mg THC SCZ Trial Trial # 2 Minimum Minimum Score Maximum Score Trial Trial #3 Conclusions

• No evidence supporting the self-medication

hypothesis – with THC What about individuals with a Higher Risk for Psychosis? D. Cyril D’Souza CHR Individuals More Vulnerable to Cannabis

Clinically High Risk Healthy Controls

Paranoia

)

100

- 0

Anxiety Visual Analog Scale ( Scale Analog Visual

High

Vadhan et al., 2017 Preliminary Results from a study of the effects of THC in those with a Family History of Psychosis Potential Mechanisms?

THC ↑DA

Psychosis & CB1 ↓GLU Amnestic Effects

↓GABA Controls THC

or Bigger response Cannabis SCZ

• ↓GAD67 mRNA • ↓ density of axon cartridges of chandelier neurons. • ↓ expression of GAT1

GABA deficits???? • ↑ Increase in GABAA receptors • ↑ GABRA2 density • ↓ BZ receptor binding?

D’Souza 6/29/2018 THC (Low dose)

GABA deficit Bigger response (iomazenil)

D’Souza 6/29/2018 GABA Deficit Enhances Δ-9-THC Effects

50 Psychosis-like Effects

45 *

40 THC IOM THC

35 IOM PANSS Total score Total PANSS PLACEBO

25 Baseline Peak End time

D’Souza 6/29/2018 Radhakrishnan & D’Souza., 2015 GABA Deficit Enhances Δ-9-THC Effects

8 Placebo Placebo IOM P300b THC IOM 6 IOM+THC

2 THC

0 IOM+THC

Amplitude (µV) -2

-4 0 200 400 600 800 Time (ms)

D’Souza 6/29/2018 Radhakrishnan & D’Souza., 2015 Relationship #2

Acute Persistent Psychosis

Hours Days Weeks Months Years

Exposure

D’Souza 6/29/2018 Cannabinoid Induced Acute and Persistent Psychosis

1. manifests immediately following exposure,

2. lasts beyond the period of intoxication,

3. resolves within days to weeks – recovery complete,

4. recurs with cannabis use,

5. requires clinical intervention,

6. 50-75% rediagnosed with schizophrenia in later years - harbinger of schizophrenia

D’Souza 6/29/2018 Spice, K-2 etc

D’Souza 6/29/2018 Affinity of Cannabinoids present in Spice for CB1 and CB2 receptors

D’Souza 6/29/2018 Preliminary Results from a study of Psychosis occurring in the context of festivals Relationship #3

Cannabis and Later Recurrent Psychosis (SZ)

Hours Days Weeks Months Years

Exposure

D’Souza 6/29/2018 Longitudinal studies of cannabis as a risk factor for psychosis

Study Country Design No. participants Follow-up OR (95% CI) (years) (adjusted risk) Tien & Anthony US Population based 4,494 1 2.4 (1.2-7.1)

Zammit et al Sweden Conscript cohort 50,053 27 3.1 (1.7-5.5) Manrique-Garcia et al 35 1.8 (1.3-2.3) van Os et al The Netherlands Population based 4,045 3 2.8 (1.2-6.5)

Weiser et al Israel Population based 9,724 4-15 2.0 (1.3-3.1)

Fergusson et al New Zealand Birth cohort 1,265 3 1.8 (1.2-2.6) Arseneault et al New Zealand Birth cohort 1,034 15 4.5 (1.1-18.2) Ferdinand et al The Netherlands Population based 1,580 14 2.8 (1.79-4.43)

Henquet et al Germany Population based 2,437 4 1.7 (1.1-1.5)

Wiles et al UK Population based 8,580 1.5 1.5 (0.55-3.94)

Rössler et al Switzerland Community 591 30 1.8 (0.96-3.2) Survey

Gage et al UK Birth cohort 1,756 2 1.1 (0.76-1.65) Rognli et al Sweden Cohort of discharged 6,217 5 2.6 (1.40-5.0) prisoners

Adolescent boys Bechtold et al USA 1,009 5 1.51 (1.08-2.11)

~2 fold increase

D’Souza 6/29/2018 Criteria for Causality

1. dose-response or biological gradient, 2. strength of the association, 3. direction, 4. temporality, 5. consistency, 6. specificity, 7. coherence, 8. experimental evidence and 9. biologic plausibility (Aiello and Larson, 2002; Hill, 1965)

D’Souza 6/29/2018 D. Cyril D’Souza

Factors

1. Timing of exposure is very important 2. Dose 3. CBD? 4. Vulnerability

D’Souza 6/29/2018 But………………….

• Not everyone who uses cannabis develops SCZ, and • Not everyone who has SCZ was exposed to cannabis • Neither necessary nor sufficient • Component cause

D’Souza 6/29/2018 D. Cyril D’Souza Cannabinoids and Psychosis

Cannabinoids x Psychosis Outcomes Other Factors?

D’Souza 6/29/2018 Genetic Factors

COMT DAT AKT1 NRG1 CNR1

D’Souza 6/29/2018 Challenges to studying the long term consequences of cannabinoids experimentally?

D’Souza 6/29/2018 Challenges?

• Confounding effects of other drugs • Reliance on self report to measure exposure • Limited range (dose) of exposure • Reverse Causality? • Focus on positive symptoms, less focus on: – Cognition? – Negative symptoms? • Effects of very early exposure

D’Souza 6/29/2018 Consequences of Chronic Early, Heavy, Cannabis Exposure

D’Souza 6/29/2018 OVERVIEW

• Exocannabinoids hypothesis

• Endocannabinoid hypothesis

D’Souza 6/29/2018 Post Mortem Findings of CB1R in Schizophrenia

Author Method Finding Region

(Dean et al., 2001) Autoradiography: [3H]CP-55940 Increased DLPFC (CB1R agonist) No change CP, temporal lobe

(Zavitsanou et al., 2004) Autoradiography:[3H]SR141716A Increased ACC (CB1R antagonist) Autoradiography: [3H]CP-55940 Increased (Newell et al., 2006) (CB1R agonist) PCC

Autoradiography: [3H]CP-55940 (CB1R agonist) and No change (Deng et al., 2007) [3H]SR141716A (CB1R antagonist) STG

(Koethe et al., 2007) Immunohistochemistry No change ACC, DLPFC

(Eggan et al., 2008) In situ hybridization Decreased DLPFC Immunocytochemistry Decreased

(Uriguen et al., 2009) Immunocytochemistry Decreased PFC (*in un-medicated No change* patients) (Eggan et al., 2010) Immunohistochemistry Decreased DLPFC

(Dalton et al., 2011) Autoradiography: [3H]CP-55940 Increased DLPFC (CB1R agonist) Immunocytochemistry No change (Jenko et al. 2012) Autoradiography: [3H]MePPEP Increased DLPFC (CB1R inverse agonist)

Autoradiography: [3H]-OMAR Increased DLPFC (Volk et al., 2014) (CB1R inverse agonist) In situ hybridization (CB1R mRNA) Decreased Immunohistochemistry (CB1R protein) Decreased ACC = anterior cingulate cortex, CP = caudate-putamen, DLPFC = dorsolateral prefrontal cortex, PCC = posterior cingulate cortex, PFC = prefrontal cortex, STG = Superior Temporal Gyrus D. Cyril D’Souza Lower CB1R availability in Schizophrenia Patients

2.0 1.8 HCs 1.6 1.4 1.2 1.0 VT 0.8 0.6 SCZs 0.4 0.2 0.0

D’Souza 6/29/2018 Lower CB1R availability in Schizophrenia Patients vs. Healthy Controls * Unrelated to cannabis exposure

2.5 )

T 2 V #

# 1.5 # * # * # * * # * * * #

Distribution Distribution (

C]OMAR Volume of C]OMAR Volume 11 [ 0.5

0 Composite

* p <0.05 # p < 0.06-0.01

Schizophrenia Patients Healthy Controls

D’Souza 6/29/2018 D. Cyril D’Souza

Exocannabinoid hypothesis x

Endocannabinoid hypothesis

D’Souza 6/29/2018 D. Cyril D’Souza

Relationship between Cannabis Use and Onset of Psychosis

• In > 60% of patients with comorbid CUD and SZ, onset of use is before onset of psychosis • Interval between initiation of regular cannabis use and age at onset of psychosis was 6.3 years • In FEP onset of cannabis use is before onset of positive symptoms in ~75% of FEP + SZ • Cannabis associated with earlier onset of psychosis compared to other drugs/substances • Age at onset of schizophrenia ~2-3 years earlier in patients with comorbid cannabis use disorders compared to non-users, after controlling for various confounding factors • But, …………………………………………………………

(Bersani et al. 2002, Buhler al. 2002, Mauri, Volonteri et al. 2006, Sevy al. 2010, Dekker et al. 2012, Myles et al. 2012, Allegri et al. 2013, Tosato et al. 2013, Myles, et al. 2016).

D’Souza 6/29/2018 D. Cyril D’Souza

Is CBD Therapeutic?

D’Souza 6/29/2018 Conclusions

D’Souza 6/29/2018 Conclusions-I

Acute Transient Psychosis

Acute Persistent Chronic, recurrent Psychosis psychosis (schizophrenia)

Exposure

D’Souza 6/29/2018 D. Cyril D’Souza

Conclusions-1B

Fig 3: Continuum of Psychosis Related to Cannabinoids

IMMEDIATE-ONSET, LATE-ONSET, TRANSIENT, IMMEDIATE ONSET, PERSISTENT, PSYCHOSIS AND ACUTE AND PERSISTENT RECURRENT, PSYCHOSIS-LIKE PSYCHOSIS PSYCHOTIC DISORDER STATES (SCHIZOPHRENIA)

D’Souza 6/29/2018 Conclusions-II

• Cannabinoids → Acute transient psychosis-like effects

• Cannabinoids → Acute Persistent Psychosis

• Effects are dose dependent

• Clear causal relationship (temporality) for acute psychosis

• Greater vulnerability in:

– SCZ patients

– CHR are more vulnerable

– Family members are more vulnerable

D’Souza 6/29/2018 Conclusions-III

• Cannabis may precipitate/hasten psychosis in vulnerable individuals

• Mounting evidence that cannabinoids contribute to the risk for SCZ

• Interactions with specific genetic polymorphisms?

D’Souza 6/29/2018 D. Cyril D’Souza

Conclusions-IV

• Lower CB1R in schizophrenia and their relatives

• Emerging evidence of endocannabinoid dysfunction in schizophrenia

D’Souza 6/29/2018 A Harm Reduction Approach to Marijuana Use in Young Adults

Fredrick Crow, MD Massachusetts Mental Health Center 6/29/2018 Overview

• Disclosures and who am I

• Why talk about it

• Harm reduction in general

• Approach to assessing marijuana use

• Harm reduction specific to marijuana use Financial Disclosures

• None Who am I Why Talk About It

• 1st question I was asked

• General prevalence, regardless of legal status

• Complicated issue: weed is not good or bad

• Recent legalization: possible upsides Possible Upsides

• Decreased stigma

• Decreased risk of legal issues/arrests

• Increased willingness to accurately disclose use

• Fewer interactions with drug dealers

• Increased transparency – what are people buying Harm Reduction: Definition

• Harm Reduction International: – Refers to policies, programs, and practices that aim primarily to reduce adverse health, social and economic consequences of the use of legal and illegal psychoactive drugs without necessarily reducing drug consumption. Harm Reduction benefits people who use drugs, their families and the community. Harm Reduction: Origin and Examples

• Initially used in the 1980’s, alternative to abstinence only programs

• Most commonly thought of in relation to IV drug use

• Concept easily applied to many behaviors beyond substance use Harm Reduction: Examples

Drug Related Others • Needle exchanges • Beyond abstinence only sex education • Substitution therapies • Helmets • Supervised injection facilities • Seatbelts

• Sunscreen Harm Reduction: Principles

• Meet people where they are at

• Risk is everywhere; does not ignore risk

• Focus on reducing risk, not drug use

• Sees drug use as a continuum Harm Reduction: Principles

• Important to recognize positive changes individuals make

• Values the voice of users and former users

• Recognizes that drug policies themselves can increase risks to drug users Developmental Context

• Fits with what we know about young people

• Experimentation and risk taking is the norm

• Rejection of authority

• Desire for autonomy Developmental Context

• Endorsed by High Times and Leafly!

• Important to consider primary versus secondary prevention

• Motivational interviewing is a developmentally appropriate tool Assessing Use

• Complicated and charged issue – Patient’s expect mental health professionals to view marijuana in a negative light – Start out by asking about interests – “Do you smoke much weed?”

• It’s not just a yes or no question – Is drinking a glass of wine nightly the same as drinking a fifth of vodka everyday? Assessing Use

• What do you like to do when you are high?

• Who do you smoke with?

• How often do you typically smoke?

• Do you prefer eating, smoking or vaporizing? Assessing Use

• Do you buy your own? – How much do you typically buy? – How long does it last you?

• If you and your friends are passing a joint around…

• Ever had any odd or unusual experiences when you’ve been high? Assessing Use

• Are there people you like to get high with and people you don’t?

• Are there things you avoid doing when you’re high?

• Is there anything that would ever make you worry you’re using marijuana too much or that it’s not good for you? Useful Information

• Differences in smoking and eating

• Typical doses

• Differences in strains Smoking vs. Eating

Inhaled PO ingestion • Peak effects at 15-30 min • Peak effects at 30 min to 3 hours • Effects last up to 4 hours • Effects last for up to 12 • Bioavailability = 10-35% hours

• • 2-3 mg produce effects Bioavailability = 5-20%

• 5-20 mg produce effects Indica (In-Da-Couch)

• Budtender would say, use for: – Relaxation – Carefree – Sleepy – Calm – Mellow – Couch-lock • Higher concentrations of CBD compared to Sativa Sativa

• Budtender would say, use for: – Euphoria – Creativity – Alertness – Energy – Sociability – Cheerfulness • Higher THC concentrations than Indica, lower CBD concentrations Setting the Frame

• Treatment not dependent on abstinence

• Appreciate knowing about your use and changes in it, whether increasing or decreasing – Don’t want to prescribe more medications for symptoms that are due to acute intoxication

• Happy to answer questions, provide information, and share my opinion if you are interested – Feel free to bring in a menu Guidelines to Lower Risk from American Journal of Public Health

1. Abstain 6. Avoid deep inhalation 2. Delay use 7. Avoid frequent use 3. Low THC or balanced 8. Don’t drive THC:CBD ratio 9. Avoid use altogether if 4. Avoid synthetic you are at high risk of cannabis adverse effects 5. Avoid combusted 10. Avoid combining the cannabis above Harm Reduction Strategies

• Pace yourself; know yourself

• Chose strains with lower THC concentrations and/or balanced THC:CBD ratios

• Stick to the same dispensary, strains, and/or edibles – Know the doses and serving sizes – Don’t eat the whole brownie! Role Play

• So if you want to use less or avoid it altogether, how do you plan to respond when friends offer it to you? Possible Suggestions for Cutting Back

• Don’t buy in bulk

• Plan ahead

• Monitor use

• Give people a heads up

• Take a pass when the joint comes to you or take smaller hits Management of treatment- resistant psychosis

3rd Annual Conference of the MAPNET Boston, Massachusetts June 29, 2018

Oliver Freudenreich, MD, FACLP Co-Director MGH Schizophrenia Program Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Erich Lindemann Mental Health Center

Erich Lindemann 1900-1974 Chief of Psychiatry MGH 1955-1965 Disclosures

I have the following relationships to disclose: – Global Medical Education – Honoraria (CME speaker and content developer) – Alkermes – Consultant (Advisory Board) – Neurocrine –consultant (Advisory Board), honoraria (CME talk), – Janssen – Research grant, consultant (Advisory Board) – Otsuka – Research grant – Saladax – Research grant – Wolters-Kluwer – Royalties (content developer) – UpToDate – Royalties, honoraria (content developer and editor) Learning objectives

At the completion of this talk, participants will be able to

1. Identify two key factors that lead to pseudorefractoriness 2. Give an example of stepped care for refractory patients 3. Appreciate the critical role of relapse prevention for good patient outcomes

Erich Lindemann Mental Health Center Outline

A. What is a bad outcome in psychiatry? 1. Refractory psychosis 2. Differential diagnosis: pseudorefractoriness B. How can we prevent a bad outcome? 1. Stepped care 2. Relapse prevention C. How can we improve care for refractory patients?

178 What is a bad outcome in psychiatry? Social interventions have greater impact on outcomes than molecular advances.

Fleishman M. Psychiatr Serv. 2003;54:142. Farmer PE et al., PLoS Medicine 2006;3:1686. What contributes to a poor outcomes? • Cumulative social toxicity • Unresponsive biology from time spent psychotic, in hospitals, or idle at home • Poor access to treatment and no care • Substandard psychiatric care • Poor engagement in ongoing care and poor adherence • Substance use • Comorbid medical disorders • Multiple social determinants of health

Zipursky RB. J Clin Psychiatry. 2014; 75 Suppl 2:20-4. Treatment as prevention “Refractory illness”

• Schizophrenia is a syndrome – Positive symptom dimension – Negative symptoms dimension – Cognitive symptoms dimension – Affective symptom dimension – Motor dimension • “Function” is complicated • Social determinants of health matter • Structure of healthcare system matters “Pseudo-refractoriness”

• Is the diagnosis correct? • Is there drug use? • Is the patient getting enough medicine? – Adherence – Unusual metabolism • Did you wait long enough? PSEUDOREFRACTORINESS

Is the diagnosis known? Karl Bonhoeffer (1868–1948)

• Father of “organic psychiatry” • Zur Frage der Klassifikation der symptomatischen Psychosen. Berliner Klin Wochenschr 1908; 45:2257–2260 • Exogenous versus endogenous psychoses

Strohle A et al. Am J Psychiatry 2008;165:575. Is the psychiatric diagnosis correct?

“Crude exogenous organic • No help from damage of the most psychopathology!1 varying kind can produce acute psychotic clinical – Lack of pathognomonic pictures of a basically signs uniform kind.” – Lack of etiological specificity -Karl Bonhoeffer, 1909 • Balanced work-up2 • Avoid premature etiologic closure – Non-hierarchical approach

1Johnstone E et al., Br J Psychiatry. 1988;153:770-6. 2Freudenreich O et al., Early Interv Psychiatry. 2009;3:10-8. PSEUDOREFRACTORINESS

Is there drug use? New-onset psychosis

Primary Secondary

Other Schizophrenia Psychiatric nd Substance spectrum Illnesses Delirium Dementia 2 GMC Induced

“Psychiatric” “ORGANIC”

Based on: Freudenreich O. Psychiatric Times Dec 2010 PSEUDOREFRACTORINESS

Is the patient getting enough medicine? Was Osler wrong?

The desire to take medicine is perhaps the greatest feature which distinguishes man from animals. Medication adherence

• All chronic conditions have high non- adherence rates • Mean compliance rates in meta-analysis1 – Antipsychotics 58% – Antidepressants 65% – Medications for physical illness 76% • After a first hospitalization for schizophrenia, 54.3% of patients did NOT2 – Use the antipsychotic for over 30 days – Collect a new prescription within 30 days 1Cramer JA and Rosenheck R. Psychiatr Serv 1998;49:196. 2Tiihonen J et al. Am J Psychiatry 2 011;168:603. Impact of non-adherence

35 30 25 20 15 10 5

% of of % Patients 0

Adherent Non-adherent

Asher-Svanum H, et al. J Clin Psychiatry. 2006;67(3):453-460. Novick D, et al. Psychiatr Res. 2010;176(2-3):109-113. Assessment of adherence • Common errors • No gold standard5 – Overconfidence1 – Self-report – Underappreciating – Collateral information partial adherence2,3 – Drug level monitoring – Underappreciating lack of persistence over time4 Доверяй, но проверяй Trust – but verify.

1Velligan DI et al. Psychiatr Serv. 2007;58(9):1187-92. 2Weiden PJ et al. Psychiatr Serv. 2004;55(8):886-91. 3Subotnik KL et al. Am J Psychiatry. 2011;168(3):286-92. 4Misdrahi D et al. Schizophr Res. 2017 (in press). 5Velligan DI et al. J Clin Psychiatry. 2009;70(suppl 4):1-46. [Expert Consensus Guideline Series] BARS*

How many pills/capsules do you take each day?

Over the past month on how many days did you not take this medication?

Over the past month how many days did you take less than the prescribed number

of pills/capsules?

To summarize, over the past month you took this medication as prescribed:

Never/ Sometimes Usually Always/

Almost never Almost always

______

0% 25% 50% 75% 100%

*Brief Adherence Rating Scale Clinician Administered. Byerly M et al. Schizophr Res 2008;100:60. Modified from the CATIE Study Antipsychotic Therapeutic Drug Monitoring (TDM) • Long history in psychiatry – Lithium – Tricyclic antidepressants • Currently underutilized • Renewed interest – First guideline for TDM published by TDM taskforce of AGNP in 2004 (update 2011 and 2017) – Development of new assays for antipsychotics AGNP = Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie Hiemke C, et al. Pharmacopsychiatry. 2017 Sep 14. [Epub ahead of print] Horvitz-Lennon M, et al. Am J Psychiatry. 2017;174(5):421-426. Schoretsanitis G, et al. Expert Rev Clin Pharmacol. 2017;10(9):965-981. TDM – Potential benefits

• Informed decision regarding root causes of treatment complications – Poor response to antipsychotics (25% of patients) • Pseudo-refractoriness (non-adherence) vs. refractoriness – Poor tolerability of antipsychotics (15% of patients) • Slow elimination vs. high drug sensitivity • Indications – Non-response at therapeutic doses – Uncertain drug adherence – Suboptimal tolerability – Pharmacokinetic drug-drug interactions

Predmore Z et al. Psychiatr Serv. 2018;69:12-4. TDM - obstacles

• Not available for all antipsychotics • No clear “therapeutic window” for antipsychotics • Evidence-based limited regarding clinical benefit • Unfamiliarity with TDM – Interpretation of reference ranges – Interpretation of reported results (e.g., clozapine and norclozapine) • Cost • Not part of work-flow in psychiatric setting – No easy access to laboratory – Turn-around time too long TDM - summary

• A tool for personalized antipsychotic dosing – Not a tool to directly increase adherence • Unnecessary in uncomplicated situations but helpful if questions about non-response (adherence) and toxicity • Best established utility with: – Clozapine – Haloperidol, fluphenazine – Risperidone • Do not over-interpret results – No good relationship between blood level and symptoms • But we now have population-based expected drug levels for many antipsychotics – Most valuable if extreme values (zero or very high) • POC testing could solve work-flow issues in psychiatric settings

Horvitz-Lennon M et al. Am J Psychiatry. 2017;174:21-426. PSEUDOREFRACTORINESS

Did you wait long enough? Time course of response to antipsychotics • Antipsychotic effects often immediately • More improvement early rather than late1 • Benefit accrues over time • Time is necessary for resolution of psychotic worldview • Chronic delusions might not respond (“fixed”) • First-episode patients • Time to response varies2 • Early lack of improvement does not predict non-response3 1Agid O et al. J Psychiatry Neurosci 2006;31:93. • Some need 16 weeks3 2Emsley R et al. Am J Psychiatry 2006;163:743; Nordon C et al. Acta Psychiatr Scand. 2014;129(2):116-25. 3Gallego JA et al. J Clin Psychiatry 2011; 72:1691. Treatment-resistant schizophrenia (TRS) • Consensus guidelines on diagnosis and terminology developed by TRRIP Working Group – Clinical subspecifiers for positive, negative, cognitive symptom domains – Time-course (i.e., early, medium, late onset) – Ultra-treatment resistant (i.e., clozapine) • Minimum requirements for TRS: – Current symptoms • Symptom threshold at least moderate severity (rating scale!) • Symptom duration at least 12 weeks • Functional impairment at least moderate (rating scale!) – Adequate treatment • At least two trials of at least 6 weeks of at least 600 CPZ-EQ • At least 80% adherence

TRRIP = Treatment Response and Resistance in Psychosis Howes OD et al. Am J Psychiatry. 2017;174(3):16-229. How can we prevent a bad outcome? Clinical staging in psychiatry STAGE Definition Clinical features 0 Asymptomatic subjects Not help seeking No symptoms but risk 1a “Help-seeking” subjects with Non-specific anxiety/depression symptoms Mild-to-moderate severity 1b “Attenuated syndromes” More specific syndromes incl. mixed At least moderate severity 2 Discrete disorders Discrete depr/manic/psych/mixed sy Moderate-to-severe symptoms 3 Recurrent or persistent Incomplete remission disorder Recurrent episodes 4 Severe, persistent and Chronic deteriorating unremitting illness No remission for 2 years Hickie IB et al. Early Interv Psychiatry. 2013;7:31-43. McGorry PD et al. Aust N Z J Psychiatry. 2006;40:616-22. Staging model of treatment as prevention

• Rational for staging: – Avoid progression to disease stages where only amelioration is possible – Better response to treatments in early stages • Principles: – Timely care to treat patients as early as possible in the disease course – Stepped care that adjusts treatment intensity based on response* – Phase-specific care that tailors the interventions to the patient’s needs

*Cannot be done without principles of population-based management and measurement-based psychiatry Timely care: reducing duration of untreated psychosis (DUP) • Prolonged DUP1,2,3 • Social toxicity • Poorer response • Stigmatization • Worse outcome • Loss of job • Interrupted schooling • DUP can be reduced4 • Loss of friendships • Clinical advantage at • Loss of family support baseline, 2-year3 and 5- • Criminal record year f/u5 • Accidental death • Sustained information • Accidental homicide campaign is key6 Shame and demoralization 7 • Focus on outliers 1Perkins et al. 2005, 2Marshall et al. 2005, 3Penttilä et al. 2014 4Melle et al. 2004, 2008; 5Larsen et al. 2011; 6Joa et al. 2008 RAISE DUP = 74 weeks8 7Lloyd-Evans et al. Br J Psychiatry 2011;198:256. 8Addington J et al. Psychiatr Serv. 2015; 66(7):753-6. “However beautiful the strategy*, you should occasionally look at the results.**”

-Sir Winston Churchill

* = what your clinic does ** = how your patient is doing

Haas LF. JNNP 1996;61:465. Should you “augment” an antipsychotic?

• You cannot augment a non-response • Probably very limited if any benefit for most patients compared to clozapine1 – Polypharmacy is not an effective treatment for patients refractory to first-line treatments – “Augmentation” is not an example of stepped care

1Correll CU et al. JAMA Psychiatry. 2017;74(7):675-84. STEPPED CARE ______Should you switch antipsychotics? OPTiMiSE = Optimization of Treatment and Management of Schizophrenia in Europe • Good overall remission rate Amisulpride 4 w 4 after 10 weeks of treatment DOUBLE BLIND – 2/3 of patients Ami Olanzapine • Most respond completely in sulpride

four weeks to amisulpride 6 wks 6 • No benefit from switching to olanzapine • Some benefit from Clozapine switching to clozapine but

not as good as responders 12 wks 12

Leucht, S et al. Schizophr Bull. 2015;41:549-58. Preliminary results presented at EPA 2017, Florence Stepped care: use clozapine early

st nd 80 75.4 75 1 and 2 antipsychotic: Risperidone 70 Olanzapine 60 3rd antipsychotic: 50 Clozapine 40 Response in % 30 20 16.7 10 0 1st 2nd 3rd

Agid O et al. J Clin Psychiatry 2011;72:1439. Stepped care: use clozapine Over 80% of refractory patients are refractory 1 • Move to clozapine from the start.2 – Refractoriness Clozapine has real- world effectiveness for – Aggression and self-injury relapse prevention.3 • Risks of not prescribing clozapine – Accruing psychosocial toxicity – “End-stage” brain disease with poor function – Polypharmacy – Higher mortality4 1Warnez S and Alessi-Severini S. BMC Psychiatry. 2014;14:102. 2Demjaha A et al. Psychol Med. 2017; 47:1981-9. 3Tiihonen J et al. JAMA Psychiatry. 2017; 74:686-93. 4Tiihonen J et al. Lancet. 2009;374:620-7. Benefit of clozapine TDM

20% improvement 33% improvement 70 61 60 60

50 48 improved 39 40 33

30 patients patients 20 10 6

Percent of Percent 0 Low (50-150 ng/mL) Med (200-300 ng/mL) High (350-450 ng/mL) Clozapine serum levels

TDM = Therapeutic Drug Monitoring VanderZwaag C et al. Am J Psychiatry. 1996;153:1579-84. Clozapine use in clinical practice

• Too many patients who are poorly responsive to treatment do not receive clozapine • Every patient with schizophrenia who has symptoms deserves to be offered a time-limited clozapine trial • The goal is EARLY (not as treatment of last resort) and ROUTINE use of clozapine for any eligible patient • The goal is SAFE use of clozapine – Consider establishing a clozapine clinic (like a warfarin clinic) or referring to a clozapine clinic – Enroll in Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program • The goal is clozapine monotherapy. Don’t forget to eliminate unneeded medications

Freudenreich O et al. Acad Psychiatry. 2013;37:27-30. https://www.clozapinerems.com/ https://nasmhpd.org/sites/default/files/Assessment%201_Clozapine%20Underutilization.pdf What if clozapine does not work?

• Stepped care: clozapine plus ECT1 • For limited response to clozapine you are “skating on thin ice”2 • Clozapine plus topiramate3 • Clozapine plus aripiprazole4 • Polypharmacy can often be reduced5

1Petrides G et al. Am J Psychiatry 2015;172(1):52-8. 2Tracy DK et al. BMC Psychiatry 2015;15:174. 3Corell CU et al. J Clin Psychiatry. 2016;77(6):e746-56. DO NO HARM 4Siskind DJ et al. Aust N Z J Psychiatry. 2018 (in press). 5Essock SM et al. Am J Psychiatry. 2011;168(7):702-8. Add non-pharmacological treatments

• Residual psychosis – Cognitive-behavioral therapy, if available • Evidence-based treatment (NICE since 2009)1 • Negative symptoms – CBT for negative symptoms, if available2 – Social skills training, if available3 • Cognitive symptoms – Cognitive training, if available4 – Reduce anticholinergic burden!5

1Turner DT et al. Am J Psychiatry. 2014 May;171(5):523-38. 2Perivoliotis D and Cather C. J Clin Psychol. 2009:65:815-30. 3Turner DT et al. Schizophr Bull. 2017 (in press). 4Keshavan MS, et al. Am J Psychiatry. 2014;171(5):510-22. 5Lupu AM et al. J Clin Psychiatry. 2017;78(9):e1270-e1275. Screen for and treat depression

• Depression common across all illness stages • Consider citalopram for subsyndromal depression in chronic patients1 – No studies of antidepressants in first-episode psychosis but widely used2 • Limited benefit from adjunctive lithium – “Overall low methodological quality”3 • Antidepressants might work (some) for negative symptoms4 1Zisook S et al. J Clin Psychiatry 2009;70:562-71. 2Nielsen J et al. Acta Psychiatr Scand 2010;122:356-66. 3Leucht S et al. Cochrane Database Syst Rev 2015. Oct 28:CD003834. 4Galling B et al. Acta Psychiatr Scand. 2018;137(3):187-205. RELAPSE PREVENTION ______Cost of relapse in schizophrenia

• Schizophrenia as a relapsing-remitting illness with accrued disability over time • Relapse has psychosocial toxicity – Loss of job – Derailed education – Criminal problems – Suicide – Loss of reputation • Relapse might be biologically harmful1 – Emergent treatment non-response in 16% • Sustained remission is basis for accrued treatment benefits over time

1Emsley R et al. J Clin Psychopharmacol. 2013;33:80. Antipsychotic for relapse prevention

• 50 years of evidence1 • Meta-analysis of N=6493 • Median follow-up 26 weeks • Antipsychotics reduce 1-year relapse rate • Drug 27% versus placebo 64% • RR 0.40 [95% CI 0.33-0.49] • No effect of: number of episodes; length of stability; FGA vs. SGA; abrupt vs. gradual withdrawal • Clozapine and LAIs work best in real-world settings2

1Leucht S. Lancet 2012;379:2063-71. 2Tiihonen J et al. JAMA Psychiatry. 2017;74:686-93. LAI antipsychotics for FEP

Offer routinely as first-line maintenance oral choice

LAI LAI make non-adherence transparent and reduce family burden.

Subotnik KL et al. JAMA Psychiatry 2015;72:822. Carpenter WT and Buchanan RW. JAMA Psychiatry 2015;72:745 [editorial]. Long-acting injectable antipsychotic medications • Shared decision-making should be based on facts • Real-time, accurate information about adherence • Greatest benefit if started in hospital on patients who have relapsed because of non-compliance • A reasonable strategy for patients experiencing a first psychotic episode1 • Best if employed as part of comprehensive care program – Maintaining frequent clinical contact may be a valid psychosocial relapse prevention treatment2 • Can be life-saving3

1Subotnik KL et al. JAMA Psychiatry. 2015;72:822-9. 2Buckley PF et al. Psychiatr Serv. 2016;67:1370-72. 3Taipale H et al. Schizophr Res. 2017 (in press). How can we improve care for refractory schizophrenia patients? Review your treatment

• Have you considered drug use? • Have you had good medication trials? Are you sure? • Have you stepped up care with clozapine? • Have you offered a long-acting injectable? • Have you considered reducing polypharmacy? • Have you used non-medication approaches? Sequential antipsychotic trials

• Select • Lowest-risk choice • Patient preference • LAI acceptable? • Early ancillary medical prevention • Behavioral interventions • Adjunctive metformin • Monitor • Clinical response • Follow antipsychotic monitoring guidelines • Step-up • Switch antipsychotics • Early use of clozapine for refractory patients • Clozapine over polypharmacy • Add psychological treatments and behavioral interventions • Treat medical morbidities Citizenship in a republic

It is not the critic who counts; not the man who points out how the strong man stumbles, or where the doer of deeds could have done them better. The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood; who strives valiantly; who errs, who comes short again and again, because there is no effort without error and shortcoming; but who does actually strive to do the deeds; who knows great enthusiasms, the great devotions; who spends himself in a worthy cause; who at the best knows in the end the triumph of high achievement, and who at the worst, if he fails, at least fails while daring greatly, so that his place shall never be with those cold and timid souls who neither know victory nor defeat. The right treatment, at the right intensity, at the right time, in the right place • Right treatment – Safe and effective care = evidence-based* – Comprehensive care • Medications • Psychological treatments and rehabilitation • Right intensity – Stepped care • Treatment intensity adjusted based on response • Right time – Timely care = without delay* – Phase-specific care • Right place Tertiary prevention is – Patient-centered = humane care* a critical goal for – Continuum of care schizophrenia care • Includes asylum

*Based on Institute of Medicine’s 6 Aims (2001) 1924 1995 Plus ça change, plus c'est la même chose

Sisti DA et al. JAMA 2015;313:243.

Lancet Psychiatry 2015; Dec 16, 2014

BJP 2014 Why are we surpised?

“All organizations are perfectly designed to get the results they get!”

- Don Berwick, MD (and others) No more excuses …

Today, any form of the concrete world, of human life, any transformation of the technical and environment is a possibility […]. This would mean THE END OF UTOPIA, that is, the refutation of those ideas and theories that use the concept of utopia to denounce certain socio-historical possibilities.

Herbert Marcuse, 1967. From a lecture delivered at the Free University of West Berlin. Thank you!

John Umstead Hospital, Butner, NC, ca. 1995