Integrative Medications The therapeutic potential of omega-3 fatty acids and N-acetylcysteine

Erik Messamore, MD, PhD emessamore@neomed.edu Associate Professor of Psychiatry, Northeast Ohio Medical University Medical Director, Best Practices for Schizophrenia Treatment (BeST) Center

Best Practices in Schizophrenia

Treatment (BeST) Center at NEOMED

• The BeST Center’s mission: – Promote recovery and improve the lives of as many individuals with schizophrenia as quickly

as possible

– Accelerate the use and dissemination of effective treatments and best practices

– Build capacity of local systems to deliver state-of-the-art care to people affected by schizophrenia and their families

• The BeST Center offers: – Training

– Consultation

– Education and outreach activities

– Services research and evaluation

• The BeST Center was established: – Department of Psychiatry, Northeast Ohio Medical University in 2009

– Supported by The Margaret Clark Morgan Foundation and other private foundations and governmental agencies

Integrative Medications???

• Medical illness is over-represented among individuals with severe mental

illness

• Raising suspicion that certain pathophysiological processes lie at the

intersection of the physical and the mental

• Agents that impact these fundamental processes (nexus points) may affect

both physical and mental health

Nexus points in mental/physical maladies

Biochemical processes Psychological processes

Inflammation Mood

Cortisol/Stress response Impulsivity

Oxidative stress

Glucose/Insulin

Oxidative stress

• ‘Oxidation’ = transfer of electrons from electron-rich biological substrates

(e.g., DNA or cell membrane lipids) to electron-hungry oxygen atoms.

• Electron-hungry oxygen atoms are generated during metabolism (=

‘burning’ of glucose) or with the release and subsequent processing of

certain neurotransmitters.

• Oxidative stress occurs when reactive oxygen production exceeds the

body’s capacity to neutralize the reactive oxygen products cellular

damage

• Accumulated cellular damage becomes apparent as bodily damage (e.g.

age-related disorders) or neuronal dysfunction (may manifest with

neuropsychiatric symptoms)

N-acetylcysteine or Omega-3 Fatty Acids

as Integrative Medication Candidates N-acetylcysteine Omega-3 Fatty Acids

Oxidative stress Oxidative stress

Inflammation (?) Inflammation

Impulsivity Impulsivity

Mood

N-Acetylcysteine: The Molecule

• A ‘nearly-natural’ substance

• Acetyl group (widely generated/used in

normal metabolism)

• Cysteine (an amino acid)

• Joined by the amino (N) group of the

amino acid

N-Acetylcysteine: Pharmacological Actions

• Precursor to glutathione, the body’s primary anti-oxidant compound

• Reduces the release of the neurotransmitter glutamate

• Reduces inflammatory cytokines (IL-1β, TNF-α, IL-6)

Dean, O., Giorlando, F., and Berk, M. (2011). N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 36, 78–86.

N-Acetylcysteine: Medical Uses

• Treatment of acetaminophen overdose

• Mucolytic

• Prevention of radiocontrast-induced kidney failure

• Adjunctive agent in the treatment of chronic obstructive pulmonary disease

NAC: Psychiatric Uses, Trichotillomania

Grant, J.E., Odlaug, B.L., and Kim, S.W. (2009). N-acetylcysteine, a glutamate modulator, in the treatment

of trichotillomania: a double-blind, placebo-controlled study. Arch. Gen. Psychiatry 66, 756–763.

Mean Hair Pulling Scale Scores Percent with or minimal symptoms

NAC, Psychiatric Uses, Cocaine

• Glutamate levels are

elevated in the anterior

cingulate gyrus of cocaine-

dependent adults.

• Glutamate levels in the ACC

correlate with impulsivity.

• NAC normalized ACC

glutamate levels in cocaine-

dependent adults.

Schmaal, L., Veltman, D.J., Nederveen, A., van den Brink, W., and Goudriaan, A.E. (2012). N-acetylcysteine normalizes glutamate levels in cocaine-dependent patients: a randomized crossover magnetic resonance spectroscopy study. Neuropsychopharmacology 37, 2143–2152.

NAC, Psychiatric Uses, Cocaine

• NAC reduced cue-induced cocaine craving among 15 adults with cocaine

dependence (LaRowe et al., 2007)

• Though not better than placebo at obtaining abstinence in active cocaine

users, NAC produced longer times to relapse and lower cocaine cravings in

users who had already achieved abstinence (LaRowe et al., 2013)

LaRowe, S.D., Myrick, H., Hedden, S., Mardikian, P., Saladin, M., McRae, A., Brady, K., Kalivas, P.W., and Malcolm, R. (2007). Is cocaine desire reduced by N-acetylcysteine? Am J Psychiatry 164, 1115–1117. LaRowe, S.D., Kalivas, P.W., Nicholas, J.S., Randall, P.K., Mardikian, P.N., and Malcolm, R.J. (2013). A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence. Am J Addict 22, 443–452.

NAC, Psychiatric Uses, Tobacco

Studies suggesting efficacy of NAC at improving smoking cessation

success rates:

• Froeliger, B., McConnell, P.A., Stankeviciute, N., McClure, E.A., Kalivas, P.W., and Gray, K.M. (2015). The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity, withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend 156, 234–242.

• Prado, E., Maes, M., Piccoli, L.G., Baracat, M., Barbosa, D.S., Franco, O., Dodd, S., Berk, M., and Vargas Nunes, S.O. (2015). N-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study. Redox Rep. 20, 215–222.

• Schmaal, L., Berk, L., Hulstijn, K.P., Cousijn, J., Wiers, R.W., and van den Brink, W. (2011). Efficacy of N-acetylcysteine in the treatment of nicotine dependence: a double-blind placebo-controlled pilot study. Eur Addict Res 17, 211–216.

NAC, Other Uses, Marijuana

Gray, K.M., Carpenter, M.J., Baker, N.L., DeSantis, S.M., Kryway, E., Hartwell, K.J., McRae-Clark, A.L., and Brady, K.T. (2012). A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry 169, 805–812.

• N=116 cannabis-dependent adolescents

• All received contingency management and brief weekly counseling

• Cannabis-positive test was assumed for any missed visits

NAC, Other Uses, Craving

Duailibi, M.S., Cordeiro, Q., Brietzke, E., Ribeiro, M., LaRowe, S., Berk, M., and Trevizol, A.P. (2017). N-acetylcysteine in the treatment of craving in substance use disorders: Systematic review and meta-analysis. Am J Addict 26, 660–666.

NAC, Other Uses, Craving

Duailibi, M.S., Cordeiro, Q., Brietzke, E., Ribeiro, M., LaRowe, S., Berk, M., and Trevizol, A.P. (2017). N-acetylcysteine in the treatment of craving in substance use disorders: Systematic review and meta-analysis. Am J Addict 26, 660–666.

NAC, Other Uses, Bipolar Depression

and Schizophrenia

• Reduces severity of depressive episodes in bipolar disorder (Berk et al.,

2008)

• Reduces negative symptoms in schizophrenia (Berk et al., 2008; Farokhina

et al, 2013)

Berk, M., Copolov, D.L., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., Anderson-Hunt, M., and Bush, A.I. (2008). N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial. Biol. Psychiatry 64, 468–475. Berk, M., Copolov, D., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., Anderson-Hunt, M., Judd, F., Katz, F., Katz, P., et al. (2008). N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial. Biol. Psychiatry 64, 361–368.

Farokhnia, M., Azarkolah, A., Adinehfar, F., Khodaie-Ardakani, M.-R., Hosseini, S.-M.-R., Yekehtaz, H., Tabrizi, M., Rezaei, F., Salehi, B., Sadeghi, S.-M.-H., et al. (2013). N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. Clin Neuropharmacol 36, 185–192.

NAC, Psychiatric Uses, Self-Injurious

Behavior • Case report: Significantly reduced “self-injurious craving” in 25 yo woman with

PTSD and Borderline PD (Pittenger et al., 2005)

• Case report: abatement of formerly daily self-cutting in a 17 yo woman with ADHD, PTSD, and eating disorder (Rus, 2017)

• Open-label pilot study: Significant reduction of non-suicidal self injury in 24 adolescent and young adult females (Cullen et al., 2017)

Pittenger, C., Krystal, J.H., and Coric, V. (2005). Initial evidence of the beneficial effects of glutamate-modulating agents in the treatment of self-injurious behavior associated with borderline personality disorder. J Clin Psychiatry 66, 1492–1493. Rus, C.P. (2017). [A girl with self-harm treated with N-acetylcysteine (NAC)]. Tijdschr Psychiatr 59, 181–184. Cullen, K.R., Klimes-Dougan, B., Westlund Schreiner, M., Carstedt, P., Marka, N., Nelson, K., Miller, M.J., Reigstad, K., Westervelt, A., Gunlicks-Stoessel, M., et al. (2017). N-Acetylcysteine for Nonsuicidal Self-Injurious Behavior in Adolescents: An Open-Label Pilot Study. J Child Adolesc Psychopharmacol.

NAC, Other Uses

Open-access review article of NAC studies in neuropsychiatric illness:

Deepmala, D., Slattery, J., Kumar, N., Delhey, L., Berk, M., Dean, O., Spielholz, C., and Frye, R. (2015). Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neurosci Biobehav Rev 55, 294–321.

NAC: Safety

A Multi-center Comparison of the Safety of Oral versus Intravenous Acetylcysteine for Treatment of Acetaminophen Overdose. Clin Toxicol (Phila) 48, 424–430 (2010).

Another nexus point:

The Cell Membrane

Ion channels, reuptake proteins, and neurotransmitter receptors exist in, and are influenced by, cell membrane lipids

Fatty Acid Composition Affects Cell

Membrane Biophysics

Types of Fatty Acids

Saturated

All carbon atoms in the fatty acid tail

carry their maximum number of

hydrogen atoms.

Mono-unstaturated

A single pair of carbon atoms share a

double bond

Oleic acid (constituent of olive oil) is

a mono-unsaturated fatty acid

Poly-unsaturated

Multiple pairs of carbon atoms share

double bonds

“Omega Number” refers to the position from the tail where the first double bond appears.

Essential Fatty Acids

• Mammals can’t create double-bonds at omega-3 or omega-6 positions

• They must be consumed from the diet

• Most important omega-3 fatty acids are EPA and DHA

• Most important omega-6 fatty acids are Arachidonic Acid and DGLA

• Approx 30% of the dry weight of the brain is from these 4 essential fatty acids

• Arachidonic acid (omega-6) and DHA (omega-3) comprise about 90% of that

total.

• If the body can’t find the right EFA for a particular membrane, it will

incorporate what is available instead

Consequences of essential fatty acid

deficiency or imbalance

• Alterations of membrane fluidity affect function of membrane-embedded proteins - e.g., neurotransmitter receptors, reuptake pumps, ion channels

• Essential fatty acids are precursors of physiologically-active molecules

• DGLA (omega-6) —> 1-series prostaglandins • Arachidonic acid (omega-6) —> 2-series prostaglandins;

anandamide • EPA (omega-3) —> 3-series prostaglandins • Arachidonic acid products impact dopamine signaling • DHA levels affect serotonin signaling

Psychiatric Patients are Substantially

Over-Represented in the Lower 10% of

EPA+DHA Levels

• Omega is sum of EPA+DHA as % of all fatty acids

• Inversely correlates with risk of cardiovascular disease, with >8% associated with highest degree of protection

• 45% of psychiatric inpatients had omega-3 index lower than the lowest 10% of USA population

Messamore, E. & McNamara, R. K. Detection and treatment of omega-3 fatty acid deficiency in psychiatric practice: Rationale and implementation. Lipids Health Dis 15, 25 (2016).

Diet composition correlates with

schizophrenia outcome

• WHO Data

• Schizophrenia

prevalence is similar

across countries

• Resulting disability

varies significantly

• 90% of variability in

resulting disability

attributed to prevailing

dietary pattern

EPA+DHA to prevent schizophrenia?

• 81 adolescent and young adults with sub-threshold (prodromal) psychosis

• Half get 1200 mg/d* of omega-3 fatty acids; half randomized to placebo

• 12 weeks of treatment

• Assessment at 40 weeks

• Longer-term followup at 7 years Treatment Percent with schizophrenia at 40 weeks

Percent with schizophrenia at 7 years

Placebo 27% 40%

Omega-3 fatty acids

5% 9.8%

Amminger, G. P. et al.. Arch. Gen. Psychiatry 67, 146–154 (2010).

Amminger, G. P. et al., Nature Communications 6, 7934 (2015).

*EPA: 700 mg/d + DHA: 480 mg/d

EPA+DHA to prevent schizophrenia?

•304 adolescent and young adults with sub-threshold (prodromal) psychosis

• Half get 1200 mg/d* of omega-3 fatty acids; half randomized to placebo

•24 weeks of treatment

•Assessment at completion of treatment (24 weeks) and 6 months following completion

•Additional inclusion criteria (not present in the Amminger study:

•sustained (>1 yr) low-level of social/occupational functioning

•both groups had concurrent cognitive behavioral case management (CBCM)

•Concurrent antidepressant use was 5x the level of the Amminger study

Treatment Percent with schizophrenia at 1 yr

Placebo 11.2%

Omega-3 fatty acids

11.5%

*EPA: 840 mg/d + DHA: 560 mg/d

Failed to replicate earlier study, but placebo group response was more robust

McGorry et al. JAMA Psychiatry. Jan. 2017

EPA Deficiency Correlates With Impulsivity & Aggression

in Depression Comorbid with Substance Use Disorder

Beier, A.M., Lauritzen, L., Galfalvy, H.C., Cooper, T.B., Oquendo, M.A., Grunebaum, M.F., Mann, J.J., and Sublette, M.E. (2014). Low plasma eicosapentaenoic acid levels are associated with elevated trait aggression and impulsivity in major depressive disorder with a history of comorbid substance use disorder. Journal of Psychiatric Research 57, 133–140.

Omega-3 Fatty Acids Appear Relevant to

Treatment-Resistant Depression

McNamara, R.K., Strimpfel, J., Jandacek, R., Rider, T., Tso, P., Welge, J.A., Strawn, J.R., Delbello, M.P., 2014. Detection and Treatment of Long-Chain Omega-3 Fatty Acid Deficiency in Adolescents with SSRI-Resistant Major Depressive Disorder. PharmaNutrition 2, 38–46.

• 40% of adolescents achieved remission of residual depressive symptoms with low dose (2.4 g/d) fish oil supplement.

• 100% achieved remission with high dose (16.2 g/d) fish oil supplement

Reduction of ‘Antisocial Behaviors’ in Prisoners

Given Essential Fatty Acid Supplements

• Reduction versus placebo group of adjudicated in-prison offenses among

prisoners (n=231) given supplemental essential fatty acid + vitamin

supplement.

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Gesch, C.B., Hammond, S.M., Hampson, S.E., Eves, A., and Crowder, M.J. (2002). Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behaviour of young adult prisoners. Randomised, placebo-controlled trial. Br J Psychiatry 181, 22–28.

Paucity of Studies on Pathophysiology of

Borderline PD

Severe Deficits of EPA and More-Severe

Deficits of DHA in Borderline PD

BoPD

(n=25)

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Levels α-linolenic acid, a precursor omega-3 fatty acid, are higher in depression or BPD

EPA levels are severely depleted in Depression and BPD

DHA levels are even more depleted in BPD vs Depressed patients

EPA Reduces Depression and

Aggression in Borderline PD

Zanarini, M.C., and Frankenburg, F.R. (2003). omega-3 Fatty acid treatment of women with borderline personality disorder: a double-blind, placebo-controlled pilot study. Am J Psychiatry 160, 167–169.

• 20 subjects given 1 g/day ethyl-EPA • 10 given placebo • No other meds

Omega-3 Fatty Acid Treatment Reduced Depression,

Suicidal Thoughts, Stress Tolerance in Pts with

Recurrent Self-Injury

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41%

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no sucidial thoughts

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REMISSION of Depression

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Group

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Hallahan, B., Hibbeln, J.R., Davis, J.M., and Garland, M.R. (2007). Omega-3 fatty acid supplementation in patients with recurrent self-harm. Single-centre double-blind randomised controlled trial. Br J Psychiatry 190, 118–122.

• 49 subjects who presented to an E.R. after >2 acts of self-harm • 1220 mg/d EPA + 908 mg/d DHA for 12 weeks

Omega-3 Fatty Acids Reduce Symptoms and Improve

Functioning in Adolescents with Borderline PD

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Omega 3 Fatty Acids Improved Overall Level of Functioning

in Adolescents with Borderline Personality Disorder

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Omega-3 Fatty Acids Reduced Severity

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Amminger, G. P. et al. Omega-3 fatty acid supplementation in adolescents with borderline personality disorder and ultra-high risk criteria for psychosis: a post hoc subgroup analysis of a double-blind, randomized controlled trial. Can J Psychiatry 58, 402–408 (2013).

• N=15 adolescents from prodromal assessment clinic, who met criteria for BPD • Omega-3 dose was 700 mg/d EPA + 480 mg/d DHA • Treatment was for 12 weeks

Omega-3 Fatty Acids: Safety

Source: Lovaza (ethyl-EPA + ethyl DHA) prescribing information

Conclusions

• Intervening at ’nexus points’ of pathophysiology can impact seemingly

diverse expressions of illnes

• Inflammation, oxidative stress, glutamate, and cell membrane fluidity are

examples of such nexus points.

• NAC or omega-3 fatty acids influence these nexus points. Each agent

appears to have significant psychotropic activity that may cut across

diagnostic boundaries.