NATUROPATHIC APPROACHES TO SCHIZOPHRENIA PSYCHOSIS Dr Cyndi Gilbert
NATUROPATHIC APPROACHES TO SCHIZOPHRENIA & PSYCHOSIS Dr. Cyndi Gilbert ND
IN THEIR OWN WORDS “Schizophrenia is the devil on your shoulder that keeps whispering in your ear and, no matter what you try, the little demon won’t stop. ” – Michael Hedrick “To me, the best analogy of what it's like is that it's a waking nightmare, where you have all the bizarre images, the terrible things happening, and the utter terror — only with a nightmare you open your eyes and it goes away. No such luck with a psychotic episode. “ – Elyn Saks
FROM LITERATURE “The road to creativity passes so close to the madhouse and often detours or ends there. ” - Ernest Becker “The psychotic drowns in the same waters in which the mystic swims with delight. ” - Joseph Campbell “Schizophrenia cannot be understood without understanding despair. ” - R. D. Laing
DEFINING PSYCHOSIS Relevant DSM-V diagnoses include schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder May occur in bipolar disorder, depression Prodromal period is common (altered behaviour and experiences) Positive symptoms: hallucinations, delusions, disorganized speech and/or behaviour, catatonic behaviour Negative symptoms: emotional apathy / low affect, demotivation, anhedonia, poverty of speech, social withdrawal, and self‑neglect
EPIDEMIOLOGY OF SCHIZOPHRENIA Incidence: 0. 25 -0. 5 in 1, 000 per year Prevalence: 10 -15 in 1, 000 (3% prevalence for at least 1 psychotic episode) More common in males than females (RRR 1. 4; 95%CI, 1. 3 -1. 56) 0. 4% estimated in children aged 5 -18, incidence increases significantly after 15 yo Age at onset typically late adolescence to mid 30 s (peak early 20 s males, late 20 s females) Higher prevalence in northern Sweden, Croatia, western Ireland, Canadian Catholics, south Indian Tamils PROG NEUROBIOL. 2011 JAN; 93(1): 23 -58. FIRST CONSULT – SCHIZOPHRENIA. 2014.
GENETIC RISK FACTORS 45 -60% risk if have monozygotic twin with schizophrenia 10 -15% for dizygotic twins 9% in non-twin sibling 12% in child of one schizophrenic parent 40% in child of two schizophrenic parents But… Most have no family history of psychosis
OTHER RISK FACTORS Organic causes: electrolyte disorders, hypoglycemia, heat stroke, certain viral/bacterial infections Substance-related causes: medications, drugs of abuse Psychological causes: stressful life events/situation, experience of discrimination, immigration Environmental factors: social fragmentation/isolation, toxic exposures (e. g. leaded gasoline), vitamin D deficiency Prenatal factors: birth in urban environment, birth in winter or early spring, utero developmental disruptions, infections in utero, greater paternal age, fetal hypoxia PROG NEUROBIOL. 2011 JAN; 93(1): 23 -58.
DSM-V DIAGNOSTIC CRITERIA Two or more of the following features, with at least one from among the first three, and present for a significant portion of time during a 1 -month period: Delusions Hallucinations Disorganized speech Disorganized behavior or catatonia Negative symptoms Plus: decreased level of social functioning relative to time prior to onset, signs of presentation for > 6 mo
ASSOCIATED DISORDERS 20% attempt suicide 40% of premature death due to suicide >50% smoke cigarettes 30 -50% alcohol abuse 85% cannabis use 15 -25% cannabis abuse 5 -10% cocaine abuse 10 fold increase in HIV risk Increased risk of other STIs, hepatitis C
LABORATORY INVESTIGATIONS Primarily to rule out other causes of psychosis CBC, urinalysis, chemistry: megaloblastic anemia, infection, electrolyte abnormalities, renal failure LV enz: encephalopathy secondary to liver disease Serum B 12: deficiency Thyroid function: hyper- or hypo- with psychotic features Syphillis and HIV serology Toxicology CXR: primary lung malignancy with metastasis to brain EEG: seizure disorders, epilepsy
PROGNOSIS Relapse rate: 40% with treatment; 80% within 2 years without treatment 20% remain well after first episode 40 -50% make partial recovery but relapse after 5 -10 years 30 -40% experience severe illness, frequent relapses, and long-term disability Life expectancy 20% lower than general population (mostly due to metabolic adverse effects)
PATHOPHYSIOLOGY: DOPAMINE Elevated levels of dopamine in the brain (striatum) Abnormal upregulation of synaptic transmission through D 2 receptors in mesolimbic pathway Mesolimbic pathway also responsible for central processing of pain and negative stimuli Almost all antipsychotic drugs on the market act as dopamine antagonists
PATHOPHYS IOLOGY: DA, GABA, NMDA Hypofunction of NMDA receptor Decreases inhibitory effects of GABA Increases release of D 2 TRENDS NEUROSCI. 2001 JUN; 24(6): 330 -4.
PATHOPHYS IOLOGY: NMDA Complicated receptor Voltage ligand-gated ion channel Glycine modulatory site is not saturated in vivo Schizophrenia risk associated with multiple genes encoding for NMDA receptor and glutamatergic transmission Abnormalities of glycine modulatory site (GMS) SCHIZOPHR BULL. 2013 JAN; 39(1): 120 -9. CURR OPIN PHARMACOL. 2015 FEB; 20: 109 -15.
PATHOPHYSIOLOGY: OXIDATION Oxidative stress one theory related to pathophysiology of schizophrenia Not necessarily a cause but rather a factor contributing to deterioriation and poor outcomes Brain has high rate of oxidative metabolic activity, NTs oxidized to hydrogen peroxide Brian has relatively low concentrations of Mn-SOD & GSH, leading to mitrochondrial damage Serum GSH has been found to be reduced in those with schizophrenia Inconsistent results found in antioxidant enzymatic activity (e. g SOD, GSH peroxidase/catalase) and lipid peroxidation (low, high, & equivocal) OXID MED CELL LONGEV. 2015; 2015: 248529.
PATHOPHYSIOLOGY: IMMUNITY, INFLAMMATION & THE GUT Dysbiosis of microbiome theorized to play a role in pathogenesis of schizophrenia Increased rates of celiac disease, IBD, IBS, other autoimmune diseases, and gut infections Autopsy studies show high rates of gastritis (50%), enteritis (88%), and colitis (92%) Evidence of GI permeability (increased zonulin via bacteria and gluten peptides) Non-celiac disease gluten intolerance more prevalent in schizophrenia than controls SCHIZOPHR RES. 2014 may JUL 14. PII: S 0920 -9964(14)00319 -3. Casein intolerance also higher in schizophrenia, precede onset CURR PSYCHIATRY REP. 2015 MAY; 17(5): 27.
PATHOPHYSIOLOGY: IMMUNITY, INFLAMMATION & THE GUT Elevated levels of anti-Saccharmyces cerevisiae Ab (ASCA) Correlated to anti-gluten and anti-casein Ig. G Results found in medication-naïve patients, recent onset, and non-recent onset schizophrenia 1 st and 2 nd generation antipsychotics decrease intestinal motility due to anticholinergic effects Antipsychotic use correlated to lower ASCA rates, constipation, and bowel obstruction SCHIZOPHR RES. 2012 JUN; 138(1): 48 -53.
PATHOPHYSIOLOGY: IMMUNITY, INFLAMMATION & THE GUT Gut microbiome stimulates brain plasticity via expression of brain-derived neurotropic factor (BDNF) and NMDA receptors Theoretically, dysbiosis may contribute to NMDA receptor dysfunctions Overall, upregulated inflammatory responses present in schizophrenia: ↑ pro-inflammatory cytokines Th 1/Th 2 imbalances confirmed in studies ↑ PLA 2 activity + oxidative damage, ↑ release of PUFAs from neuronal membranes PROG NEUROPSYCHOPHARMACOL BIOL PSYCHIATRY. 2015 JAN 2; 56: 155 -60.
EXPECTED OUTCOMES OF TREATMENT Duration of untreated psychosis Reducing premature mortality Hospital admissions Educational attainment Health‑related quality of life Service user experience of mental health services Quality of life for caregivers Detention rates
ST 1 GENERATION ANTIPSYCHOTICS Typical antipsychotics Drugs: haloperidol, chlorpromazine, thioridazine, trifluoperazine, perphenazine, fluphenazine Haloperidol and fluphenazine available as long-acting injectables As effective as 2 nd generation antipsychotics (SGAs) More extrapyramidal adverse effects, fewer metabolic effects (vs SGAs)
COMPARISON OF TYPICAL ANTIPSYCHOTICS Drug Initial Dosage Potency Contraindications Adverse Effects Chlorpromazin 50 -100 mg e qd Available IM Low Coma Phenothiazine sensitivity Most sedating Anticholinergic effects, orthostatic hypotension, corneal & lens pigmentation Perphenazine 4 -12 mg qd Intermediat e Coma Phenothiazine sensitivity Hematological diseases Little sedation, higher EPS, increased PRL, tardive dyskinesia Haloperidol 1. 5 -3 mg qd Available IM High CNS depression Very high EPS Coma (dystonia, COMPENDIUM OF THERAPEUTIC CHOICES. 7 TH ED. Parkinson’s disease pseudoparkinsonism, OTTAWA: CPA; 2014.
ND 2 GENERATION ANTIPSYCHOTICS Atypical antipsychotics Drugs: aripiprazole, lurasidone, paliperidone, ziprasidone, risperidone, olanzapine, quetiapine, clozapine Fewer EPS, more metabolic effects (weight gain, insulin resistance/DM, hyperlipidemia) Greater 5 HT affinity relative to D 2 affinity, may be more effective in treating depressive sxs (vs FGAs) Limited evidence of efficacy in children and teens Adolescents more sensitive to the adverse effects (vs adults) COMPENDIUM OF THERAPEUTIC CHOICES. 7 TH ED. OTTAWA: CPA; 2014.
COMPARISON OF ATYPICAL ANTIPSYCHOTICS Drug Initial Dosage Metabolism Adverse Effects Risperidone 0. 5 -1 mg qd CYP 2 D 6, 3 A 4 EPS, weight gain, hyper. PRL Aripiprazole 10 -15 mg qd CYP 2 D 6, 3 A 4 EPS, insomnia Quetiapine 50 -100 mg qd CYP 3 A 4 Sedation, weight gain, metabolic abnormalities (↑TG) Ziprasidone 40 mg bid CYP 3 A 4 CV effects, EPS Olanzapine 5 -10 mg qd CYP 1 A 2 Sedation, weight gain, metabolic abnormalities Clozapine 12. 5 -25 mg qd CYP 1 A 2 Sedation, weight gain, metabolic abnormalities, CV effects, agranulocytosis, hypersalivation TH COMPENDIUM OF THERAPEUTIC CHOICES. 7 ED. OTTAWA: CPA; 2014.
DRUG METABOLISM, SMOKING, CAFFEINE CYP 1 A 2 inducers decrease drug toxicity of clozapine/olanzapine Polycyclic aromatic hydrocarbons from cigarette smoking and cannabinoids induce CYP 1 A 2 Inductive effects may take 2 -4 weeks to disappear May need to adjust dosage of medications with smoking cessation CYP 1 A 2 inhibitors increase plasma AUC values Caffeine a weak competitive inhibitor Strong inhibitors: fluoroquinolones, fluvoxamine, verapamil More a concern with clozapine PSYCHIATRIC SERVICES. 2004 MAY; 55(5): 491 -3.
ADVERSE EFFECTS: HYPERPROLACTINEMIA Common with FGAs, risperidone and paliperidone (also olanzapine, ziprasidone) Associated with menstrual irregularities and galactorrhea in women, galactorrhea and gynecomastia in men Also associated with sexual dysfunction Reducing dose of antipsychotic may help
ADVERSE EFFECTS: TARDIVE DYSKINESIA Repetitive, involuntary movements Usually affects buccal-oral-lingual muscles, face, trunk, extremities, respiratory muscles Incidence is 5% per year with FGAs Cumulative risk up to 50% Quetiapine and clozapine equal rates to placebo
ADVERSE EFFECTS: METABOLIC SYNDROME 33. 4% prevalence of metabolic syndrome in schizophrenia (95%CI: 30. 836. 0) RR=1. 87 in schizophrenia and related psychotic disorders (95%CI: 1. 532. 29) 60% of increased mortality risk related to physical comorbidities, most notably CVD Significant factors: number of episodes, BMI, age, polypharmacy, use of antipsychotic medications, illness duration Weight gain may be rapid Usually plateaus after 1 year Dose reductions unlikely to result in weight loss WORLD PSYCHIATRY. 2015 OCT; 14(3): 339– 347.
ADVERSE EFFECTS: METABOLIC SYNDROME Prevalence of Metabolic Syndrome and Antipsychotic Medication Clozapine 47. 2 Quetiapine 37. 3 Olanzapine 36. 2 Risperidone 30. 7 Typical antipsychotics 28 Amisulpride 22. 8 Aripiprazole 19. 4 Antipsychotic naïve 10. 2 0 5 10 15 20 25 30 35 40 45 50 Prevalence ADAPTED FROM: WORLD PSYCHIATRY. 2015 OCT; 14(3): 339– 347.
ADVERSE EFFECTS: CARDIOVASCULAR EFFECTS Orthostatic hypotension Elderly, heart disease, DM most at risk Common with FGAs and clozapine QTc interval prolongation Associated with torsades de pointes, syncope, ventricular fibrillation, sudden cardiac death Most common with chlorpromazine, pimozide, haloperidol Ziprasidone has greatest risk compared to other antipsychotics (CI in recent MI or uncompensated HF) Do not combine with other drugs/herbs known to prolong QTc Other adverse CV effects Clozapine associated with risk of myocarditis, pericardial effusion, cardiomyopathy, HF, MI, mitral insufficiency
NATUROPATHIC THERAPIES
HYDROTHERAPY Introduced in 1891 by Emil Kraeplin, German psychiatrist, who wrote about the benefits of prolonged bathing for psychosis Alois Alzheimer introduced baths at an asylum in Frankfurt, spread across Europe and North America Popular form of psychological treatment in early 20 th century, considered standard treatment by 1910, used for almost all patients regardless of mental health diagnosis Phased out in 1940 s or 50 s with hospital overcrowding and development of neuroleptic medications, antipsychotics ISSUES IN MENTAL HEALTH NURSING. 2009; 30: 491– 494.
PROLONGED BATHS
PROLONGED BATHS Hot water (95 -100 F) baths were used to calm and relax patients, reduce agitation, induce fatigue, relieve insomnia, depress frontal cortex activity Cold water used in cases of extreme hyperactivity to slow blood flow and brain activity, for Prolonged baths lasted 8 -24 hours Shorter baths less than 3 hours, were given once or twice daily (common in the 1950 s) Required constant monitoring of vitals, but also to prevent accidental or intentional drowning Often viewed as punishments by patients, used as threats by staff (therapeutic treatment vs therapeutic restraint)
WET SHEET PACKS Preferred since they required little equipment compared to baths Temperature ranged from 40 -100 F Hot sheets used for frail patients; sweating was often promoted Cold sheets used for agitated, uncooperative, or self-harming patients Often alternated, depending on physician’s orders MENTAL HEALTH SERVICES RESEARCH. 1999; 1(4).
WET SHEET PACKS Facilitated verbal communication by controlling motor expression Restored sensory integration and body representations Provided respite from destructiveness, humane “holding” environment like swaddling Helped re-establish clear self-object boundaries and control destructive thoughts Increased awareness of repressed feelings/memories Decreased need for locked-door seclusion and 4 -point restraints Increased control over impulses HOSP COMMUNITY PSYCHIATRY. 1986; 37(3): 287 -288. AM J PSYCHIATRY. 1988 FEB; 145(2): 242 -245.
HYDROTHERAPY MOA Gate control theory of pain 1 neural pathway, 2 functions Execution of 1 pathway inhibits, or precludes execution of, the other Mesolimbic dopamine pathway activated by temperature-related pain is same area involved in psychosis Analgesia from hydrotherapy inhibits psychosis mediated within same mesolimbic pathway Frequent repetition required MEDICAL HYPOTHESES. 2008; 70: 230– 238.
EXERCISE People with schizophrenia engage in less physical activity, especially moderate to vigorous activity Aerobic fitness correlated to depression, neurocognitive functioning, and overall daily functioning BMI inversely related to neurocognition PSYCHIATRY RES. 2014 DEC 30; 220(3): 784 -91.
EXERCISE BENEFITS Prevents weight gain, improves weight loss Improves cardiorespiratory fitness (J Sports Sci. 2016 Aug; 34(16): 1500 -15. ) Reduces risk of diabetes, obesity, and metabolic syndrome Increases self-esteem, positive relationship, overall function, QOL Reduces positive and negative symptoms and improve cognition (Early Interv Psychiatry. 2016 Mar 14. Psychosom Med. 2010 Apr; 72(3): 239 -52. Rev Bras Psiquiatr. 2015 Oct-Dec; 37(4): 271 -9. ) Increases brain-derived neurotrophic factor (Schizophr Bull. 2015 Jul; 41(4): 859 -68. Psychiatry Res. 2014 Dec 30; 220(3): 792 -6. ) BIOL RES NURS. 2016 JUN 5. PII: 1099800416653184. J NERV MENT DIS. 2016 MAY 23. [EPUB AHEAD OF PRINT] PSYCHIATRY RES. 2015 OCT 30; 229(3): 828 -39. PSYCHOL MED. 2015 MAY; 45(7): 1343 -61.
COUNSELING & PSYCHOTHERAPY For the patient For the family CBT-Psychosis (CBTp) Family intervention Memorization strategies Carer-focused education and support, including individual counseling and peer support groups Supportive problem-solving strategies Motivational interviewing Smoking cessation COCHRANE DATABASE SYST REV. 2012 APR 18; (4): CD 008712. COCHRANE DATABASE SYST REV. 2015; (10: CD 010646. NICE GUIDELINES 2015
MIND-BODY TECHNIQUES Art therapy 2 RCTs showed some evidence of benefit on mental state in short-medium term Dance therapy 1 single-blind study compared to routine care Reductions in PANSS negative symptom scores (>20% reduction) but no difference overall Yoga Improvements in mental state, social functioning, and COCHRANE DATABASE SYST QOL REV. 2015 OCT 21; (10): CD 010554. COCHRANE DATABASE SYST REV. 2005 OCT 19; (4): CD 003728.
MIND-BODY TECHNIQUES Music therapy Improvements in global state, mental state, and social functioning Horticultural therapy 1 small single blind study; 1 hour per day x 2 weeks; decrease in Depression Anxiety Stress Scale in horticultural group but wide CI Strength of evidence for dementia is much better; risk of harm is low COCHRANE DATABASE SYST REV. 2011 DEC 7; (12): CD 004025. Promotes socialization, rehabilitation, mobility, and QOL COCHRANE DATABASE SYST REV. 2014 MAY 19; (5): CD 009413. CLIN REHABIL. 2004 AUG; 18(5): 483 -6. AM J GERIATR PSYCHIATRY. 2001 FALL; 9(4): 439 -42. Animal-assisted therapy
DIETARY RECOMMENDATIONS Increase fruits, vegetables, fibre to improve motility and reduce cardiometabolic risk Include lacto-fermented food to improve gut bacteria environment Decrease refined carbohydrates, high glycemic index foods to reduce risk of diabetes and obesity Decrease discretionary food intake Consider gluten and/or casein avoidance Celiac Disease prevalence 2. 6% vs 1% in general pop’n GFCF diet studies (1960 s & 1970 s) allowed for greater movement of patients from locked to NUTR J. 2014 SEP 16; 13: 91. DOI: 10. 1186/1475 -2891 -13 -91. open wards BR J NUTR. 2016 JUN; 115(11): 1987 -93. NUTRIENTS. 2015 JUL 8; 7(7): 5532 -9. SCHIZOPHR RES. 2014 NOV; 159(2 -3): 539 -42
FOLATE & B 12 High prevalence of smoking associated with decreased serum folate Lower brain levels of B 12 than age-matched controls Influenced by genetic variations in folate metabolism Increased risk of schizophrenia related to plasma total homocysteine (OR: 2. 15 per 1 -SD increase in t. Hcy, 95%CI: 1. 39 -3. 32) 5 µmol/L increase in homocysteine associated with 70% greater risk (95%CI: 27 -129) MTHFR 677 T homozygous polymorphism associate with 36% greater risk vs CC genotype (95%CI: 7 -72) Other SNPs also likely involved: MTR 2756 A, FOLH 1 484 C, COMT 675 A (Schizophr Bull. 2013 Mar; 39(2): 330 -8. ) MOL PSYCHIATRY. 2006 FEB; 11(2): 143 -9. SCHIZOPHR BULL. 2014 SEP; 40(5): 1154 -63. BMC MED GENET. 2015 JUL 26; 16: 54. PLOS ONE. 2016 JAN 22; 11(1): E 0146797.
FOLATE & B 12 Supplementation of folate and B 12 improved negative symptoms RCT, n=140, 16 wk trial Folic acid 2 mg + B 12 400 mcg qd Significant benefit only found amongst those with FOLH 1 484 T genotype RCT, n=46, 12 wk trial Folic acid 2 mg qd Significant reduction in negative symptoms, only amongst those with at least one copy of MTHFR 677 T allele RCT crossover design, n=55 with hyperhomocysteinemia, 6 months total Folic acid 2 mg, B 12 400 mcg, and pyridoxine 25 mg qd Decreased total PANSS scores (p=0. 019) and t. Hcy (p<0. 00001) vs placebo JAMA PSYCHIATRY. 2013 MAY; 70(5): 481 -489. SCHIZOPHR RES. 2011 APR; 127(1 -3): 41 -5. BIOL PSYCHIATRY. 2006 AUG 1; 60(3): 265 -9.
GLYCINE & D-AMINO ACIDS > 70 RCTs exploring use of GMS agonists (D-serine, glycine, D-cycloserine, D-alanine) in treatment of schizophrenia D-serine less effective in trials D-cycloserine may have negative effects Effectiveness shown with blocking reuptake of GMS agonists through Nmethylglycine (sarcosine) but many adverse effects Inhibiting DAAO with sodium benzoate may increase GMS agonist availability COCHRANE DATABASE SYST REV. 2006 APR 19; (2): CD 003730.
GLYCINE & D-AMINO ACIDS Glycine shown in several small RCTs to reduce negative symptoms on PANSS when given adjunctively to antipsychotic medication Trend towards positive effects on cognitive symptoms Dosage ranges from 20 -60 g qd or 0. 8 g/kg qd Results were best in patients with low serum glycine levels at baseline No significant improvement in symptoms (possible worsening) with clozapine in multiple small RCTs PHARMACOPSYCHIATRY. 2014 SEP; 47(6): 185 -94. INT J NEUROPSYCHOPHARMACOL. 2001 DEC; 4(4): 385 -91. BIOL PSYCHIATRY. 2004 JAN 15; 55(2): 165 -71.
N-ACETYL CYSTEINE Oxidative stress theory of schizophrenia related to inflammation, mitochondrial dysfuction, lipid perozidation, DNA damge, apoptosis, and hypoactive NMDA receptors GSH reduced in CSF of drug-naïve people with schizophrenia Polymorphisms in genes for glutamate cysteine ligase subunits linked to schizophrenia Neuronal oxidative stress induced by abnormal metabolism of dopamine and glutamate is exaggerated by GSH deficiency NAC shown to increase plasma GSH in schizophrenia NEUROPSYCHOPHARMACOLOGY. 2008 AUG; 33(9): 2187 -99. BIOL PSYCHIATRY. 2008 SEP 1; 64(5): 361 -8. INT J NEUROPSYCHOPHARMACOL. 2011 FEB; 14(1): 12330.
N-ACETYL CYSTEINE NAC vs placebo as adjunctive tx RCT, n=140, 1 g bid x 24 wks Improved scores on PANSS total (p=0. 009), PANSS negative (p=0. 018), and PANSS general (p=0. 035); also improvements in CGI-S (p=0. 004), and CGI-Improvement (p=0. 025) Chronically ill for >20 yr gained most from NAC intervention NAC vs placebo with adjunctive risperidone RCT, n=42, 1 g bid x 8 wks Improved scores on PANSS total (p=0. 006) and PANSS negative (p<0. 001) No difference in adverse effects or drop outs in either study PROG NEUROPSYCHOPHARMACOL BIOL PSYCHIATRY. 2015; 3(57): 69 -75. CLIN NEUROPHARMACOL. 2013 NOV-DEC; 36(6): 185 -92.
POLYUNSATURATED FATTY ACIDS Based on hypothesis of altered neuronal membrane structure/metabolism, decreased PUFAs in RBCs and brains Cochrane review (2006, n=8 studies) found limited evidence to support use EPA vs placebo in unmedicated, 1 rst episode (Schizophr Res. 2001; 49(3): 243– 51. ) RCT, n=30; 2 g qd >25% improvement on PANSS (RR: 0. 54 CI: 0. 30 -0. 96, NNT=3) E-EPA +/- vitamin E+C vs placebo in acute (Transl Psychiatry. 2013 Dec; 3(12): e 335. ) RCT, n=99; 2 g E-EPA, 364 mg vit E, 1 g vit C Induced psychosis & increased PANSS when given separately to low baseline PUFA participants; no negative effects when combined COCHRANE DATABASE OF SYST REV. 2006; 3: CD 001257.
POLYUNSATURATED FATTY ACIDS EPA vs placebo in first episode (J Psychiatr Res. 2016 Feb; 73: 34 -44. ) RCT, n=71, 26 wk 2. 2 g qd (1. 32 g EPA/880 mg DHA) w/ concomittant antipsychotic meds >50% improvement on PANSS (RR=1. 74; NNT=4) EPA+DHA vs placebo as psychosis prevention in high-risk individuals (Arch Gen Psychiatry. 2010; 67(2): 146 -154. ) RCT, n=81, 12 wk 1. 2 g qd (700 mg EPA/480 mg DHA) + 40 wk monitoring Reduced progression to a psychotic disorder (ARR=22. 6%, p=0. 007) Also decreased positive sxs, negative sxs, and general sxs on PANSS PUFAs may help reduce dyslipidemia and tardive dyskinesia related to antipsychotics
PROBIOTICS Improve microbiome, modulate immune response, increase integrity of intestinal lining, improve motility affected by antipsychotic drugs Probiotics vs placebo in chronic patients RCT, n=65, 14 wk trial, 109 L. rhamnosus GG + 109 B. animalis lactis Bb 12 qd No significant difference in PANSS Probiotic gp less likely to report severe bowel difficulty (HR: 0. 23; 95%CI: 0. 09 -0. 61, p=0. 003) No difference in laxative use or diarrhea PRIM CARE COMPANION CNS DISORD. 2014; 16(1). PII: PCC. 13 M 01579.
MELATONIN Important role in regulating sleep-wake cycle, also powerful antioxidant Melatonin enhances intracellular GSH Secretion decreased in both drug-naïve and those treated with antipsychotics Olanzapine known to decrease melatonin secretion, theorized to play a role in its metabolic adverse effects Melatonin may attenuate these effects (Bipolar Disord. 2014 Jun; 16(4): 410 -21. ) 2 small RCTs found improvements in sleep efficiency, improved sleep quality, increased morning wakefulness, improved mood, and overall daily functioning NUTR J. 2014 SEP 16; 13: 91. DOI: 10. 1186/1475 -2891 -13 -91. J CLIN PSYCHIATRY. 2000 MAY; 61(5): 373 -7.
NIACIN Deficiency can present with neuropsychiatric symptoms consistent with psychosis Higher tolerance before flushing documented in those with schizophrenia Orthomolecular case studies support the use of niacin in schizophrenia RCTs are lacking; case studies are dated; best effects were noted in acute cases Orthomolecular doses typically used (3 -6 g qd) Bonus: Adjunctive to address metabolic adverse effects (especially hyperlipidemia) of antipsychotic medications ISR J PSYCHIATRY RELAT SCI. 2008; 45(1): 3 -10. EUR REV MED PHARMACOL SCI. 2015; 19(6): 988 -97.
BOTANICAL MEDICINES Not well studied, especially as single treatment options Drug-herb interactions with antipsychotic medications Hypericum perforatum Vitex agnus-castus Help address adverse effects and support adjacent body systems Adaptogens Bitters Carminatives Hepatics Nervines
ADAPTOGENS Withania somnifera Reduced serum TG and FBG after 4 wks in 1 RCT Panax quinquefolius Improved working memory and reduced extrapyramidal AEs in 1 RCT Rhodiola rosea Russian conference proceedings from the 1970 s reported reductions in extrapyramidal AEs Schisandra chinensis Also used in Russia for schizophrenia with sxs of asthenia, depression, and psychosis PHYTOTHER RES. 2012 AUG; 26(8): 1166 -72. PHARMACEUTICALS (BASEL). 2010 JAN; 3(1): 188– 224. INDIAN J PHARMACOL. 2013 JUL-AUG; 45(4): 417 -8.
TCM FORMULAS Yi Gan San (restrain the liver decoction) Ingredients: 3 g Atractyloides macrocephalae, 4 g Poria cocus, 3 g Angelica sinensis, 3 g Ligusticum wallichi, 2 g Bupleurum chinensis, 1. 5 g Glycyrrhiza uralensis, 3 g Uncaria uncis cum ramulus Adjunctive in tx-resistance, decrease excitement/hostility, depression/anxiety, and total PANSS May help reduce tardive dyskinesia Peony & Licorice (Shao Yao Gan Cao tang) Ingredients: Paeonia alba, baked Glycyrrhiza uralensis PSYCHOPHARMACOLOGY (BERL). agonist 2015 JAN; 232(1): 155 -64. Traditionally used for muscle cramps, studied in PCOS for dopamine effects J CLIN PSYCHOPHARMACOL. 2013 FEB; 33(1): 122 -3. Case study of for resolving hyperprolactinemia and amenorrhea secondary to antipsychotic J CLIN PSYCHOPHARMACOL. 2008 JUN; 28(3): 264 -370. meds EVID BASED COMPLEMENT ALTERNAT Comparable to bromocriptine in crossover RCT MED. 2015; 2015: 201592.
TCM FORMULAS Jia Wei Xiao Yao Wan (Free & Easy Wanderer Plus) Ingredients: Bupleurum chinensis, Angelica sinensis, Paeonia alba, Atractyloides macrocephalae, Poria cocus, Glycyrrhiza uralensis, Paeonia suffruticosa, Gardenia jasminoides, Mentha haplocalyx Reduced tardive dyskinesia in an open-label trial Warm Supplementing Kidney Yang Ingredients: Aconitum lateralis, Morinda off. , Epimedium, Cinnamomum cassia, Zingiber off. , Codonopsis pilosula, Astragalus membranaceous, Rehmannia glutinosa, Glycyrrhiza uralensis Improved QOL, social function, cognitive function, and depression sxs in 3 RCTs PSYCHIATRY CLIN NEUROSCI. 2007 OCT; 61(5): 509 -14. CLIN REHABIL. 2009 NOV; 23(11): 963 -72. HUM PSYCHOPHARMACOL. 2008 AUG; 23(6): 465 -70. CURR THER RES CLIN EXP. 2008 APR; 69(2): 104 -17
GINKGO BILOBA (EGB-761) Use based on theory of free radical production, oxidative stress, and lipid peroxidation Meta-analysis of 8 RCTs Improvement in total sxs (BPRS/PANSS) Improvement in negative sxs (SANS/PANSS) Antipsychotic-induced tardive dyskinesia also believed to be mediated by free radicals and subsequent reduction in BDNF Meta-analysis of 3 RCTS Significant reduction severity of TD (AIMS) PHARMACOPSYCHIATRY. 2016 MAY; 49(3): 107 -11. PSYCHIATRY RES. 2015 JUL 30; 228(1): 121 -7.
BERBERINE Well studied for improvements in metabolism, weight gain and insulin in diabetes, PCOS Can cross BBB Neuroprotective effects theorized to reduce dopamine and NMDA receptor binding; confirmed in limited animal studies Antimicrobial effects may help correct dysbiosis Single animal study on metformin or berberine (380 mg/kg qd) showed both attenuated olanzapine-induced weight gain and adiposity Berberine additionally prevented liver weight increase (vs metformin) PLOS ONE. 2014; 9(3): E 93310. PHYTOTHER RES. 2010 MAR; 24(3): 317 -24.
CHALLENGES WITH CURRENT EVIDENCE Overall, trial quality is poor and isn’t adequately powered to draw conclusions in meta-analyses Few trials have long enough follow-up periods to account for measures of improvement and relapse Significantly more men with schizophrenia represented in research studies (results may not apply across genders or cultures) Reporting bias is common and adverse events are poorly reported in many trials Other potential outcome measures should include relapse and service use COCHRANE DATABASE SYST REV. 2016 FEB 5; 2: CD 008919
SUMMARY OF TREATMENT OPTIONS Schizophrenia is an extremely complex disease with multiple systems involved in pathophysiology No single approach will treat all aspects of schizophrenia or be effective for all patients Integrated, personalized, multisystemic approach is necessary to improve outcomes Prevent metabolic effects of SGAs with lifestyle modifications Use strategies to address immunity, oxidation, inflammation, and neurotransmitter function using a wide range of treatments
- Slides: 62