Transcript Naturopathic Approaches to Schizophrenia

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 15yo
Age at onset typically late adolescence to mid 30s (peak early 20s males, late 20s
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 B12: 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 D2 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
PATHOPHYSIOLOGY:
DA, GABA, NMDA
Hypofunction of NMDA
receptor
Decreases inhibitory effects
of GABA
Increases release of D2
TRENDS NEUROSCI. 2001 JUN;24(6):330-4.
PATHOPHYSIOLOGY:
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
Casein intolerance also higher in schizophrenia, may precede onset
SCHIZOPHR RES. 2014 JUL 14. PII: S0920-9964(14)00319-3.
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 IgG
Results found in medication-naïve patients, recent onset, and non-recent onset
schizophrenia
1st and 2nd 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
 Th1/Th2 imbalances confirmed in studies
 ↑ PLA2 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
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GENERATION ANTIPSYCHOTICS
Typical antipsychotics
Drugs: haloperidol, chlorpromazine, thioridazine, trifluoperazine, perphenazine,
fluphenazine
Haloperidol and fluphenazine available as long-acting injectables
As effective as 2nd generation antipsychotics (SGAs)
More extrapyramidal adverse effects, fewer metabolic effects (vs SGAs)
COMPARISON OF TYPICAL ANTIPSYCHOTICS
Drug
Initial Dosage Potency
Contraindications
Adverse Effects
Chlorpromazine
50-100 mg qd Low
Available IM
Coma
Phenothiazine sensitivity
Most sedating
Anticholinergic effects,
orthostatic hypotension,
corneal & lens
pigmentation
Perphenazine
4-12 mg qd
Intermediate Coma
Phenothiazine sensitivity
Hematological diseases
Little sedation, higher EPS,
increased PRL, tardive
dyskinesia
Haloperidol
1.5-3 mg qd
Available IM
High
Very high EPS (dystonia,
pseudoparkinsonism,
akathisia), increased PRL,
tardive dyskinesia, NMS
CNS depression
Coma
Parkinson’s disease
COMPENDIUM OF THERAPEUTIC CHOICES. 7TH ED. OTTAWA: CPA; 2014.
ND
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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 5HT affinity relative to D2 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. 7TH ED. OTTAWA: CPA; 2014.
COMPARISON OF ATYPICAL ANTIPSYCHOTICS
Drug
Initial Dosage
Metabolism
Adverse Effects
Risperidone
0.5-1 mg qd
CYP2D6, 3A4
EPS, weight gain, hyperPRL
Aripiprazole
10-15 mg qd
CYP2D6, 3A4
EPS, insomnia
Quetiapine
50-100 mg qd
CYP3A4
Sedation, weight gain,
metabolic abnormalities (↑TG)
Ziprasidone
40 mg bid
CYP3A4
CV effects, EPS
Olanzapine
5-10 mg qd
CYP1A2
Sedation, weight gain,
metabolic abnormalities
Clozapine
12.5-25 mg qd
CYP1A2
Sedation, weight gain,
metabolic abnormalities, CV
effects, agranulocytosis,
hypersalivation
COMPENDIUM OF THERAPEUTIC CHOICES. 7TH ED. OTTAWA: CPA; 2014.
DRUG METABOLISM, SMOKING, CAFFEINE
CYP1A2 inducers decrease drug toxicity of clozapine/olanzapine
 Polycyclic aromatic hydrocarbons from cigarette smoking and cannabinoids induce CYP1A2
 Inductive effects may take 2-4 weeks to disappear
 May need to adjust dosage of medications with smoking cessation
CYP1A2 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: 30.8-36.0)
RR=1.87 in schizophrenia and related psychotic disorders (95%CI: 1.53-2.29)
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
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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, pericarditis, 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 20th century, considered standard
treatment by 1910, used for almost all patients regardless of mental health diagnosis
Phased out in 1940s or 50s with hospital overcrowding and development of
neuroleptic medications, antipsychotics
ISSUES IN MENTAL HEALTH NURSING. 2009;30:491–494.
PROLONGED BATHS
PROLONGED BATHS
Hot water (95-100F) 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 1950s)
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 40-100F
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.
SCHIZOPHR RES. 2016 MAY 31.
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 OctDec;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):CD008712.
COCHRANE DATABASE SYST REV. 2015;(10:CD010646.
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 QOL
COCHRANE DATABASE SYST REV. 2015 OCT 21;(10):CD010554.
COCHRANE DATABASE SYST REV. 2005 OCT 19;(4):CD003728.
COCHRANE DATABASE SYST REV. 2013 OCT 4;(10):CD006868.
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
Animal-assisted therapy
 Promotes socialization, rehabilitation, mobility, and QOL
COCHRANE DATABASE SYST REV. 2011 DEC 7;(12):CD004025.
COCHRANE DATABASE SYST REV. 2014 MAY 19;(5):CD009413.
CLIN REHABIL. 2004 AUG;18(5):483-6.
AM J GERIATR PSYCHIATRY. 2001 FALL;9(4):439-42.
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 (1960s & 1970s) allowed for greater movement of patients from locked to open
wards
NUTR J. 2014 SEP 16;13:91. DOI: 10.1186/1475-2891-13-91.
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 & B12
High prevalence of smoking associated with decreased serum folate
Lower brain levels of B12 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
tHcy, 95%CI: 1.39-3.32)
 5 µmol/L increase in homocysteine associated with 70% greater risk (95%CI: 27-129)
 MTHFR 677T homozygous polymorphism associate with 36% greater risk vs CC genotype (95%CI: 772)
 Other SNPs also likely involved: MTR 2756A, FOLH1 484C, COMT 675A (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):E0146797.
FOLATE & B12
Supplementation of folate and B12 improved negative symptoms
 RCT, n=140, 16 wk trial
 Folic acid 2 mg + B12 400 mcg qd
 Significant benefit only found amongst those with FOLH1 484T 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 677T
allele
 RCT crossover design, n=55 with hyperhomocysteinemia, 6 months total
 Folic acid 2 mg, B12 400 mcg, and pyridoxine 25 mg qd
 Decreased total PANSS scores (p=0.019) and tHcy (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 N-methylglycine
(sarcosine) but many adverse effects
Inhibiting DAAO with sodium benzoate may increase GMS agonist availability
COCHRANE DATABASE SYST REV. 2006 APR 19;(2):CD003730.
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):123-30.
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, 1rst 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): e335.)
 RCT, n=99; 2 g E-EPA, 364mg 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: CD001257.
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/880mg 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 1.2g 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
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RCT, n=65, 14 wk trial, 109 L. rhamnosus GG + 109B. animalis lactis Bb12 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.13M01579.
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 (3-6g 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
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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 1970s 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)
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Ingredients: Paeonia alba, baked Glycyrrhiza uralensis
Traditionally used for muscle cramps, studied in PCOS for dopamine agonist effects
Case study of for resolving hyperprolactinemia and amenorrhea secondary to antipsychotic meds
Comparable to bromocriptine in crossover RCT
PSYCHOPHARMACOLOGY (BERL). 2015 JAN;232(1):155-64.
J CLIN PSYCHOPHARMACOL. 2013 FEB;33(1):122-3.
J CLIN PSYCHOPHARMACOL. 2008 JUN;28(3):264-370.
EVID BASED COMPLEMENT ALTERNAT 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 (380mg/kg qd) showed both
attenuated olanzapine-induced weight gain and adiposity
Berberine additionally prevented liver weight increase (vs metformin)
PLOS ONE. 2014; 9(3): E93310.
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:CD008919
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