Download Antidepressant Drug Effects and Depression

An Integrative
Approach for
Addressing
Depression
DR. SURUCHI CHANDRA
ACIM OCTOBER 2015
Mechanism of SSRI Action
Selective Serotonin Reuptake Inhibitor (SSRI) Use during Pregnancy and Effects on the Fetus and Newborn: A Meta-Analysis
Keri A Lattimore, Steven M Donn, Niko Kaciroti, Alex R Kemper, Charles R Neal Jr. and Delia M Vazquez
Antidepressant Drug Effects and
Depression Severity
A Patient-Level Meta-analysis
Conclusions: The magnitude of benefit of
antidepressant medication compared with
placebo increases with severity of depression
symptoms and may be minimal or nonexistent,
on average, in patients with mild or moderate
symptoms.
Flaws in Monoamine
Hypothesis
SSRIs increase serotonin levels within hours after
drug administration. However, it takes at least 2-4
weeks to see the beneficial effects of SSRI
medications.
Reducing levels of serotonin in the brain does not
cause depression. There is no consistent body of
literature to support the hypothesis that serotonin
deficiency causes depression.
A significant number of people either fail to respond
to SSRI or have only partial improvement with
SSRI medications.
SSRIs and Neurogenesis
This delay in treatment suggests that another process
may be involved in SSRI medications.
The scientists think SSRIs might promote
synaptogenesis and neurogenesis.
The selective serotonin reuptake inhibitor
antidepressant, sertraline, increases neuronal
differentiation and promotes neuronal maturation of
human hippocampal progenitor cells.
Side effects of SSRI
medications
Concerns on long lasting effects on brain development and
behavior.
‘Switching’ to manic episode
Serotonin syndrome
Sedation
Agitation
Increased anxiety
Gastrointestinal disturbances
Discontinuation syndrome
Revolution in thinking in brain
science
The idea of the brain as ‘plastic’
and changing replaces an
earlier notion of the brain as a
fixed machine.
Offers hope for a number of
psychological neurological
conditions in place of a
‘neurological nihilism.’
Depression as a Subtle
Neurodegenerative Event
Curr Med Chem. 2011;18(2):245-55.
Inflammatory and neurodegenerative pathways
in depression: a new avenue for
antidepressant development?
Ageing research reviews, 2005
The stress system in the human brain in
depression and neurodegeneration
Oxidative Medicine and Cellular Longevity. Volume 2013
Accelerated Aging in Major Depression: The
Role of Nitro-Oxidative Stress
How Is Depression Related to
Dementia?
Depression is a risk factor for dementia,
researchers report, and people with
more symptoms of depression tend to suffer a
more rapid decline in thinking and memory
skills.
The investigators found that high levels of
depression prior to a diagnosis of dementia are
linked to a more drastic decrease in thinking
and memory skills later on.
Incidence and Prevelance
of Depression
The incidence of depression has
risen every year since the early 20th
century
In the United States, one in six
people experience a depressive
episode during their lifetime.
Cost of Depression
Neurogenesis, Hippocampus,
and Depression
Mateus-Pinheiro et al. Clinical Epigenetics 2011 3:5 doi:10.1186/1868-7083-3-5
Pathways leading to
hippocampal growth or
atrophy.
Tryptophan and IDO
Serotonin
5HTP
Tryptophan
Proinflammatory
IDO
Cytokines
Kynurenine
Quinolinate
Kynurenate
Depression as a Whole Body
Phenomenon
Emerging View of
Depression
•Cellular event rather than
neurotransmitter depletion
•Whole body rather then focused on just
the brain
•Multiple pathways and systems usually
involved
Causes of Physiological
Stress
Emotional abuse and
neglect
Excess heat
Chemical toxins
Loud noises
Heavy metals
Nutritional deficiencies
Infections
Pain response
High electromagnetic
fields
Excess cold
Physical trauma
Systems/Pathways
Implicated in Depression
Monoamine neurotransmitters
NMDA/Glutamate
Neuroendocrine/Stress response e
Immune/Inflammatory
Mitochondrial dysfunction
Gastrointestinal imbalances
The Other Brain
The GI system contains about 100
million neurons, more than either the
spinal cord or the peripheral nervous
system
95% of the bodies serotonin is in the gut
SSRI medications can cause nausea, diarrhea,
and constipation. But, low doses of SSRIs can
be used to treat nausea, diarrhea, and
constipation.
Gut Brain Axis
A bidirectional communication system between the
brain and gastrointestinal systems.
Communication occurs along immunologic, neural,
and biochemical pathways.
Gut microbiota can effect both brain development
and behavior.
Stress also can alter the composition of gut
microbiota.
Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal
gastrointestinal function and disease. Gastroenterology. 2009 May;136(6):2003-14. Epub 2009 May 7. Review.
Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal
gastrointestinal function and disease. Gastroenterology. 2009 May;136(6):2003-14. Epub 2009 May 7.
Pathways
involved in
bidirectional
communication
between the gut
microbiota and
the brain.
John F. Cryan & Timothy G. Dinan
Nature Reviews
Neuroscience 13, 701-712 (October
2012)
Bipolar Disord. 2010 Dec;12(8):834-42.
Immune activation by casein dietary
antigens in bipolar disorder.
Anti-casein IgG associations with bipolar I diagnoses,
psychotic symptom history, and mania severity scores
suggest that casein-related immune activation may relate to
the psychosis and mania components of this mood disorder.
Case-control differences in epitope recognition implicate
disease-related alterations in how the casein molecule is
digested and/or how resulting casein-derived structures are
rendered immunogenic.
.
Examining the role of
neuroinflammation in
major depression.
P
Recent findings have established a connection
between inflammation and
major depression and specifically the role of
the hypothalamic-pituitary-adrenal (HPA) axis
in depression. This article reviews clinical and
experimental studies examining the role of the
HPA axis, HPA hyperactivity (resulting in
increased cortisol levels), as well as the
proinflammatory cytokines tumor necrosis
factor, C-reactive protein, and the interleukins,
in depressed patients.
Psychiatry Res. 2015 Sep 30;229(1-2):27-36.
Examining the role of neuroinflammation in major depression.
Late stage neuropsychiatric symptoms of
Lyme disease
Depression
Mood Swings
Psychosis
Violent
behaviors/irritability
• OCD
• Anxiety/Panic Attacks
• Sleep disorders
•
•
•
•
Seizures
ADHD-like symptoms
Autism-like behavior
Chronic Fatigue
Syndrome
• Fibromyalgia
•
•
•
•
Misconceptions About Lyme Disease
◦ All patients recall a tick bite or bulls eye rash.
◦ Lyme disease is only a concern in Northeastern
states.
◦ ELISA is a sensitive screening test
◦ Only one infectious pathogen is transmitted by
the tick bite.
◦ A short course of antibiotics resolves all cases of
Lyme disease.
In Vitro Effectiveness of Samento and Banderol
Herbal Extracts on the Different Morphological
Forms of Borrelia Burgdorferi
mento (1:300 dilution)
Control
Banderol (1:300 dilu
Mitochondria
PLoS One. 2015 May 6;10(5
Mitochondria DNA change and oxidative
damage in clinically stable patients with
major depressive disorder.
Our study suggests that oxidative stress
and mitochondria may play a role in the
pathophysiology of MDD. More large-scale studies are
warranted to assess the interplay between oxidative
stress, mitochondria dysfunction and MDD.
Mitochondria and Toxins
Mitochondria are like canaries in a coalmine:
susceptible to early early-stage effects that
predict cell and organ toxicity later.
Mitochondrial DNA is uniquely susceptible to the
damaging effects of ROS.
Mitochondrial DNA generally has less capacity
to repair itself, relying on just one enzyme for
both replication and repair of DNA
Schmidt CW, 2010 Mito-Conundrum: Unraveling Environmental Effects on
Mitochondria. Environ Health Perspect 118(7).
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Tests for Mitochondrial
Dysfunction
Ammonia
Alanine/Lysine ratio (Plasma Amino Acids)
Lactate
Pyruvate
Acylcarnitine levels
Free and total carnitine levels
Creatine kinase
Urine organic acid screening
COPYRIGHT SURUCHI CHANDRA, 2012
Mitochondrial Cocktail
Co-factor for pyruvate carboxylase
◦ Biotin
Precursors for electron acceptors(NAD and NADP)
◦ Niacin (B3) or nicotinamide
Antioxidant support for reactive oxygen species
◦ Coenzyme Q10, lipoic acid, vitamin C and vitamin E
Complex I
◦ Carnitine, thiamine (B1), pantothenic acid (B5), and riboflavin (B2)
Complex IV
◦ Copper (only if low)
Glutathione reductase support
◦ Selenium
“Treatment of Mitochondrial Disease With Vitamin Co-Factors” by Richard I. Kelley, MD
COPYRIGHT SURUCHI CHANDRA, 2012
Holistic Model for Treatment of
Mitochondrial Dysfunction
Avoid toxins that may interfere with function
Avoid medicines that interfere with mitochondrial
function
Use herbs that protect and support mitochondria
Individualized mitochondrial cocktail
High ORAC/antioxidant foods
Reduce excess consumption of omega 6 oils
Treat any chronic bacterial issues and infections
COPYRIGHT SURUCHI CHANDRA, 2012
Adaptogens
Are plant derivatives, not simple compounds such minerals or
vitamins.
Many have been used in traditional medical systems for centuries
to deal with anxiety, fatigue, or trauma.
Are believed to normalize bodily responses to stress and to help
maintain homeostasis by acting in a non-specific manner
May modulate the immune, antioxidant, hormonal, and nervous
systems.
Plant Adaptogens
Summa (Pfaffia paniculata)
Golden Artic Root (Rhoiola rosea)
Astragalus (Astragalus membranaceus)
Tulsi or Holy Basil (Ocimum sanctum)
Schisandra (Schisandra chinensis)
Aswhaganda (Withania somnifera)
Licorice (Glycyrrhiza glabra and G. uralensis )
Plant Adaptogens
Asian ginseng (Panax ginseng)
American ginseng (Panax quinquefolius)
Siberian ginseng (Eleutherococcus senticosus)
Georgian Snow Rose (Rhododendron Caucasicum)
Maca (Lepidium meyenii)
Rhodiola rosea
In depressive rats, Rhodiola rosea improved
serotonin levels in the hippocampus and induced neural stem cell
proliferation. (Chen, 2009)
Rhodiola rosea
Rhodiola rosea activates the synthesis or resynthesis of ATP in
the mitochondria in rats. (Abidov, 2003)
Rhodiola enhances superoxide levels and protects against the
toxic effects of paraquat (herbicide) in Drosophila (Schriner,
2009)
Rhodiola rosea extract protects human cortical neurons against
glutamate and hydrogen peroxide-induced cell death through
reduction in the accumulation of intracellular calcium. (Palumbo,
2012)
COPYRIGHT SURUCHI CHANDRA, 2012
Anxiolytic-antidepressant activity
of Withania somnifera
glycowithanolides: an experimental
study
Phytomedicine. 2000 Dec;7(6):463-9.
WSG also exhibited an antidepressant
effect, comparable with that induced by
imipramine, in the forced swim-induced
'behavioural despair' and 'learned
helplessness' tests. The investigations
support the use of WS as a mood
stabilizer in clinical conditions of anxiety
and depression in Ayurveda.
Standardized extracts of Bacopa monniera
protect against MPP+ and paraquat-induced
toxicity
by modulating mitochondrial activities, proteasomal
functions, and redox pathways. (Singh M, 2012)
Pretreatment with Bacopa monnieri extract offsets 3nitropropionic acid induced mitochondrial oxidative
stress and dysfunction in the striatum of prepubertal
mouse brain. (Shinomol GK, 2012)
Protective effect of Bacopa monniera on methyl
mercury induced oxidative stress in cerebellum of rats.
(Sumathi T, 2012)
COPYRIGHT SURUCHI CHANDRA, 2012
Minerals and
Depression
Should We All Take a Bit of
Lithium?
Opinion SEPT. 13, 2014
“Evidence is slowly accumulating that relatively tiny
doses of lithium can have beneficial effects. They
appear to decrease suicide rates significantly and
may even promote brain health and improve mood.”
“Some scientists have, in fact, proposed that lithium
be recognized as an essential trace element
nutrient. Who knows what the impact on our society
would be if micro-dose lithium were again part of
our standard nutritional fare? “
J Affect Disord. 2015 Oct 3;189:282-286.
Trace lithium is inversely associated
with male suicide after adjustment of
climatic factors.
Biol Trace Elem Res. 2015 Apr;164(2):165-8. Jan 6.
A negative association
between lithium in drinking water and
the incidences of homicides, in
Greece
Front Neurosci. 2015 Jan 14;8:457
Lithium-induced neuroprotection is
associated with epigenetic modification of
specific BDNF gene promoter and altered
expression of apoptotic-regulatory proteins
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2011 Jun;36(6):461-76. doi:
10.3969/j.issn.1672-7347.2011.06.001.
Neuroprotective action of lithium in
disorders of the central nervous system.
Lithium forms and Dosing
Lithium carbonate
Lithium orotate
Ionic lithium liquid
Organic vegetable bound lithium
J Neural Transm. 2008 Dec;115(12):1621-8. doi: 10.1007/s00702-008-0115-7. Epub 2008 Sep 3.
Antidepressant-like activity of zinc:
further behavioral and molecular
evidence.
Chronic treatment with zinc induced a 17-39%
increase in the BDNF mRNA and protein level in the
hippocampus. These data indicate a rapidly acting
antidepressant-like activity of zinc in CMS and the
involvement of zinc in the regulation of BDNF.
Magnesium and
Depression
Antidepressant-like activity
of magnesium in the olfactory bulbectomy
model is associated with the
AMPA/BDNFpathway
Dietary magnesium deficiency alters gut
microbiota and leads to depressive-like
behaviour.
Magnesium threonate/brain
Pain Physician. 2013 Sep-Oct;16(5):E563-75.
Magnesium L-threonate prevents and restores memory
deficits associated with neuropathic pain by inhibition of
TNF-α.
Mol Brain. 2014 Sep 13;7:65. doi: 10.1186/s13041-014-0065-y.
Elevation of brain magnesium prevents synaptic loss and
reverses cognitive deficits in Alzheimer's disease mouse
model.
Why Do We Need Mineral
Supplementations?
Many patients do not have ideal diets
Decreasing mineral content of in soil
Some minerals are wasted in under
periods of stress
Minerals imbalances may occur in
setting of chronic infections, such as
Lyme disease
Rising CO2 poses significant
threat to human nutrition
At the elevated levels of atmospheric CO2
anticipated by around 2050, crops that provide a
large share of the global population with most of
their dietary zinc and iron will have significantly
reduced concentrations of those nutrients,
according to a new study led by Harvard School of
Public Health (HSPH).
Loss of Minerals Under
Stress
Anxiety and stress among science students.
Study of calcium and magnesium
alterations
Magnes Res. 2006 Jun;19(2):102-6
It is known that anxiety is related to partial
magnesium reduction associated with a
urinary magnesium excretion increase, as
observed in the present data.
Zinc/Copper Imbalances and Chronic
Infections
Zinc levels are lower and copper levels are
increased in pulmonary tuberculosis and other
chronic infections.
Zinc and copper levels normalize after antitubercular therapy.
Zinc and copper given together was found to be
more effective in treating Trypanosoma infection
than either zinc or copper alone.
Diet, Stress, and the Brain
SUPPORT
STRESS
Increase reliance
Cause stress to the system
Support detoxification
Introduce toxins
Provide essential nutrients and
building blocks
Lead to nutrient depletion and
deficiency
Provide anti-inflammatory and
immune support
Contribute to inflammation and
immune deficiency
Phytochemicals, the Brain,
and Stress
Phytochemical constituents
as future antidepressants: a
comprehensive review.
Plant metabolites from different categories
including polyphenols (flavonoids, phenolic
acids, lignanes, coumarins), alkaloids,
terpenes and terpenoids, saponins and
sapogenins, amines, and carbohydrates
were found to possess antidepressant
activity.
Phytochemical constituents
as future antidepressants: a
comprehensive review.
Naringenin has represented its antidepressant
effect by elevation of serotonin (5-HT),
norepinephrine, brain-derived neurotrophic
factor (BDNF), and glucocorticoid receptors.
Piperine demonstrated inhibition of
monoamine oxidase enzymes, elevation
of brain 5-HT and BDNF levels, and
modulation of the hypothalamus-pituitaryadrenal axis.
Cruciferous Vegetables and
the Brain
Nrf2 participates
in depressive disorders through an
anti-inflammatory mechanism.
Psychoneuroendocrinology. 2013 Oct;38(10):2010-22. doi:
10.1016/j.psyneuen.2013.03.020. Epub 2013 Apr 23.
Furthermore, treatment of Nrf2 knockout mice with the antiinflammatory drug rofecoxib reversed their depressive-like
behavior, while induction of Nrf2 by sulforaphane, in an
inflammatory model of depressionelicited by LPS, afforded
antidepressant-like effects. In conclusion, our results indicate that
chronic inflammation due to a deletion of Nrf2 can lead to
a depressive-like phenotype while induction of Nrf2 could become
a new and interesting target to develop novel antidepressive
drugs
Beige Food Diet
J Am Coll Nutr. 2015;34 Suppl 1:48-55. doi: 10.1080/07315724.2015.1080527.
Mitigation of Inflammation-Induced Mood
Dysregulation by Long-Chain Omega-3
Fatty Acids
Major mood disorders are associated with both
LCn-3 fatty acids deficiency and elevated immuneinflammatory signaling. • Prospective evidence
suggests that low LCn-3 fatty acid biostatus
increases risk for developing inflammation-induced
mood dysregulation. • Taken collectively, this
evidence suggests that increasing LCn-3 fatty acid
intake and biostatus represents a promising
strategy to mitigate the detrimental effects of
elevated immune-inflammatory signaling on mood.
Balancing Omega 6/Omega 3 fats: Reduce consumption of processed and
foods and polyunsaturated vegetable oils (corn, sunflower, safflower, soy,
and cottonseed.)
COPYRIGHT SURUCHI CHANDRA, 2012
Brain Research Bulletin
Volume 31, Issue 6, 1993, Pages 697-700
Phosphatidylserine increases
hippocampal synaptic efficacy
J Neuroimmunol. 2004 Jun;151(1-2):12-23.
Evidence of a protective effect
of phosphatidylserine-containing
liposomes on lipopolysaccharideinduced impairment of long-term
potentiation in the rat hippocampus
Cholesterol and Mood:
What’s the Link?
The relationship between serum cholesterol and mood is
complex and research findings to date are inconsistent.
Research findings going back to the early 90s show that serum
cholesterol - especially the HDL fraction - is significantly lower in
many patients with major depressive disorder than in nondepressed individuals, and that clinical improvement following
antidepressant therapy is often associated with a significant
increase in serum total cholesterol. A review of 6 randomized
trials dating from the 1980s through the early 1990s found that
while lowering abnormally high serum cholesterol levels (below
150 mg/dL) decreased the number of deaths from coronary
heart disease, cholesterol lowering was actually associated with
increased mortality due to suicide or violence.
Food, toxins, and
depression
Vet Q. 2014;34(3):120-31. doi: 10.1080/01652176.2014.980934.
In vitro dopaminergic neurotoxicity
of pesticides: a link
with neurodegeneration?
Environ Sci Pollut Res Int. 2015 Jul 1
Urinary heavy metals, phthalates and
polyaromatic hydrocarbons independent of
health events are associated with
adult depression: USA NHANES, 2011-2012.
Physical Exercise Habits Correlate with
Gray Matter Volume of the Hippocampus
in Healthy Adult Humans
Scientific Reports 3, Article number: 3457 (2013)
Underlying Causes
Ideally Want to Address and Remove:
Hormonal imbalances
Microbiome disturbances
Nutritional imbalances
Infections
Toxicity (metals, chemical toxins, and EMFs)
Emotional stress
Genetic SNPs
It’s Not All in Your Head:
Treat the Whole Body
Assess and address:
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◦
◦
◦
◦
◦
◦
Mitochondrial dysfunction
Possible infections and dysbiosis
Hormonal imbalances
Gastrointestinal disturbances
Oxidative stress
Detoxification and limit exposure to environmental toxins
Fatty acid and cholesterol imbalances
◦ Omega 6/omega 3 ratio
◦ Low cholesterol