Obsessive-compulsive Disorder (OCD) Naturopathic Protocol

Obsessive-compulsive Disorder (OCD) Naturopathic Protocol

    This Obsessive-compulsive Disorder (OCD) Naturopathic Protocol is provided as information for patients of HealthMasters Naturopath Kevin Tresize ND as part of a treatment plan to assist patients with understanding of their treatment plan. It is important to note that this is a summary only and is intended to assist discussion between practitioner and patient as part of consultations and should not be substituted for medical advise, diagnosis or treatment. This Obsessive-compulsive Disorder (OCD) Naturopathic Protocol may be changed to suit the individual requirements of the patient and should not be substituted for medical advice, diagnosis or treatment.

    HealthMasters Naturopath Kevin Tresize ND

     

    Overview:

    1.0 Pathophysiology
    2.0 Consultation Overview
    3.0 Key Drivers
    4.0 Treatment Priorities
    5.0 Red Flags
    6.0 Treatment Recommendations
    7.0 Supportive Programs
    8.0 Diet and Lifestyle Recommendations
    9.0 Clinical Investigation and Pathology
    10.0 Pharmaceutical Treatments
    11.0 Additional Resources
    12.0 References

     

    1.0 Pathophysiology:

    • Obsessive-compulsive disorder (OCD) is characterised by obsessions such as recurrent and persistent thoughts, images or impulses experienced that are intrusive, unwanted and anxiety-provoking. In many cases, the obsessions give rise to compulsions (repetitive behaviours or mental acts that are effected in accordance with rigid, self-imposed rules), which are repetitively/routinely performed to relieve the anxiety or distress.[i],[ii]
    • OCD patients also experience deterioration of cognitive functions, such as attention, memory, decision-making ability, and inhibitory control.[iii]
    • Altered functional connectivity between the cerebellum and cortico-striato-thalamo-cortical (CSTC) circuits are prominent in OCD, in addition to abnormalities in structure, function and bloodflow. The CSTC pathway is a multi-synaptic neuronal circuit that connects the cortex, striatum and thalamus.
    • Hyperactivity of this pathway can lead to hyperactivation of the orbitofrontal cortex (OFC), triggering excessive concern/sustained attention to perceived threats in OCD patients and subsequent development of compulsive behaviour aimed at eliminating obsessions.[iv]
    • In addition to motor regulation, the cerebellum plays a key role in cognition and emotion. Separate cerebellar regions are connected with different cerebral areas, forming multiple cognitive circuits that are involved in attention, language, working memory, visuospatial processing, and decision-making; reported to be deficient in OCD patients.[v]
    • Hyperactivity of the striatum, involved in habit formation and goal-directed action, and the thalamus, which relays sensory signals that activate the frontal cortex, have also been reported.[vi]
    • Meta-analyses have noted alterations in grey matter volumes within CTSC loops in OCD patients, including increased grey matter volume in the dorsal striatum and thalamus, and decreased grey matter volume in the anterior cingulate cortex (ACC).[vii]
    • Alterations in dopamine, glutamate and gamma-aminobutyric acid (GABA) neurotransmitter systems (seen in Figure 1), as well as serotonin neurotransmission are associated with ritualistic instinctual behaviours, with dysfunction of these pathways contributing to OCD.[viii]

     

    Figure 1 The CSTC circuitry implicated in OCD - HealthMasters

    Figure 1: The CSTC circuitry implicated in OCD.[ix]

    Key: GPe: globus pallidus pars externa; STN: subthalamic nucleus; GPi: globus pallidus; SNc: substantia nigra, pars compacta; SNr: substantia nigra, pars reticulata.

     

    2.0 Consultation Overview:

    2.1 Identify Risk Factors

    In Clinic Investigations- Refer to Key Drivers and the Clinical Investigation and Pathology sections below for further guidelines:

    • If the patient is considered a suicide risk, seek immediate guidance from a Crisis Assessment and Treatment Team (CATT) or call triple zero (000) in an emergency.
    • Have patient complete the Depression Anxiety Stress Scales (DASS) and the Mood and Stress Questionnaire (MSQ).
    • Investigate comorbid anxiety, depression or other psychiatric disorders.
    • Evaluate thyroid function via signs and symptoms to determine if hyperthyroidism is a contributing factor to OCD symptoms. Have patient complete the Basal Body Temperature Tracker.
    • Assess patient’s history of heavy metal/toxin exposure.

    Pathology Investigations- Refer to Key Drivers and the Clinical Investigation and Pathology sections below for guidelines:

    • Consider using cortisol awakening response (CAR) test or adrenocortex stress profile to examine hypothalamic-pituitary-adrenal (HPA) axis function.
    • Investigate inflammatory markers where indicated, including erythrocyte sedimentation rate (ESR) and high sensitivity C-reactive protein (hs-CRP).
    • If presenting with signs of thyroid dysfunction, refer patient for thyroid studies.

     

    2.2 Identify Signs of OCD

    Common presentations associated with OCD include:

    • Thoughts of contamination, giving rise to repeated and ritualised hand washing, showering or grooming[x]
    • Thoughts of having forgotten something, causing time-consuming repeated checking[xi]
    • Aggressive fears of harming self or others[xii]
    • Hoarding or saving rituals[xiii]
    • Religious obsessions, with concerns about sacrilege, blasphemy and/or morality[xiv]
    • Need for symmetry/exactness[xv]
    • Somatic obsessions focussed on appearance/body image or concern for illness[xvi]
    • Checking obsessions, including checking locks, stove, appliances etc.[xvii]
    • Counting rituals[xviii]
    • Ordering/arranging rituals[xix]
    • Repeating rituals including re-reading, re-writing or routine activities such as entering through a door in a specific way[xx]

     

    3.0 Key Drivers:

    • Chronic or severe stress: A causal association exists between stressful life events and the onset of OCD symptoms, with patients reporting significant stressful life events six to 12 months before disease onset, as well as over their lifetime. Stress-induced structural and functional changes in corticostriatal and limbic circuits stimulate neuronal atrophy and synaptic loss in the prefrontal cortex (PFC), hippocampus, dorsomedial striatum and ventral striatum, impairing neurogenesis.[xxi] Prolonged stress is also associated with neuronal hypertrophy and synaptic potentiation in the amygdalaand dorsolateral striatum. Stress-induced changes in brain structure leads to grey matter loss throughout corticostriatal-limbic circuitry, inducing or exacerbating OCD symptoms.[xxii]
    • Glutamate/GABA imbalance: Converging evidence from genetic, neuroanatomical, pharmacological, and preclinical studies in both humans and animal models support that glutamate/GABA dysregulations contribute to OCD pathophysiology.[xxiii] Cortico-striato-thalamo-cortical (CSTC) loops use both excitatory glutamate and inhibitory GABA to modulate their function. Glutamatergic signals originate from the orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC), which are then modulated by inhibitory GABAergic signalling. However, pathological hyperactivity of the OFC and ACC increase glutamate release in OCD, disturbing glutamate/GABA homeostasis and increasing CSTC circuitry activation.[xxiv] Additionally, excess glutamate is associated with excitotoxicity and neuronal death,[xxv] contributing to grey matter loss.
    • Reduced brain-derived neurotrophic factor (BDNF): A large volume of data has shown that low levels of BDNF correlate with OCD.[xxvi] A key promoter of neuroplasticity, BDNF encourages neurogenesis, neuritegrowth, maturation and survival, as well as regulation of synaptic function. Reduced neuroplasticity and BDNF expression are associated with OCD pathogenesis, likely contributing to the structural changes observed in OCD patients.[xxvii]
    • Inflammation: Studies have associated OCD aetiology with increased production of inflammatory markers. Cortisol and noradrenalin released via stress-induced HPA axis activation stimulate immune cells, such as white blood cells, to trigger inflammation.[xxviii] Immune cells possess both catecholamine and glucocorticoid receptors on their cell surface, which activate innate immunity via release of proinflammatory cytokines,[xxix] including hs-CRP, interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α).[xxx],[xxxi] Cytokines travel through the circulation to the blood-brain barrier and activate a microglial stress response, resulting in neuroinflammation and persistent synaptic changes.[xxxii]
    • Gonadal hormone imbalance: Testosterone also functions as a neurosteroid, with dysfunctional levels implicated in the development of psychiatric disorders.[xxxiii] Decreased production of testosterone from the testicles, due to suppression of the hypothalamic-pituitary-gonadal axis (HPG) by HPA axis hyperactivity, has been observed in males with OCD.[xxxiv]
    • Thyroid dysfunction: Thyroid hormone receptors are present throughout the brain, with studies demonstrating an association between thyroid dysfunction and anxiety-type symptoms. Thyroid hormones influence psychiatric disorders via interfering with the serotonin systems to increase serotonergic transmission, reduce serotonin receptor sensitivity and alter serotonin metabolism during states of hyperthyroidism.[xxxv]
    • Heavy metal exposure: Toxic metal exposure can result in a wide array of common mental health disorders; particularly lead and cadmium exposure, which can damage the brain and increase the risk of psychiatric illness. In the brain, lead and cadmium cause lesions that decrease total cortical volume, white matter and grey matter, and stimulate cerebroventricular enlargement.[xxxvi] Lead adversely affects numerous cell functions, including the release of neurotransmitters such as dopamine and serotonin via mimicking or inhibiting calcium-mediated processes.[xxxvii] Lead exposure also affects HPA axis activity and can lead to permanent HPA axis dysfunction that alters glucocorticoid and catecholamine levels, contributing to the development of neuropsychiatric disorders.[xxxviii]
    • Traumatic brain injury (TBI): Neuropsychiatric disorders are also a common consequence of TBI, with OCD symptomology reported to emerge during the post-acute injury phase (one week to two months post-TBI), as well as up to two years post-injury. Cognitive impairments, such as deficits in memory, executive function, attention, and processing speed, are commonly observed in patients with post-TBI OCD, which are thought to result from brain injury lesions (damage to frontal, temporal, and cingulate regions, and the basal ganglia) or psychological distress from TBI-related disturbances.[xxxix]
    • Birth hypoxia: OCD is associated with premorbid neurological conditions including birth hypoxia. Alterations in airflow and blood perfusion reduces oxygen supply to the brain, leading to neuroinflammation. Additionally, hypoxia stimulates anaerobic glycolysis in neural tissue, causing aberrant oxidative phosphorylation and oxidative stress in areas of the brain. These functions reduce neuronal plasticity, alter neuronal function and cause cell injury and death.[xl]

     

    4.0 Treatment Priorities:

    • If the patient is considered a suicide risk, seek immediate guidance from a Crisis Assessment and Treatment Team or call triple zero (000) in an emergency.
    • Address and/or manage OCD triggers including acute/chronic stressors, gonadal hormone imbalance, thyroid dysfunction, and/or heavy metal exposure.
    • Regulate HPA axis activity, reducing excessive production of glucocorticoids and subsequent stimulation of glutamate release via N-methyl-D-aspartate (NMDA) receptor signalling.
    • Minimise neuroinflammation to reduce activation of the microglial stress response and alterations in neuroplasticity.
    • Enhance neuroplasticity by increasing production of BDNF, to encourage neurogenesis, neurite growth, maturation and survival, and regulation of synaptic function.
    • Determine if onset is sudden, acute and highly unusual, following infectious symptoms (e.g. fever, sore throat, cold and flu symptoms) to evaluate risk of infectious driver.
    • Monitor OCD prevalence via signs and symptoms, in addition to the DASS and MSQ questionnaires.
    • Monitor patient’s adherence to dietary, lifestyle and supplementary recommendations using Your Guide to Stress Less patient booklet.
    • Monitor patient wellbeing at regular intervals and strongly advise patient to receive additional care/support from a mental health professional, including a Psychologist and/or General Practitioner (who may refer to a Psychiatrist). Maintain communication with Practitioner regarding treatment and patient progress.

     

    5.0 Red Flags:

    • Obsessive-compulsive personality disorder (OCPD): A maladaptive personality style defined by excessive rigidity, interpersonal control, preoccupation with details, and excessive perfectionism in all aspects of life.[xli] Unlike OCD compulsions, which are ego-dystonic (patient realises that the obsessions are unreasonable), OCPD is ego-syntonic and based on dysfunctional beliefs established in early adolescence.[xlii] Straying away from these rigid beliefs can cause inner cognitive dissonance, leading them to push their beliefs onto others (inflexible cognition), creating difficulties in social interactions. Inadequacies are only recognised in others and the external environment.[xliii] If patient is suspected of having OCPD, refer to a General Practitioner or Psychologist for assessment.
    • Additional psychiatric disorders: Psychiatric conditions also characterised by obsessive or intrusive thoughts are common comorbidities with OCD including anxiety, depression, Tourette syndrome, body dysmorphic disorder, eating disorders, hypochondriasis, phobias, post-traumatic stress disorder, and attention-deficit hyperactivity disorder.[xliv] Use the DASS questionnaire and the MSQ to assess patient’s mental wellbeing and refer to a General Practitioner or Psychologist where indicated. If patient is deemed at risk of self-harm or harm to others, seek immediate guidance from a Crisis Assessment and Treatment Team or call triple zero (000) in an emergency.
    • Impulse control disorders (ICD): Both OCD and ICD patients experience difficulty in resisting the urge to engage in behaviours that interfere with functioning. However, ICDs are more specifically associated with a failure to resist an impulse, drive, or temptation that is harmful to the person or to others.[xlv] Examples include trichotillomania (hair-pulling disorder), excoriation (skin-picking) disorder, pathologic gambling disorder, compulsive shopping, kleptomania, and paraphilias/sexual compulsions.[xlvi] If ICD is suspected, refer patient to a General Practitioner or Psychologist for assessment.
    • Delusions or psychosis: These may be mistaken for obsessive thoughts, however unlike OCD, delusional or psychotic individuals do not believe their obsessions are unreal and may likely meet criteria for another psychotic spectrum disorder that accounts for the obsessions (e.g. schizophrenia).[xlvii] If delusions or psychosis are suspected, refer patient to a General Practitioner or Psychologist for assessment. If patient is deemed at risk of self-harm or harm to others, seek immediate guidance from a Crisis Assessment and Treatment Team  or call triple zero (000) in an emergency.
    • Paediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS): In patients aged between three years and puberty, abrupt and dramatic onset of OCD can occur following Group A Streptococcal infection. Additional presentations include symptoms that mimic Tourette syndrome, resulting in involuntary movements, and additional comorbidities, including urinary frequency, development regression and insomnia.[xlviii] Screen patients for infectious markers, including the Cunningham Panel, mycoplasma pneumonia serology, throat swab and viral and bacterial antibody screening, and refer to General Practitioner for further investigation.
    • Paediatric acute-onset neuropsychiatric syndrome (PANS): Research indicates that various non-streptococcus infections, including viral gut infections[xlix] and post infectious encephalitis,[l] may trigger OCD. Patients may also develop tic disorders including Tourette syndrome, resulting in involuntary movements and OCD-like behaviours (i.e. compulsive handwashing, symmetry issues etc.).[li] Screen patients of infectious markers, including the Cunningham Panel, mycoplasma pneumonia serology, throat swab and viral and bacterial antibody screening, and refer to General Practitioner for further investigation.

     

    6.0 Treatment Recommendations:

    6.1 Core Recommendations

     

    6.1.1 Herbal Support for Hyper HPA and Stress

    Dosage: Take 1-2 tablets three times daily.

    Anxiolytic herbs that enhance GABA activity, working against glutamate-mediated excitability in the brain and hyperactive CSTC loop function that contribute to OCD.

    Mechanism of Action/Clinical Research:

    • Zizyphus has been shown to modify the GABAα receptor subunits expressional levels,[lii] which opposes glutamate-mediated excitability in the brain, contributing to its anxiolytic effects.[liii]
    • Passionflower has been found to modulate the GABA system, demonstrating an affinity for both GABAα and GABAβ receptors, increasing its inhibitory effects.[liv]

    A clinical trial involving 154 participants with prolonged nervous tension were treated with 1,020 mg/d of passionflower for 12 weeks. Passionflower significantly improved stress-associated symptoms including restlessness, sleep disturbances, exhaustion, anxiety, poor concentration, nausea, tremors, and palpitations.[lv]

    • Kudzu has demonstrated β-adrenoceptor blocking activity[lvi],[lvii] similar to pharmacological beta-blockers, which are used to reduce the physical effects of anxiety and stress such as palpitations, high blood pressure, tremor and sweating.
    • Magnolia exhibits muscle relaxing effects via GABAergic mechanisms,[lviii] as well as neuroprotective properties.[lix],[lx]

     

    6.1.2 Meta Mag® Magnesium, Taurine & Glutamine for Stress

    Dosage: Add 2 level scoops (11.9 g) to 200 mL of water, twice daily.

    Magnesium, taurine and glutamine to support a healthy stress response by decreasing excessive neuronal activity in CSTC circuits and reducing catecholamine levels; minimising the effects of physical and psychological stress on the body.

    Mechanism of Action/Clinical Research:

    • Magnesium improves resistance to neuropsychological stressors, such as glutamate excitotoxicity, through its actions as a voltage-gated antagonist at the glutamate, NMDA receptor site.[lxi] The reduction of glutamate activity has been shown to increase the actions of the GABA.[lxii]

    In a randomised trial of subjects with hypomagnesaemia, supplementation with 450 mg/d of elemental magnesium for 12 weeks was shown to be as effective as a tricyclic antidepressant (TCA) in the treatment of low mood.[lxiii]

    • Taurine acts as an inhibitory neurotransmitter or neuromodulator, interacting with NMDA receptors to suppress glutamatergic transmission and protect against glutamate excitotoxicity.[lxiv]
    • Zinc acts as an inhibitory neuromodulator of glutamate release, regulating NMDA receptors.[lxv]
    • L-Glutamine is involved in neurotransmitter synthesis and is the precursor for glutamate and GABA.[lxvi]
    • Vitamin C is required for the synthesis of neurotransmitters, including noradrenaline and serotonin.[lxvii]
    • Vitamin B6 is fundamental to the production of many neurotransmitters[lxviii] and is specifically involved in the creation of histidine to histamine, tryptophan to serotonin, glutamate to GABA, and dihydroxyphenylalanine to dopamine,[lxix] as well as the synthesis of adrenaline and noradrenaline.[lxx]

     

    6.2 Additional Considerations

     

    6.2.1 If patient presents with low mood/depression:

    BCM-95™ Turmeric & Saffron for Depression

    Dosage: Take 1 capsule twice daily with food.

    An anti-inflammatory herbal blend to reduce HPA axis activity, preventing stress-induced elevation of cortisol and glutamate excitotoxicity, while also supporting BDNF production for enhanced neurogenesis in OCD patients.

    Mechanism of Action/Clinical Research:

    • Both saffron and turmeric have been found to inhibit the activity of proinflammatory transcription factors, such as nuclear factor kappa beta (NFκB) and mitogen activated protein kinase (MAPK).[lxxi],[lxxii] Saffron and turmeric also inhibit inflammatory cytokines including TNF-α, IL-1β and IL-6, all of which can affect neurotransmitter metabolism.

    A randomised, double-blind, placebo controlled study involving 123 participants that were prescribed 500 mg/d of BCM-95™ Turmeric combined with 30 mg/d of saffron revealed significant reductions in depression and anxiety symptoms after 12 weeks.[lxxiii]

    • Safranal and crocin, present in saffron, have been shown to reduce HPA axis activity and decrease stress-induced plasma corticosterone levels.[lxxiv] Safranal has also been shown to exert anxiolytic and sedative effects via activation of the GABAergic pathway.[lxxv]
    • Turmeric activates glutamate decarboxylase (GAD), which converts glutamate to GABA.[lxxvi]

    A randomised, double-blind, placebo controlled study involving 123 participants that were prescribed 500 mg/d of BCM-95™ Turmeric combined with 30 mg/d of saffron revealed significant reductions in anxiety and depressive symptoms after 12 weeks.[lxxvii]

     

    6.2.2 If patient presents with persistent stress and anxiety:

    Herbal and Nutrition Support for Adrenal Health

    Dosage: 1 tablet three times daily.

    Contains adaptogenic herbs, withania, Siberian ginseng, rhodiola, liquorice and Korean ginseng, in addition to amino acid, tyrosine, which enhance stress adaptation, cognitive function and energy production via modulation of HPA axis function.

    Mechanism of Action/Clinical Research:

    • Withania, Siberian ginseng and rhodiola have been shown to effectively modulate the expression of upstream HPA axis mediators, including corticotropin-releasing hormone (CRH), involved in the regulation of allostasis. Specifically, withania and Siberian ginseng were shown to down-regulate cortisol-inducing CRH, while rhodiola has been observed to exert a stress protective effect via inhibition of CRH, resulting in a modulatory effect on cortisol production.[lxxviii]

    Fifty-two subjects experiencing chronic stress received 600 mg/d of withania extract and demonstrated reductions in perceived stress after four and eight weeks of supplementation, as well as a reduction in serum cortisol levels.[lxxix]

    • Withania[lxxx] and liquorice[lxxxi],[lxxxii] have been found to moderate levels of nitric oxide (NO) and inducible nitric oxide synthase (i-NOS) in models of cellular stress, which ameliorates the impact of stress upon impaired cellular energy production.
    • Tyrosine is the core amino acid involved in the synthesis of dopamine and noradrenaline, and provides essential neurotransmitter support for cognitive enhancement.[lxxxiii]

     

    6.2.3 For emotional support:

    Bupleurum Complex for Nervous Tension and Irritability

    Dosage: 3 capsules twice daily.

    A traditional Chinese herbal blend specifically designed to address disordered neurological and hormonal patterns in patients adversely affected by stress. This combination is formulated for patients who have changeable moods and may be irritable, anxious and/or impatient.

    Mechanism of Action/Clinical Research:

    Contains herbs that are traditionally used to relieve symptoms of stress, unrest and tension. These herbal constituents are proposed to influence GABA and dopaminergic receptors, mediating its mood regulating and anxiolytic activity.

    OR

    Ginseng Complex for Emotional Resilience

    Dosage: 3 capsules twice daily.

    A traditional Chinese herbal blend specifically designed to address disordered neurological and hormonal patterns in patients adversely affected by stress. This blend of herbs is particularly indicated to support emotional resilience in sensitive patients who may be teary, weepy and anxious.

    Mechanism of Action/Clinical Research:

    • Korean  ginseng has been used in Asian medicine for over 500 years.  Korean ginseng has been found to inhibit the activity of enzyme, 11-beta hydroxysteroid dehydrogenase 1, which catalyses the conversion of cortisol to inactive cortisone. It is proposed that inhibition of enzyme activity preserves cortisol levels and abolishes excess glucocorticoid production by the adrenals at times of stress, leading to maintenance of normal adrenal function.[lxxxiv]
    • Zizyphus is widely used in Chinese herbal formulas for the treatment of anxiety, frustration, irritability, and excessive night sweats.[lxxxv]  Jujuboside A, an active constituent of zizyphus, may protect neurons by blocking the release of extracellular glutamate in the hippocampus of the brain.[lxxxvi]

     

    6.2.4 If patient presents with symptoms of low testosterone:

    Tribulus Reproductive Support

    Dosage: Take 2 tablets twice daily for four weeks with food.

    A blend of herbs and zinc to support male sexual health and function by enhancing HPO axis activity and increasing testosterone production, which may be suppressed in OCD.

    Mechanism of Action/Clinical Research:

    • Tribulus has been shown to increase testosterone, dihydrotestosterone (DHT) and dihydroepiandosterone sulphate (DHEAS).[lxxxvii] This may be via stimulation of androgen production or from direct activity from steroidal components of tribulus such as protodioscin.[lxxxviii]
    • Zinc is highly concentrated in male genital organs. A cofactor for more than 80 metalloenzymes involved in DNA transcription and protein synthesis and in DNA transcription for germ cell development, zinc has a role in testicular development, sperm maturation and release and testosterone synthesis, as well as providing antioxidant protection to counteract reactive oxygen species that impact fertility.[lxxxix]

     

    6.2.5 If presenting with symptoms of hyperthyroidism:

    Herbal Support for Thyroid Health

    Dosage: 1 tablet three times daily.

    Contains herbal ingredients to alleviate symptoms associated with OCD that are influence by thyroid dysfunction, including irritability, nervous tension and anxiety,

    Mechanism of Action/Clinical Research:

    • Lemon balm exerts anxiolytic activity, which is attributed to an elevation of GABA levels via inhibition of GABA transaminase (an enzyme that metabolises GABA).[xc]
    • Rehmannia and lemon balm influence thyroid hormones by inhibiting conversion of thyroxine (T4) to triiodothyronine (T3),[xci],[xcii] with lemon balm further disrupting thyroid stimulating hormone (TSH) binding to its receptor.[xciii]

     

    6.2.6 If patient has had exposure to heavy metals:

    Refer to the Liver Chemical Clearance Program in Metagenics Clinical Detoxification Programs

     

    7.0 Supportive Programs:

    The Metagenics Clinical Detoxification Program is designed to reduce toxic burden, increase toxin resilience and improve the efficiency of waste elimination. Through implementation of the Liver Chemical Clearance Program; reduced burden of heavy metals can decrease the damaging neurotoxic effects of metal exposure on neurological and psychological health.

    The Wellness and Healthy Ageing Program combines diet, lifestyle and herbal and nutritional interventions to support optimal health, wellbeing and quality of life, while also reducing factors that contribute to psychiatric disease development including dietary sources of inflammation.

     

    8.0 Diet and Lifestyle Recommendations:

    8.1 Diet:

    • Adherence to a Mediterranean diet is associated with lower incidences of stress-associated psychological distress.[xciv]
    • The Mediterranean diet is inclusive of high intake of fruits and vegetables, lean protein, quality essential fatty acids, and wholegrains (limiting starchy grains and vegetables).
    • Wholefood diets have also been found to increase hippocampal volume compared to typical Western diets, which were associated with hippocampal atrophy.[xcv]
    • The Metagenics Wellness Diet reflects the wholefood principles of the Mediterranean diet and provides a simple guide to moderate portion size and the overall balance of macronutrients.

    8.2 Lifestyle:

    • Cognitive behavioural therapy (CBT) including exposure/response prevention encourage patients to expose themselves to the feared thought or situation without performing the anxiety-relieving compulsions.[xcvi]
    • Physical symptoms of stress can be reduced through relaxation exercises, including activities that involve progressive muscle relaxation and breathing control (e.g. yoga, Pilates, meditation).[xcvii]

    Applications such as Headspace provide access to guided meditations, including specific sessions that concentrate on anxiety, stress, sleep and focus.

    • Exercise has been shown to reduce chronic manifestations of stress.[xcviii]

    The current recommendations are between 2½ to 5 hours of moderate intensity physical activity or 1¼ to 2½ hours of vigorous intensity physical activity, or an equivalent combination of both moderate and vigorous activities, each week.[xcix]

    • Muscle strengthening activities are recommended on at least two days each week.[c] A graded approach to exercise (increasing in frequency and intensity) is recommended for individuals who are not regularly active.
    • The Beyond Blue organisation can provide information and additional support to patients affected by anxiety, depression, substance abuse and other mental health conditions.

     

    9.0 Clinical Investigation and Pathology:

    9.1 Clinical Screening

    Clinical Screening Rationale
    Mood and Stress Questionnaire (MSQ)

    A questionnaire designed to help Practitioners establish:

    • Levels of stress, anxiety and mood concerns, prioritised in relation to each other.
    • Appropriate treatment strategies based on common response patterns under stress and neurotransmitter patterns.
    Depression Anxiety Stress Scales (DASS) A self-report questionnaire designed to measure the three related negative emotional states of depression, anxiety and tension/stress.
    Basal Body Temperature Tracker Using a digital thermometer, take temperature under the tongue on waking (before getting out of bed), preferably at the same time each day. Record temperature on Basal Body Temperature Tracker for at least four consecutive mornings, with an average taken of the readings. Normal reading: 36.5-37.0ºC


     

    9.2 Pathology Testing

    Pathology Test Ideal Reference Range Rationale
    Cortisol Awakening Response Profile (CAR)

    Cortisol waking: 8.0 to 18.0 nmol/L

    Cortisol waking +30 min: 8.0 to 18.0 nmol/L

    Cortisol waking +60 min: 8.0 to 18.0 nmol/L

    Cortisol profile, Total CAR: 23.0 to 42.0 nmol/L

    A non-invasive saliva test that serves as a reliable marker of the stress response. The CAR test measures the predictable rise and fall in cortisol within the first hour of awakening and can be used to evaluate the overall function of the HPA axis.
    Adrenocortex Stress Profile

    Cortisol morning: 6.0 to 42.0 nmol/L

    Cortisol noon: 2.0 to 11.0 nmol/L

    Cortisol afternoon: 2.0 to 11.0 nmol/L

    Cortisol evening: 1.0 to 5.0 nmol/L

    DHEA profile morning: 2.5 to 25.0 nmol/L

    DHEA/cortisol AM: 0.20 to 0.60 ratio

    Salivary cortisol and dehydroepiandrosterone (DHEA) testing is a non-invasive saliva test that evaluates bioactive levels of the body’s important stress hormones. This test examines four saliva samples over a 12-hour period for levels of cortisol and DHEA at 8 am, 12 pm, 4 pm, and 8 pm.
    Erythrocyte Sedimentation Rate (ESR)

    Female:

    17 to 50 years: 3 to 12 mm/hr

    >50 years: 5 to 20 mm/hr

    Male:

    17 to 50 years: 1 to 10 mm/hr

    >50 years: 2 to 15 mm/hr

    ESR is a non-specific indicator of inflammation.
    High-sensitivity C-reactive Protein (Hs-CRP)

    Normal value <10 mg/L

    However, ideal is <1 mg/L

    Assessment of acute phase reaction in inflammatory disorders.
    Serum TSH

    0.4 to 4.0 mlU/L

    Ideal range: 0.4 to 2.0 mlU/L

    Ideal range for preconception/pregnancy:

    Preconception: <2.5 mlU/L

    First trimester: 0.1 to 2.5 mlU/L

    Second trimester: 0.2 to 3.0 mlU/L

    Third trimester: 0.3 to 3.0 mlU/L

    TSH is the first line test for assessment of thyroid function.
    Serum fT4 10 to 25 pmo/L Considered to provide a reliable indication of true thyroid function.
    Serum fT3 4 to 8 pmol/L Performed as part of a more comprehensive evaluation of thyroid function.
    Cunningham Panel

    Anti-Dopamine Receptor : 500 – 2,000 Titre

    Anti-Dopamine Receptor: D2L 2,000 – 8,000 Titre

    Anti-Lysoganglioside GM1: 80 - 320 Titre

    Anti-Tubulin 250 – 1,000 Titre CaM Kinase II: 53.0 – 130 (% of baseline)

    Research indicates that positive changes in neuropsychiatric symptoms (associated with PANS) align with improvements in the level of anti-neuronal antibodies and antibody-mediated CaMKII human neuronal cell activation.[ci]
    Mycoplasma Pneumonia Serology Antibodies not detected. May be performed in an effort to determine the infectious aetiology of neurological syndromes, such as PANS. Recent infection is confirmed by a four-fold rise in titre between acute and convalescent (three weeks or more) sera. High titres can persist for more than one year and may not indicate recent infection.
    Throat Swab (bacterial culture)

    Negative.

    Absence of significant bacterial isolates makes a viral cause (e.g. Influenza A) most likely

    Used to establish the diagnosis of bacterial infection with ß-haemolytic streptococci, especially Group A subtypes (Streptococcus pyogenes). May be performed in an effort to determine the infectious aetiology of neurological syndromes, such as PANS.
    Viral and Bacterial Antibody Screening (e.g. herpes simplex, borrelia burgdorferi, varicella and influenza) Antibodies not detected. May be performed in an effort to determine the infectious aetiology of neurological syndromes, such as PANS.

     

    10.0 Pharmaceutical Treatments:

    • Selective Serotonin Re-uptake Inhibitors (SSRIs): SSRIs block the reuptake of serotonin in the presynapse from the synaptic cleft, increasing levels of serotonin in the brain.[cii]
    • Tricyclic Antidepressants (TCAs): TCA agents inhibit re-uptake of the amines, noradrenaline (norepinephrine) and serotonin, at synaptic clefts. The therapeutic effect is noticeable within one to two weeks, however adverse effects can be troublesome during this period (sedation, anticholinergic effects, postural hypotension, lowering of the seizure threshold and cardiotoxicity).[ciii]

    *Ensure product recommendations are suitable for use in conjunction with pharmaceutical medications.

     

    11.0 Additional Resources:

    Depression Anxiety Stress Scales (DASS): A self-report questionnaire designed to measure the three related negative emotional states of depression, anxiety and tension/stress.

     

    12.0 References:

     

    [i] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 984.

    [ii] Colledge NR, Walker BR, Ralston SH. Davidson’s principles and practice of medicine. 21st ed. Edinburgh (UK): Elsevier/Churchill Livingstone; 2010. p. 911-79.

    [iii] Zhang H, Wang B, Li K, Wang X, Li X, Zhu J, et al. Altered functional connectivity between the cerebellum and the cortico-striato-thalamo-cortical circuit in obsessive-compulsive disorder. Front Psychiatry. 2019 Jul 24;10:522. doi: 10.3389/fpsyt.2019.00522.

    [iv] Zhang H, Wang B, Li K, Wang X, Li X, Zhu J, et al. Altered functional connectivity between the cerebellum and the cortico-striato-thalamo-cortical circuit in obsessive-compulsive disorder. Front Psychiatry. 2019 Jul 24;10:522. doi: 10.3389/fpsyt.2019.00522.

    [v] Zhang H, Wang B, Li K, Wang X, Li X, Zhu J, et al. Altered functional connectivity between the cerebellum and the cortico-striato-thalamo-cortical circuit in obsessive-compulsive disorder. Front Psychiatry. 2019 Jul 24;10:522. doi: 10.3389/fpsyt.2019.00522.

    [vi] Zhang H, Wang B, Li K, Wang X, Li X, Zhu J, et al. Altered functional connectivity between the cerebellum and the cortico-striato-thalamo-cortical circuit in obsessive-compulsive disorder. Front Psychiatry. 2019 Jul 24;10:522. doi: 10.3389/fpsyt.2019.00522.

    [vii] Adams TG, Kelmendi B, Brake CA, Gruner P, Badour CL, Pittenger C. The role of stress in the pathogenesis and maintenance of obsessive-compulsive disorder. Chronic Stress (Thousand Oaks). 2018 Jan-Dec;2. doi: 10.1177/2470547018758043.

    [viii] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 984.

    [ix] Pittenger C, Bloch MH, Williams K. Glutamate abnormalities in obsessive compulsive disorder: neurobiology, pathophysiology, and treatment. Pharmacol Ther. 2011 Dec;132(3):314-32. doi: 10.1016/j.pharmthera.2011.09.006.

    [x] Ralston SH, Penman ID, Strachan MW, Hobson RP. Davidson's principles and practice of medicine. 23rd ed. Edinburgh (UK): Elsevier/Churchill Livingstone; 2018. p. 1179-1207.

    [xi] Ralston SH, Penman ID, Strachan MW, Hobson RP. Davidson's principles and practice of medicine. 23rd ed. Edinburgh (UK): Elsevier/Churchill Livingstone; 2018.p. 1179-1207.

    [xii] Goldman L, Schafer AI. Goldman-Cecil medicine. 26th ed. USA: Elsevier/Churchill Livingstone; 2020. p. 2305-15.

    [xiii] Goldman L, Schafer AI. Goldman-Cecil medicine. 26th ed. USA: Elsevier/Churchill Livingstone; 2020. p. 2305-15.

    [xiv] Goldman L, Schafer AI. Goldman-Cecil medicine. 26th ed. USA: Elsevier/Churchill Livingstone; 2020. p. 2305-15.

    [xv] Goldman L, Schafer AI. Goldman-Cecil medicine. 26th ed. USA: Elsevier/Churchill Livingstone; 2020. p. 2305-15.

    [xvi] Goldman L, Schafer AI. Goldman-Cecil medicine. 26th ed. USA: Elsevier/Churchill Livingstone; 2020. p. 2305-15.

    [xvii] Goldman L, Schafer AI. Goldman-Cecil medicine. 26th ed. USA: Elsevier/Churchill Livingstone; 2020. p. 2305-15.

    [xviii] Goldman L, Schafer AI. Goldman-Cecil medicine. 26th ed. USA: Elsevier/Churchill Livingstone; 2020. p. 2305-15.

    [xix] Goldman L, Schafer AI. Goldman-Cecil medicine. 26th ed. USA: Elsevier/Churchill Livingstone; 2020. p. 2305-15.

    [xx] Goldman L, Schafer AI. Goldman-Cecil medicine. 26th ed. USA: Elsevier/Churchill Livingstone; 2020. p. 2305-15.

    [xxi] Adams TG, Kelmendi B, Brake CA, Gruner P, Badour CL, Pittenger C. The role of stress in the pathogenesis and maintenance of obsessive-compulsive disorder. Chronic Stress (Thousand Oaks). 2018 Jan-Dec;2. doi: 10.1177/2470547018758043.

    [xxii] Adams TG, Kelmendi B, Brake CA, Gruner P, Badour CL, Pittenger C. The role of stress in the pathogenesis and maintenance of obsessive-compulsive disorder. Chronic Stress (Thousand Oaks). 2018 Jan-Dec;2. doi: 10.1177/2470547018758043.

    [xxiii] Escobar AP, Wendland JR, Chávez AE, Moya PR. The neuronal glutamate transporter EAAT3 in obsessive-compulsive disorder. Front Pharmacol. 2019 Nov 15;10:1362. doi: 10.3389/fphar.2019.01362.

    [xxiv] Sheshachala K, Narayanaswamy JC. Glutamatergic augmentation strategies in obsessive-compulsive disorder. Indian J Psychiatry. 2019 Jan;61(Suppl 1):S58-S65. doi: 10.4103/psychiatry.IndianJPsychiatry_520_18.

    [xxv] Pittenger C, Bloch MH, Williams K. Glutamate abnormalities in obsessive compulsive disorder: neurobiology, pathophysiology, and treatment. Pharmacol Ther. 2011 Dec;132(3):314-32. doi: 10.1016/j.pharmthera.2011.09.006.

    [xxvi] Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry. 2004 Nov;161(11):1957-66. PMID: 15514393.

    [xxvii] Oliveira-Maia AJ, Castro-Rodrigues P. Brain-derived neurotrophic factor: a biomarker for obsessive-compulsive disorder? Front Neurosci. 2015 Apr 16;9:134. doi: 10.3389/fnins.2015.00134.

    [xxviii] Cruz-Topete D, Cidlowski JA. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation. 2015;22(1-2):20-32.

    [xxix] Hodes GE, Kana V, Menard C, Merad M, Russo SJ. Neuroimmune mechanisms of depression. Nat Neurosci. 2015 Oct;18(10):1386-93. doi: 10.1038/nn.4113.

    [xxx] Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimäki M. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav Immun. 2015 Oct;49:206-15. doi: 10.1016/j.bbi.2015.06.001.

    [xxxi] Rao NP, Venkatasubramanian G, Ravi V, Kalmady S, Cherian A, Yc JR. Plasma cytokine abnormalities in drug-naïve, comorbidity-free obsessive-compulsive disorder. Psychiatry Res. 2015 Oct 30;229(3):949-52. doi:10.1016/j.psychres.2015.07.009.

    [xxxii] Hodes GE, Kana V, Menard C, Merad M, Russo SJ. Neuroimmune mechanisms of depression. Nat Neurosci. 2015 Oct;18(10):1386-93. doi: 10.1038/nn.4113.

    [xxxiii] Erbay LG, Kartalci S. Neurosteroid levels in patients with obsessive-compulsive disorder. Psychiatry Investig. 2015 Oct;12(4):538-44. doi: 10.4306/pi.2015.12.4.538.

    [xxxiv] Erbay LG, Kartalci S. Neurosteroid levels in patients with obsessive-compulsive disorder. Psychiatry Investig. 2015 Oct;12(4):538-44. doi: 10.4306/pi.2015.12.4.538.

    [xxxv] Savaheli S, Ahmadiani A. Obsessive-compulsive disorder and growth factors: a comparative review. Behav Brain Res. 2019 Oct 17;372:111967. doi:10.1016/j.bbr.2019.111967.

    [xxxvi] Orisakwe OE. The role of lead and cadmium in psychiatry. N Am J Med Sci. 2014 Aug;6(8):370-6. doi: 10.4103/1947-2714.139283.

    [xxxvii] Orisakwe OE. The role of lead and cadmium in psychiatry. N Am J Med Sci. 2014 Aug;6(8):370-6. doi: 10.4103/1947-2714.139283.

    [xxxviii] Orisakwe OE. The role of lead and cadmium in psychiatry. N Am J Med Sci. 2014 Aug;6(8):370-6. doi: 10.4103/1947-2714.139283.

    [xxxix] Rydon-Grange M, Coetzer R. What do we know about obsessive-compulsive disorder following traumatic brain injury?. CNS spectrums. 2015;20:1-3. doi:10.1017/S109285291500053X.

    [xl] Zhao F, Yang J, Cui R. Effect of hypoxic injury in mood disorder. Neural Plast. 2017;2017:6986983. doi:10.1155/2017/6986983.

    [xli] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 984.

    [xlii] Rowland TA, Jainer AK, Panchal R. Living with obsessional personality. BJPsych Bull. 2017 Dec;41(6):366-67. doi:10.1192/pb.41.6.366a.

    [xliii] Rowland TA, Jainer AK, Panchal R. Living with obsessional personality. BJPsych Bull. 2017 Dec;41(6):366-67. doi:10.1192/pb.41.6.366a.

    [xliv] Murphy DL, Timpano KR, Wheaton MG, Greenberg BD, Miguel EC. Obsessive-compulsive disorder and its related disorders: a reappraisal of obsessive-compulsive spectrum concepts. Dialogues Clin Neurosci. 2010;12(2):131-48.

    [xlv] Potenza MN, Koran LM, Pallanti S. The relationship between impulse-control disorders and obsessive-compulsive disorder: a current understanding and future research directions. Psychiatry Res. 2009 Nov 30;170(1):22-31. doi:10.1016/j.psychres.2008.06.036.

    [xlvi] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 984.

    [xlvii] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 984.

    [xlviii] Chang K, Frankovich J, Cooperstock M, Cunningham MW, Latimer ME, Murphy TK, et al. Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacol. 2015 Feb;25(1):3-13. doi:10.1089/cap.2014.0084.

    [xlix] Tsai CS, Yang YH, Huang KY, Lee Y, McIntyre RS, Chen VC. Association of tic disorders and enterovirus infection: a nationwide population-based study. Medicine (Baltimore). 2016 Apr;95(15):e3347. doi:10.1097/MD.0000000000003347.

    [l] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 1379-1380.

    [li] Swedo SE, Leckman JF, Rose NR. From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (pediatric acute-onset neuropsychiatric syndrome). Pediatr Therapeut. 2012;2(2):113.

    [lii] You ZL, Xia Q, Liang FR, Tang YJ, Xu CL, Huang J, et al. Effects on the expression of GABAA receptor subunits by jujuboside A treatment in rat hippocampal neurons. J Ethnopharmacol. 2010 Mar 24;128(2):419-23. doi:10.1016/j.jep.2010.01.034

    [liii] Zhang M, Ning G, Shou C, Lu Y, Hong D, Zheng X. Inhibitory effect of jujuboside A on glutamate-mediated excitatory signal pathway in hippocampus. Planta Med. 2003 Aug;69(8):692-5. PMID: 14531016.

    [liv] Fiebich BL, Weiss G, Hoffmann C. Modulation of the y-aminobutric acid (GABA) system by Passiflora incarnate L. Phytother Res. 2011; 25(6):838-843.

    [lv] Gibbert J, Kreimendahl F, Lebert J, Rychlik R, Trompetter I. Improvement of stress resistance and quality of life of adults with nervous restlessness after treatment with a passionflower dry extract. Complement Med Res. 2017 April 12;24:83-9. doi:10.1159/000464342.

    [lvi] Wang LY, Zhao AP, Chai XS. Effects of puerarin on cat vascular smooth muscle in vitro. Acta Pharmacologica Sinica. 1994;15(2):180-182.

    [lvii] Wong KH, Li GQ, Li KM, Razmovski-Naumovski V, Chan K. Kudzu root: traditional uses and potential medicinal benefits in diabetes and cardiovascular diseases. J Ethnopharmacol. 2011 Apr 12;134(3):584-607. doi:10.1016/j.jep.2011.02.001.

    [lviii] Ma H, Kim CS, Ma Y, Nam SY, Kim DS, Woo SS, et al. Magnolol enhances pentobarbital-induced sleeping behaviors: possible involvement of GABAergic systems. Phytother Res. 2009 Sep;23(9):1340-4. doi: 10.1002/ptr.2773.

    [lix] Lee YJ, Lee YM, Lee CK, Jung JK, Han SB, Hong JT. Therapeutic applications of compounds in the Magnolia family. Pharmacol Ther. 2011 May;130(2):157-76. doi:10.1016/j.pharmthera.2011.01.010.

    [lx] Han H, Jung JK, Han SB, Nam SY, Oh KW, Hong JT. Anxiolytic-like effects of 4-O-methylhonokiol isolated from Magnolia officinalis through enhancement of GABAergic transmission and chloride influx. J Med Food. 2011 Jul-Aug;14(7-8):724-31. doi: 10.1089/jmf.2010.1111.

    [lxi] Galland L. Magnesium, stress and neuropsychiatric disorders. Magnes Trace Elem. 1991-1992;10(2-4):287-301. PMID: 1844561.

    [lxii] Vink R, Nechifor M. Magnesium in the central nervous system. Adelaide: University of Adelaide Press; 2011. p. 269-81.

    [lxiii] Barragan-Rodriguez L, Rodriguez-Moran M, Guerrero-Romero F. Magnes Res. Efficacy and safety of oral magnesium supplementation in the treatment of depression in the elderly with type 2 diabetes: a randomized, equivalent trial. 2008 Dec;21(4):218-223.

    [lxiv] El Idrissi A, Trenkner E. Taurine as a modulator of excitatory and inhibitory neurotransmission. Neurochem Res. 2004;29(1):189-197.

    [lxv] Gower-Winter SD, Levenson CW. Zinc in the central nervous system: From molecules to behavior. BioFactors. 2012;38(3):186-193.

    [lxvi] Newsholme P, Procopio J, Lima MM, Pithon-Curi TC, Curi R. Glutamine and glutamate--their central role in cell metabolism and function. Cell Biochem Funct. 2003 Mar;21(1):1-9. PMID: 12579515.

    [lxvii] Gropper SS, Smith JL. Advanced nutrition and human metabolism. 4th ed. Belmont, CA: Wadsworth. 2013. p. 260-75. 

    [lxviii] Gropper SS, Smith JL. Advanced nutrition and human metabolism. 4th ed. Belmont, CA: Wadsworth. 2013. p. 316-21.

    [lxix] Gropper SS, Smith JL. Advanced nutrition and human metabolism. 4th ed. Belmont, CA: Wadsworth. 2013. p. 316-21.

    [lxx] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4thed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 1079.

    [lxxi] Xiong Y, Wang J, Yu H, Zhang X, Miao C. Anti-asthma potential of crocin and its effect on MAPK signaling pathway in a murine model of allergic airway disease. Immunopharmacol Immunotoxicol. 2015 Jun;37(3):236-43.

    [lxxii] Dong HJ, Shang CZ, Peng DW, Xu J, Xu PX, Zhan L, et al. Curcumin attenuates ischemia-like injury induced IL-1β elevation in brain microvascular endothelial cells via inhibiting MAPK pathways and nuclear factor-κB activation. Neurol Sci. 2014 Sep;35(9):1387-92.

    [lxxiii] Lopresti AL, Drummond PD. Efficacy of curcumin, and a saffron/curcumin combination for the treatment of major depression: a randomised, double-blind, placebo-controlled study. J Affect Disord. 2017 Jan 1;207:188-96. doi:10.1016/j.jad.2016.09.047.

    [lxxiv] Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Hum Psychopharmacol. 2014 Nov;29(6):517-27.

    [lxxv] Hosseinzadeh H, Noraei NB. Anxiolytic and hypnotic effect of Crocus sativus aqueous extract and its constituents, crocin and safranal, in mice. Phytother Res. 2009 Jun;23(6):768-74.

    [lxxvi] Kurohara S, Asai M, Hayashi M, Yokoigawa K, Ueno H. Microanalysis of GABA: an application for evaluating GABA production in yeast strains and the effect of spice extracts on glutamate decarboxylase. J Biol Macromol. 2001;1:45-8.

    [lxxvii] Lopresti AL, Drummond PD. Efficacy of curcumin, and a saffron/curcumin combination for the treatment of major depression: a randomised, double-blind, placebo-controlled study. J Affect Disord. 2017 Jan 1;207:188-96. doi:10.1016/j.jad.2016.09.047.

    [lxxviii] Panossian A, Seo EJ, Efferth T. Novel molecular mechanisms for the adaptogenic effects of herbal extracts on isolated brain cells using systems biology. Phytomedicine. 2018 Sep 20;50(1):257-84. doi: 10.1016/j.phymed.2018.09.204.

    [lxxix] Choudhary D, Bhattacharyya S, Joshi K. Body weight management in adults under chronic stress through treatment with ashwagandha root extract: a double-blind, randomized, placebo-controlled trial. J Evid Based Complementary Altern Med. 2017 Jan;22(1):96-106. doi:10.1177/2156587216641830.

    [lxxx] Devkar ST, Kandhare AD, Zanwar AA, Jagtap SD, Katyare SS, Bodhankar SL et al. Hepatoprotective effect of withanolide-rich fraction in acetaminophen-intoxicated rat: decisive role of TNF-α, IL-1β, COX-II and iNOS. Pharm Biol. 2016 Nov;54(11):2394-2403.

    [lxxxi] Li K, Ji S, Song W, Kuang Y, Lin Y, Tang S et al. Glycybridins A-K, bioactive phenolic compounds from Glycyrrhiza glabra. J Nat Prod. 2017 Feb 24;80(2):334-46. doi: 10.1021/acs.jnatprod.6b00783.

    [lxxxii] Yehuda I, Madar Z, Leikin-Frenkel A, Tamir S. Glabridin, an isoflavan from licorice root, downregulates iNOS expression and activity under high-glucose stress and inflammation. Mol Nutr Food Res. 2015 Jun;59(6):1041-52. doi: 10.1002/mnfr.201400876.

    [lxxxiii] Coull N, Chrismas B, Watson P, Horsfall R, Taylor L. Tyrosine ingestion and its effects on cognitive and physical performance in the heat. Med Sci Sports Exerc. 2016 Feb;48(2):277-86. doi: 10.1249/MSS.0000000000000757.

    [lxxxiv] Liao LY, He YF, Li L, Meng H, Dong YM, Yi F, et al. A preliminary review of studies on adaptogens: comparison of their bioactivity in TCM with that of ginseng-like herbs used worldwide. Chin Med. 2018 Nov 16;13:57. doi: 10.1186/s13020-018-0214-9.

    [lxxxv] Chen CJ, Li M, Wang XL, et al. Effect of Sour Date (Semen ziziphi spinossae) seed extract on treating insomnia and anxiety. Nuts and Seeds in health and disease prevention. Elsevier. 2011. Chapter 123: 1037-1041.

    [lxxxvi] Sarris J. Herbal medicines in the treatment of psychiatric disorders: a systemic review. Phytotherapy Research. 2007;21(8):703-716.

    [lxxxvii] Gauthaman K, Ganesan AP. The hormonal effects of Tribulus terrestris and its role in the management of male erectile dysfunction--an evaluation using primates, rabbit and rat. Phytomedicine 2008;15(1-2):44-54.

    [lxxxviii] Gauthaman K, Adaikan PG. Effect of Tribulus terrestris on nicotinamide adenine dinucleotide phosphate-diaphorase activity and androgen receptors in rat brain. J Ethnopharmacol. 2005;96(1-2):127-32.

    [lxxxix] Ebisch IM, Thomas CM, Peters WH, Braat DD, Steegers-Theunissen RP. The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Hum Reprod Update. 2007;13(2):163-74.

    [xc] Awad R, Levac D, Cybulska P, Merali Z, Trudeau VL, Arnason JT. Effects of traditionally used anxiolytic botanicals on enzymes of the gamma-aminobutyric acid (GABA) system. Can J Physiol Pharmacol. 2007;85:933-42.

    [xci] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4thed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 1037-54.

    [xcii] Duntas LH. Selenium and the thyroid: a close-knit connection. J Clin Endocrinol Metab. 2010 Dec;95(12):5180-8. doi: 10.1210/jc.2010-0191.

    [xciii] Duntas LH. Selenium and the thyroid: a close-knit connection. J Clin Endocrinol Metab. 2010 Dec;95(12):5180-8. doi: 10.1210/jc.2010-0191.

    [xciv] Sadeghi O, Keshteli AH, Afshar H, Esmaillzadeh A, Adibi P. Adherence to Mediterranean dietary pattern is inversely associated with depression, anxiety and psychological distress. Nutr Neurosci. 2019 Jun 11:1-12. doi:10.1080/1028415X.2019.1620425.

    [xcv]Jacka FN, Cherbuin N, Anstey KJ, Sachdev P, Butterworth P. Western diet is associated with a smaller hippocampus: a longitudinal investigation. BMC Med. 2015 Sep 8;13:215. doi: 10.1186/s12916-015-0461-x.

    [xcvi] Colledge NR, Walker BR, Ralston SH. Davidson’s principles and practice of medicine. 21st ed. Edinburgh (UK): Elsevier/Churchill Livingstone; 2010. p. 911-79.

    [xcvii] Andrews G, Bell C, Boyce P, Gale C, Lampe L, Marwat O, et al. Royal Australian and New Zealand College of psychiatrists clinical practice guidelines for the treatment of panic disorder, social anxiety disorder and generalised anxiety disorder. Aust N Z J Psychiatry. 2018 Nov 30;52(12):1109-72. doi: https://doi.org/10.1177/0004867418799453.

    [xcviii] Rimer J, Dwan K, Lawlor DA, Greig CA, McMurdo M, Morley W, et al. Exercise for depression. Cochrane Database Syst Rev. 2012 Jul 11;(7):CD004366. doi:10.1002/14651858.CD004366.pub5.

    [xcix] Australian Government Department of Health. Australia's physical activity and sedentary behaviour guidelines and the Australian 24-hour movement guidelines [Internet]. Canberra ACT: Australian Government Department of Health; 2019 [updated 2019 Apr 12: cited 2020 Feb 13]. Available from: https://www1.health.gov.au/internet/main/publishing.nsf/content/health-pubhlth-strateg-phys-act-guidelines#npa1864.

    [c] Australian Government Department of Health. Australia's physical activity and sedentary behaviour guidelines and the Australian 24-hour movement guidelines [Internet]. Canberra ACT: Australian Government Department of Health; 2019 [updated 2019 Apr 12: cited 2020 Feb 13]. Available from: https://www1.health.gov.au/internet/main/publishing.nsf/content/health-pubhlth-strateg-phys-act-guidelines#npa1864.

    [ci] Shimasaki C, Frye RE, Trifiletti R, Cooperstock M, Kaplan G, Melamed I, et al. Evaluation of the Cunningham Panel™ in pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS): Changes in antineuronal antibody titers parallel changes in patient symptoms. J Neuroimmunol. 2020 Feb 15;339:577138. doi:10.1016/j.jneuroim.2019.577138.

    [cii] Sangkuhl K, Klein TE, Altman RB. Selective serotonin reuptake inhibitors pathway. Pharmacogenet Genomics. 2009 Nov;19(11):907-9. doi: 10.1097/FPC.0b013e32833132cb.

    [ciii] Ralston SH, Penman ID, Strachan MW, Hobson RP. Davidson's principles and practice of medicine. 23rd ed. Edinburgh (UK): Elsevier/Churchill Livingstone; 2018. p. 1179-1207.

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