10-17-2019 Neuroendocrinology in Mental Health An Update

GOVERNMENT OF INDIA
CENTRAL INSTITUTE OF PSYCHIATRY

KANKE, RANCHI
SEMINAR: NEUROENDOCRINOLOGY IN MENTAL HEALTH: AN UPDATE
Chairperson: Dr. K.K. Kshitiz

Presenter: Dr. Shalini Bhakta
Discussant: Dr. V.M. Rajamani
Venue: R.B. Davis Hall Plagiarism: 9% Date: 17th October 2019
PRESENTER DISCUSSANT
• Introduction • Why talk about it?

• Endocrine System: A quick glance • Let’s Get Talking – Neuro-
• Neuroendocrinology endocrinological Aspects of Various
• Hypothalamic-Pituitary-Adrenal axis Disorders
• Hypothalamic-Pituitary-Gonadal axis • Do we need to talk of it as an isolated
• Hypothalamic-Pituitary-Thyroid axis entity? (immune-endocrine interaction)
• Hypothalamic-Pituitary-Somatotropic axis • Why is Estrogen all over the place?
Where do we stand?
• Endogenous Opioids
• Is sleep an important link going ahead?
• Ghrelin
• Future
• Leptin
• Limiting Factors
• Posterior Pituitary Hormones
• Conclusion
• Vitamin D
• Hormones and their role in mental disorders
• Conclusion
INTRODUCTION
The study of mental health has been an ever-evolving field, with extensive research to its credit. In continued
attempts to understand mental health and illnesses and to ensure a better quality of life for the masses, a number
of factors have been studied with regard to its pathophysiology and management. Most commonly,
neurotransmitters, genetics, brain defects and infections have played a major focus of investigation. However,
only recently, a much different line of consideration is taking shape, in trying to establish a link between
psychiatry and the endocrine system.
With studies of Walter Canon and Hans Selye on adrenal medullary and cortical response to stress, earlier this
century, the field of neuroendocrinology has begun to take on its current respectability. However, the fact that
it has roots in the classical times cannot be overlooked. As early as 4th century B.C., the concept of human
behaviour or mood being affected by bodily secretions or humour is found mentioned in the works of
Hippocrates. Quite evidently, even though this concept had made its appearance so many centuries ago, it lay
dormant for a significant amount of time, and has only recently resurfaced, giving us an opportunity to delve
further into the possible role the endocrine system can play in psychiatric illnesses and thus opening up new
avenues perhaps to encompass therapeutic, diagnostic as well as prognostic qualities, with promising results
already at hand!
ENDOCRINE SYSTEM: A QUICK GLANCE
The role of the endocrine system is to maintain whole body homeostasis via the coordination of the
hormonal-signalling pathways that control cellular activity in target organs throughout the body. The
endocrine system is also concerned with reproductive functions of humans. Classic endocrine glands are
Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M
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scattered throughout the body and they secrete hormones into the circulatory system. Classically, hormones
have been defined as the products of endocrine glands which are transported by the blood and which exert
their effects distant from their sites of release. Target organs express receptors specific to hormones that bind
to them to initiate a cellular response (Barrett et al., 2009; Sargis 2015).
Following is a table of some of the endocrine glands and their functions:

Glands Hormones Functions
Hypothalamus Thyrotropin-releasing hormone, Gonadotropin- These in turn stimulate or inhibit
releasing hormone, Growth hormone-releasing secretion of hormones from the
hormone, Corticotropin-releasing hormone, pituitary gland.
Somatostatin, Vasopressin, Oxytocin
Pituitary Growth hormone, Thyroid stimulating hormone, These act on various target organs
Follicle stimulating hormone, Luteinizing and controls the function of most
hormone, Adreno-corticotropic hormone, of the other endocrine glands.
Prolactin
Adrenal gland Glucocorticoids (e.g. cortisol), They affect metabolism, blood
mineralocorticoids (e.g., aldosterone), androgens pressure, the immune system, sex
from the cortex. hormones and the body's response
Catecholamines from the medulla to stress.
Pineal gland Melatonin - controls circadian rhythm
- can also block the secretion of
gonadotropins (LH, FSH) from the
anterior pituitary
Thymus gland Thymosin helps stimulate the development of
the T-cells, thus protecting the body
against autoimmunity.
Thyroid gland Thyroxine, Triiodothyronine, Calcitonin Plays a major role in the
metabolism, growth and
development of the human body
Parathyroid Parathyroid hormone Helps regulate the calcium levels in
gland our body
Gut Some important ones are gastrin, Controls gastric and intestinal
Cholecystokinin, Ghrelin, Vasoactive intestinal motility, regulates water and
peptide, Leptin, Secretin electrolyte secretion from different
parts of the gut.
Controls appetite
Liver Insulin-like growth factor - 1, Thrombopoietin, Helps in metabolic functions of
Angiotensinogen body and elimination of toxins from
the blood
Pancreas Gastrin, Insulin, Somatostatin, Glucagon and Most notable in its effect in the
Vasoactive intestinal polypeptide neuroendocrine system is insulin
which regulates blood glucose
Gonads: Testosterone Reproductive functions and
Testes and Estrogen and Progesterone development of secondary sexual
Ovaries characteristics
Kidneys -1,25-dihydroxyvitamin D3 (1,25D) -maintains the molecular signalling
systems that promote growth,
development, antioxidation ,
- Erythropoietin
and homeostasis in crucial tissues,
- Renin also guarding against malignancy
and degeneration
- shows an essential role in
production of RBC in bone marrow
especially under hypoxic conditions.

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Classification:
Group Structure Examples Storage Lipid Soluble

Steroids and Cortisol, oestrogen, testosterone, Diffusion after Yes
I steroid-like progesterone, synthesis
compounds dehydroepiandrosterone
II Proteins, Adrenocorticotropic hormone, beta- Vesicles No
polypeptides & endorphin, luteinizing hormone,
glycoproteins thyrotropin-releasing hormone,
follicle stimulation hormone
Mechanism of action of hormones:
Hormones act via two main mechanisms:

(a) Class I hormones act via intracellular receptors
(b) Class II hormones act via cell surface receptors
Steroid or thyroid hormones are small lipophilic hormones that control a diverse list of biological processes.
They easily pass through the cell membrane of the target cell to bind to specific intracellular receptors forming
hormone-receptor complexes that enter the nucleus to regulate gene expression and protein synthesis. They
can also affect cell-surface events via receptors at or near the cell surface.
The receptors for lipophilic hormones are not identical and belong to a large superfamily called the nuclear
receptor superfamily. The lipophilic hormone receptors are present in cytosol, nucleus, or both where they are
complexed with other proteins. The complex dissociates and the receptor dimerizes after ligand-binding,
undergoing phosphorylation and binding to DNA and induces transcription of specific target genes. Initially
these receptors directly activate the transcription of a small number of specific genes. These primary phase gene
products then activate other genes to produce a delayed, secondary response (Edelman, 1975).
Figure 1: Diagrammatic representation of steroid hormone action
On the other hand, peptide hormones and amino acid derivatives, such as epinephrine, act on cell surface
receptors, which open up ion channels causing rapid electrical responses, enabling exocytosis of hormones or
neurotransmitters. Alternatively, they activate second-messenger systems at the cell-membrane, such as those
involving cAMP, Ca2+ /calmodulin or phosphoinositides, leading to phosphorylation of proteins inside various
parts of target cells. Water-soluble hormones cannot diffuse across the plasma membrane and exert their effects
by binding to receptors on the surface of the target cell, called hormone-receptor complexes. These complexes
induce release of Guanosine diphosphate from G protein. While the α subunit of the G protein separates out,

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the remaining β and γ subunits are activated and in turn activate adenyl cyclase. This activated adenyl cyclase
catalyses the formation of cyclic adenosine monophosphate(cAMP) from ATP. Four molecules of cAMP now
bind to inactive protein kinase complex to activate protein kinase A. Eventually a cascade effect begins where
every activated molecule in turn activates molecules of inactive enzymes of the next category in the target cell
eventually resulting in the desired effect (Norman & Litwack , 1997).
Figure 2: Diagrammatic representation of mechanism of protein hormone action
These agents mediate rapid responses to the environment and are hence stored in secretory vesicles adjacent to
the plasma membrane, being available for immediate release. Hormones once released are in the blood for only
a few seconds or minutes before they get degraded by blood/tissue proteases or taken up into cells. Unlike the
lipophilic hormones, the effect of the peptide hormones is almost immediate and usually persist for only a short
period, with the exception of growth hormone, which can produce long-lasting and even irreversible changes
owing to downstream changes in gene transcription.
NEUROENDOCRINOLOGY
Endocrine disorders are frequently associated with secondary psychiatric symptoms, such as disturbance of
thought, low mood, etc. in addition to that, certain psychiatric disorders are associated with endocrine
dysfunction. Neuroendocrinology encompasses the brain’s regulation of and interaction with the endocrine
system; it entails the inseparable structural and functional relationship between hormones and the central
nervous system and associated behaviours.
The major anatomic components are the hypothalamus and extrahypothalamic regions, the hypothalamic–
pituitary stalk and portal vessels, and the pituitary.
Quite naturally, the question arises: “Does hormone affect behaviour?”
While animal studies have shown possibilities of behaviour change linked to hormonal changes in a
unidirectional linear fashion, it appears to be much more complex and multidirectional in human beings.
Hormones alter neural circuitry which in turn influence behaviour. In other words, they do not cause direct
behavioural changes (McMinn et al, 2000; Neave, 2007).
Based on experiments by Phoenix et al (1959), Beach argued that hormones affected behaviour in two principal
ways:

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ORGANISATIONAL ACTIVATIONAL
Hormones sculpt neural/behavioural machinery in At a later stage in development, the same
prenatal period that underlie behavioural responses. neural/behavioural machinery is affected by
fluctuating levels of the hormones.
5 key characteristics (Arnold and Breedlove,1985):
5 key characteristics (Arnold and Breedlove):
(a) Permanent, irreversible effects
(a) Impermanent; depends on the presence of
the hormones.
(b) Occur during specific stages of development.
(b) Effects occur in adulthood
(c) Effects occur during “sensitive” periods after
(c) These effects occur only after associated
which no further change can take place.
neural circuits have been organised and have
(d) Effects must lead to permanent structural no developmental or temporal constraints.
changes in the brain or to long-term
(d) Involves subtle changes, perhaps in
physiological changes like altered neuronal
neurotransmitter production, neurological
responsiveness.
wiring etc.
(e) Such effects are assumed to be asymmetric (e) Activational effects are assumed to be
with regard to sexes. symmetrical
HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
Psycho-endocrine research has been dominated by investigations into the HPA axis since the earliest
conceptions of the stress response. In response to a variety of physical and psychological stresses, Adreno-
corticotropic hormone (ACTH), Corticotropin releasing hormone (CRH) and Cortisol are all elevated and serve
as prime factors in the maintenance of homeostasis and help in developing adaptive responses to challenging
stimuli. Glucocorticoids regulate blood pressure, immune response, glucose and lipid metabolism, glycogen
deposition and energy homeostasis or the flight or fight response. A normal glucocorticoid stress response
helps to recover after a challenging stimulus and helps to store the experience to guide in the future should the
need arise (Chrousos et al, 2007). Studies have documented effects on arousal, pain, sleep, memory, sensory
processing, stimulus habituation and sensitisation with CRH, ACTH & cortisol. Exposure to chronic stress
leads to increased production of CRH and arginine vasopressin (AVP) which lead to simultaneous activation
of the noradrenergic circuit of locus ceruleus which ultimately
increases arousal and selective attention and decreases vegetative
functions like sex drive and appetite (Miller et al, 2007).
Serotonergic and cholinergic inputs have been shown to amplify

the glucocorticoid release while GABA and opioids inhibit it.
Acute addition of glucocorticoids can increase a dopaminergic
activity in certain areas of the brain; probably exerting their
influence by acting on promoter regions of dopamine receptors,
also regulating catecholamine synthesis, thereby functioning as a
transcriptional regulator (Mcewen et al, 2015).
A number of psychiatric disorders have been associated with the

pathological alterations of the HPA axis (Chrousos et al,, 2007).
For e.g.,
Figure 3: Representation of HPA axis

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(a) In Cushing’s syndrome, which is characterised by elevated cortisol levels, a great number of patients
suffer from mood disturbances, psychosis or suicidal thoughts. Cognitive impairments are common
and is affected by the increased levels of cortisol and the reduced hippocampal size.
(b) In Addison’s disease, which is characterised by adrenal insufficiency and reduced glucocorticoid output,
frequently seen symptoms are apathy, social withdrawal, decreased concentration, disturbed sleep.
(c) Excessive glucocorticoid activity can contribute to the symptoms of psychotic mood disorders.
Excessive exogenous administration of synthetic corticosteroids can lead to depression, mood lability
and impairments in memory and attention.
HYPOTHALAMIC-PITUITARY-GONADAL AXIS
Primarily concerned with reproductive functions, the HPG axis is also affected by stressful stimuli. Stress related
hormones can influence the HPG axis at three levels: the hypothalamus (to inhibit the GnRH secretion), the
pituitary (interferes with the GnRH induced LH release) and the gonads (alters the effect of gonadotropins on
sex steroid secretion) (Rivier & Rivest, 1991). GnRH administration leads to rapid release of LH and FSH from
the pituitary in healthy subjects. Its release is stimulated by norepinephrine and inhibited through negative
feedback of gonadal steroids. In pathological states like Acromegaly, administration of GnRH can lead to
abnormal production of growth hormone and prolactin. Administration of GnRH can also lead to hot flashes,
insomnia, decreased libido, fatigues, anxiety in euthymic individuals; but studies relating to mechanisms of such
effects is hardly exhaustive.
Figure 4: Representation of HPG axis
The ovaries and testes principally secrete the gonadal hormones like progesterone, testosterone,
androstenedione and others. However, significant amounts are secreted by the adrenal cortex as well.
Developmentally, these hormones have a crucial role to play in organizing various sexually dimorphic CNS
structures and their functions, for e.g., language ability, neuronal density in the temporal cortex, size of the
hypothalamic nuclei, etc. Sexual differentiation of the brain occurs much later than the sexual differentiation of
the genitals, therefore these two processes can be influenced independently of each other. Differences in
cognition, gender identity, sexual orientation and the vulnerability to neuropsychiatric disorders are
programmed into our brain at early stages of development. The human foetal brain develops into the male
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direction through masculinizing effects of testosterone and develops in the female direction through the
absence of such an action (Bao & Swaab, 2011).
Sex differences in the prevalence of neuropsychiatric disorders are often pronounced (Celec et al., 2015). For
e.g.,
a. For Rett syndrome, anorexia and bulimia nervosa, a majority of the cases are found in women.
b. For dyslexia, attention deficit hyperactivity disorder, autism, sleep apnea, Gilles de la Tourette
syndrome, Kallmann syndrome and Kleine–Levin syndrome, men are more affected.
Sex differences have also been studied as contributors in various other psychiatric disorders, like depression,
schizophrenia, eating disorders, gender identity disorders, etc.
HYPOTHALAMIC-PITUITARY-THYROID AXIS
Thyroid hormones are involved in the regulation of

nearly all organ systems in the body. Rates of secretion
and metabolism of major hormones, like cortisol, gonadal
hormones, insulin, etc are dependent on the thyroid
status. The hypothalamus secretes the Thyrotropin
releasing hormone (TRH) in the capillaries of the pituitary
portal venous system which in turn synthesizes and
secretes Thyroid-stimulating hormone (TSH) that act on
thyroid cells. There is a general consensus that central
noradrenergic systems have stimulatory effect on TSH
secretions while central dopaminergic systems are
inhibitory. Behavioural changes have been reported in
individuals with primary thyroid gland dysfunction.
Fig 5: Representation of HPT axis
Hypothyroidism: Psychiatric symptoms of chronic hypothyroidism are well recognized. In this condition,
classically, fatigue, decreased libido, cold intolerance, memory impairment is generally noticed; frequently
associated with slow thought process, slow motor function and drowsiness. Hypothyroidism, even subclinical
form has been associated with mood disorders, mainly depression (Haggerty & Prange, 1995).
Thyroid deficits have been frequently observed in patients with bipolar disorder, especially in women with the
rapid cycling form of the disease (Bauer etal.,2008). A true secondary psychotic disorder or dementia like state
can develop in cases of chronic hypothyroidism (Fliers et al, 2006). Myxedema is associated with severe mental
disorders including psychoses, sometimes called ‘myxedema madness’. A blunted response of TSH to TRH
(Thyrotropin-releasing hormone) infusion has been seen in various disorders like eating disorders, alcoholism,
schizophrenia, panic disorder and very frequently in major depressive disorders (Bunevicius et al, 2010).
Hyperthyroidism: This condition has been associated with restlessness, fatigue, difficulty in concentration,
memory impairments, anxiety, insomnia, weight loss, emotional lability. Sometimes a true psychosis develops
with paranoia as a common presenting feature. Some cases also show psychomotor retardation, apathy and
withdrawal. Manic like symptoms have also been reported. Severe cases may also go into delirium.
Hyperthyroidism causes overactivity of the noradrenergic system which may explain the similarity between

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presentation of hyperthyroidism and manic and anxiety states. It may also explain its role as a precipitating
factor in mood or anxiety disorders (Bunevicius et al, 2005; Bunevicius et al, 2006; Bunevicius et al, 2010).
HYPOTHALAMIC-PITUITARY-SOMATOTROPIC AXIS
Also called Somatotropin, the growth hormone (GH) is synthesized by the anterior pituitary and required for
normal growth. Evaluation for GH abnormalities typically relies upon measurement of insulin-like growth
factor-1 (IGF-1) as a more stable marker of GH functioning, since levels of GH fluctuates greatly throughout
the day.
A study by Brambilla et.al (2018) found evidence of significant correlation between GH hypersecretion and
psychological impairments in eating disorders. Central nervous system functions affected by GH include sleep,
cognition, mood, and neuroprotection (Schneider et al., 2003). Contrary to earlier beliefs, adult GH-deficiency
is seen as a serious condition that leads to disturbances in cognitive, emotional and physical functioning, which
improve on GH supplementation (Deijen et al, 2005). A study by Butler and colleagues (2019) concludes that
growth hormone deficiency in adults contributes to depression and poor quality of life.
ENDOGENOUS OPIOIDS
Endogenous opioid receptors were discovered in the early 1970s and since then extensive research has ensued
to find any possible behavioural roles. It comprises a family of peptides known as β-endorphin, the enkephalins,
dynorphins, and their G-protein-coupled receptors known as µ, δ, and κ, and the non-opioid receptor,
nociceptin. Rodent and human studies have both characterized the expression of these peptides and their
receptors in those areas of the brain, such as limbic and paralimbic regions, that are centrally involved in the
modulation of affective states, mood and motivational processes and neuroendocrine and autonomic stress
responses. Pre-clinical studies gather evidence that activation of µ-opioid receptor have antidepressant like
effects (Berrocoso et al, 2013; Zomkowski et al., 2005). However, activation of κ receptor shows aversive and
depressive like states (Pfeiffer et al, 1986). A few studies have attempted to investigate the underlying
mechanism of the opioid receptors in humans. Locations of µ-opioid receptors in brain overlap with regions
implicated in emotional regulation (Oroszi & Goldman, 2004). Early clinical trials have shown improvement in
depressive symptoms when subjects were treated with opioidergic agents. Recent clinical studies aiming to
evaluate buprenorphine (a µ-opioid partial agonist and κ receptor antagonist) in the treatment of depression
show significant improvements in depressive symptoms (Callaway, 1996; Karp et al, 2014; Nyhuis et al, 2008).
Exposure to opioids have shown an improvement in suicidality as evidenced by a meta-analysis (Yovell et al,
2016). These suggest a potential area of therapeutic interest.
Endogenous opioids have also been studied in Post-traumatic stress disorder (PTSD) where its modulation is
believed to have a positive effect. Hypersecretion of opioids in the CNS of patients with PTSD has been
postulated to be an adaptive response to traumatic experience. In a recent survey of PTSD researchers, opioid
receptor drugs were ranked in the top five therapeutic targets for PTSD (Krystal et al., 2017).
GHRELIN
A neuropeptide, Ghrelin secreted mainly from the stomach, is known to stimulate release of growth hormone
and also stimulate appetite in humans. In young healthy males, oral treatment with a growth hormone (GH)
releasing peptide-mimetic GHS MK-677, for one-week lead to an increase in slow wave sleep while decreasing
wakefulness (Copinschi et al, 1997). Pulsatile administration of ghrelin in humans showed that its effect on

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sleep is influenced by time of administration, gender and age. Early hour administration showed no EEG
change while growth hormone and cortisol increased (Kluge et al, 2007c). Sexual dimorphism was apparent, in
that slow-wave-sleep, NREM sleep, growth hormone and cortisol increased in healthy male volunteers above
60 years old, while wakefulness decreased. This was in direct contrast to women in the same age range where
EEG remained unchanged (Kluge et al, 2010a). Considering sleep-EEG effects were absent in pre and
postmenopausal women, it is unlikely estrogen contributes to the sexual dimorphism.
A growing number of studies suggest a possible role of ghrelin on memory. However clinical studies are sparse.
Contrary to results of rodent studies, ghrelin levels were recently shown to be negatively correlated with
declarative memory on elderly individuals (Spitznagel et al, 2010; Steiger et al, 2011). Current data on ghrelin’s
role in depression remains contradictory. While a few studies found ghrelin to exhibit anti-depressant properties
(Schmid et al, 2011; Kluge et al., 2011; Lutter et al, 2008) in animals or in humans, several studies have found a
decrease in ghrelin levels after anti-depressant treatments (Ozsoy et al, 2014; Kurt et al, 2007).
LEPTIN
Leptin is a protein hormone secreted by the adipose tissues in a pulsatile fashion and is involved in the regulation
of food intake. Apart from these, recently it has become clear that leptin has many other brain regulatory
functions that also involve neuroendocrine, neuroinflammatory and neurodevelopmental processes (Ahima,
2004; Valleau & Sullivan, 2014). Leptin receptors are present throughout the HPA axis which is an important
area for regulation of stress and emotional responses (Roubos et al, 2012). It has also been hypothesized to
exert modulatory actions on both dopaminergic and serotonergic systems (Yadav et al, 2009; Burghardt et al,
2012).
A study by Gohar et al (2019) found an inverse relationship between leptin and severity of suicidal behaviour
in individuals suffering from schizophrenia. However, causality could not be commented upon.
Previous studies have shown leptin to have an antidepressant like properties (Lu et al, 2006). In addition, it also
seems to have effects on the modulation of anxiety behaviours (Liu et al, 2011). Studies have shown that leptin-
deficient or leptin receptor-selective deleted mice display higher levels of anxiety-related behaviour (Finger et
al, 2010). Considering leptin has been shown to probably have some effect on the amygdala owing to presence
of leptin receptors there, Wang and colleagues (2015) hypothesized that amygdala is the main target region for
the anxiolytic effects as amygdala plays an important role in responses to stress stimuli. Their study found leptin
to have an anxiolytic-like effect and displayed an accelerated extinction of conditioned fear.
POSTERIOR PITUITARY HORMONES
OXYTOCIN
A posterior pituitary hormone, oxytocin is known to be involved in osmoregulation, milk ejection reflex, food
intake, and female maternal and sexual behaviours. Extensive animal studies have established a role of oxytocin
in social recognition and bonding and human studies have attempted to explore its therapeutic role in social
dysfunction in psychiatric disorders.
An increasing number of studies have linked intranasal oxytocin to brain reward system. A high density of
oxytocin receptors has been found to be present in the reward circuitry particularly the striatal regions (Loup
et al, 1991) and plays an important role in the processing of social reinforcers, social attachments and approach
behaviour. Preliminary research has investigated the potential role of oxytocin in a number of disorders
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including depression, borderline personality, anxiety. However, most have focused on two key developmental
disorders with significant social dysfunction, namely autism and schizophrenia (Bakermans-Kranenburg &
Ijzendoorn, 2013; Cochran et al, 2013; Guastella & Hickie, 2016). Modahl and colleagues found that children
with autism had lower mean plasma oxytocin level than age matched healthy controls (1998). On the contrary,
a study by Jansen and colleagues (2016) found adults with autism to have an increased basal plasma oxytocin
level when compared to matched heathy controls. These studies suggest that Autism spectrum disorder (ASD)
may be associated with a dysfunction in oxytocin processing and that the oxytocin system of individuals with
ASD may change over the course of the lifespan.
Preclinical mouse models demonstrate that the oxytocin system is affected in psychosis and a potential
antipsychotic effect of oxytocin through inhibitory regulation of the mesolimbic dopamine pathway
(MacDonald & Feifel, 2012). However human studies show contradictory results regarding association of
oxytocin levels in humans and their role in schizophrenia.
There is revived interest in the role of oxytocin as a therapeutic agent in schizophrenia. Studies have
demonstrated improvement in total scores on the PANSS scale with improvement in positive and negative
symptoms subscales (Feifel et al, 2010; Pedersen et al, 2011) when administered intranasally.
Oxytocin has been found to modulate neuroendocrine response to stress in social interactions and decreases
anxiety (Carter et al, 2001; Parker et al, 2005) via its receptors in the limbic system, including the amygdala
(Huber et al, 2005).
Evidence suggests that changes in oxytocin levels are associated with anxiety levels and depression, but the
findings of studies related to oxytocin levels in depression are inconsistent. It is reported that an association
exists between increased oxytocin levels and elevated mood particularly in postpartum women (Lee et al., 2009).
Oxytocin levels were also found to be negatively correlated with self-reported psychological distress, including
depressive symptoms (Gordon et al, 2008).
ARGININE VASOPRESSIN
AVP or Anti Diuretic Hormone (ADH) is a posterior pituitary hormone that maintains plasma osmolarity
through the regulation of renal water excretion. AVP has two major systems in the brain; one that has effects
on blood pressure and water conservation and the other that’s responsible for the regulation of the HPA axis
via the paraventricular nucleus secreting AVP into the hypothalamo-hypophyseal portal circulation. The actions
of AVP are mediated through two main G-protein coupled receptors: V1 receptors (V1a and V1b) and V2
receptors.
AVP has been demonstrated to have both anxiogenic (Neumann & Landgraf, 2012) and depressive effects
(Keck et al, 2003), actions mediated in part through their regulation of the HPA axis and the release of ACTH.
It is also important to note that AVP augments the effects of corticotropin releasing factor on ACTH release
from the anterior pituitary, thereby increasing HPA axis activity (Holsboer et al, 1984).
DOES VITAMIN D PLAY A ROLE IN PSYCHIATRIC ILLNESSES?
Vitamin D has been established to have many important bodily functions like controlling blood calcium
concentration and impacting the immune system. Its deficiency can lead to osteomalacia, muscle aches and
weakness, global bone discomfort, risk of hypertension, dyslipidaemia and diabetes.

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But, does Vitamin D also have a role in psychiatry?
Region-specific expression of vitamin D receptors (VDR) in the cingulate cortex, thalamus, cerebellum,
amygdala, and hippocampus suggest a possible role in psychiatry. Vitamin D regulates expression of tyrosine
hydroxylase, the rate-limiting enzyme in the biosynthesis of dopamine, norepinephrine, and epinephrine. It also
plays a role in neuronal survival and neuroprotection. (Garcion et al., 1997). Several epidemiologic studies have
linked low vitamin D levels to schizophrenia and other psychotic disorders. Berg and colleagues (2010) in their
study consistently found low levels of 25(OH) D in immigrants and native Norwegians with psychotic
symptoms. Similar results were obtained in a study by Hedelin and co-workers (2010) in 8411 Spanish women.
Low vitamin D concentrations have been associated with impairments in cognitive functions such as memory
and orientation (Przybelski & Binkley, 2007), executive function impairments (Lee et al, 2009) and Alzheimer’s
disease (AD) (Buell et al, 2010).
Recently Vitamin D and its role in Depression is also being explored. A study in the Netherlands, involving
1,102 people aged 18-65 years with current depressive disorder and 790 with former but not current depressive
disorder, found lower vitamin D levels among those with current depressive disorder and lower symptom
severity for those with higher vitamin D levels. There was also a significant correlation between vitamin D
status and developing depressive symptoms at a 2-year follow up (Milaneschi et al, 2014). A study in Sweden
found that those who attempted suicide had significantly lower vitamin D levels than non-suicidal depressed
patients or healthy controls (Grudet et al, 2014). These studies suggest a possible therapeutic role of Vitamin
D which need to be explored in the near future.
HORMONES AND THEIR ROLE IN MENTAL DISORDERS
Schizophrenia
According to a study investigating insulin levels in schizophrenic patients, it was found that drug naïve first
onset schizophrenia patients had high levels of circulating insulin (Guest et al, 2010). High insulin levels are
also associated with metabolic problems, like insulin resistance. Studies have found evidence to support the
hypothesis that some subjects with schizophrenia show signs of metabolic conditions such as insulin resistance
(Guest et al, 2011).
Contrary to earlier beliefs, current researches show evidence that schizophrenia is a sexually dimorphic disorder.
The disorder is seen more in males than in females. Studies have shown that premenopausal women suffer a
relatively benign course of the disorder with higher levels of insight, functioning and response to antipsychotic
medications. This holds true until menopause after which the second spike in incidence is believed to be
associated with increased severity, thereby suggesting a protective role of oestrogen against psychosis up until
that time (Kulkarni et al, 2012). Life cycle studies demonstrate that in women suffering from schizophrenia,
the severity of the symptoms appear to fluctuate, with the exacerbation seen during low circulating oestradiol
levels (Kulkarni et al., 2012).
Altogether, from the literature analysis of various studies investigating the role of thyroid hormone in
schizophrenia, a dynamic relationship emerged. A study by Roca and colleagues concluded that 49% of
psychiatric patients, in their study population, exhibited significant changes in one or more thyroid hormone
levels, with a significant positive correlation between illness severity and elevations of thyroid hormone levels.
Furthermore, clinical case reports indicate that hyperthyroid individuals may show psychotic symptoms,

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(Marian et al, 2009; Snabboon, et al, 2009) a characteristic of the positive symptoms observed in schizophrenic
patients (MacDonald & Schulz, 2009) and that hypothyroid individuals display impairment of mood, like
depressive symptoms, reduced motivation, a presentation similar to the negative symptoms in schizophrenic
individuals (MacDonald & Schulz, 2009; Santos et al, 2012).
Mood Disorders
A number of hormones have been studied with regard to mood disorders. Studies over the last couple of
decades have demonstrated the HPA axis hyperactivity in major depressive disorder, which is thought to be
related, at least in part, to reduced feedback inhibition by endogenous glucocorticoids. Data in favour of the
notion that glucocorticoid-mediated feedback inhibition is impaired in major depression has been collected
from a multitude of studies demonstrating that the HPA axis is not suppressed by pharmacological stimulation
of the glucocorticoid receptor with an oral dose of the synthetic glucocorticoid dexamethasone; whereas in
healthy subjects a small amount is sufficient to initiate a potent feedback mechanism.
Recent evidence shows that abnormalities in the glucocorticoid receptor (GR) may play a crucial role in the
pathophysiology of HPA axis hyperactivity in depression. The GR has a high affinity for dexamethasone and a
lower affinity for endogenous corticosteroids, while the mineralocorticoid receptor has a high affinity for the
latter. Therefore, the GR is believed to play a more important role in the regulation of the response to stress
when endogenous levels of glucocorticoids are high, such as in depression. Normalisation of GR function by
antidepressant treatment has been found to be a significant predictor of long-term clinical outcome. (Pariante,
& Lightman, 2008).
As previously mentioned under HPT axis, hyperthyroidism or hypothyroidism could also present with
symptoms similar to many psychiatric illnesses. While depression has been associated with both, manic like
symptoms are more commonly seen in patients of hyperthyroidism via the action of the HPT axis on the
noradrenergic system; while depression is more commonly associated with hypothyroidism.
Depressive and anxiety disorders have been found to be more prevalent in women than in men; suggesting a
possible role of sex steroids in the pathophysiology of the disorders. A study by Walther et al (2019) on 2105
Indian women, which sought to collect hair-sample based data about levels of progesterone, testosterone and
dehydroepiandrostenedione and their relation with depressive and anxiety symptoms, found that lower levels
of DHEA and higher levels of testosterone are associated with increased psychological distress in women;
however these findings emerge clearer for depressive symptoms as opposed to anxiety symptoms. The same
study found no association between progesterone levels from hair and depressive or anxiety symptoms.
However, a metabolite of progesterone—ALLO was found to be inversely related to depressive disorders in
women.
A study by Kamali et al (2012) on 135 participants with bipolar disorder found that in bipolar individuals with
a history of suicide attempts had an elevated bedtime cortisol levels as compared to non-suicidal bipolar
individuals. Furthermore, secondary analysis of the intensity of suicidal behaviour and level of bedtime cortisol
indicated a positive correlation, with individuals having a history of a serious suicidal attempt having the highest
cortisol levels.
Eating Disorders

12
Studies investigating the global burden of eating disorders found significant burden of anorexia nervosa and
bulimia nervosa especially in young females in developed countries. In developing countries, the numbers
continue to change (Erskine et al, 2016).
Much remains to be understood regarding the etiology of eating disorders. Studies have found evidence
regarding a possible role of oestrogen with regard to eating behaviour and their abnormalities. Estradiol plays
a role in normal food intake. Data obtained across animal species show an inhibiting effect of estradiol (Brown,
& Clegg, 2010). A review paper by Baker et al (2012) states that food intake decreases throughout the follicular
phase and is lowest during periovulation when estradiol concentrations are at their highest suggesting an
inhibitory effect. During the premenstrual period, peak in food intake is observed as progesterone
concentrations are high in women. However, this occurs only in the presence of estrogens, which points
towards the indirect effect of progesterone as an estradiol antagonist. Eating disorder symptoms, specifically
binge eating and body dissatisfaction, show an inverse association with estradiol and positive association with
progesterone.
Testosterone stimulates food intake by increasing the number of meals rather than the size of the meal (Asarian,
& Geary, 2006). Animal studies show, neonatal exposure to testosterone in female mice enhances food intake
during adulthood, likely through the prenatal organization of neural circuits. Studies examining testosterone in
eating disorders show findings that indicate that circulating concentrations of testosterone are elevated in
women with Bulimia and may be decreased in women with Anorexia Nervosa (Monteleone et al, 2001).
However, it remains unclear whether this is a cause or consequence of the disorder. Interestingly , several
medical (i.e., acne and polycystic ovary syndrome) and psychological (i.e., impulsivity, irritability and
aggressiveness) conditions associated with elevated testosterone are more commonly seen in women with
Bulimia Nervosa than in the general population; perhaps suggesting that elevated testosterone concentrations
promote bulimic behaviours via its effects on impulse control (Cassin & Von Ranson, 2005).
A study by Atalayer et al (2013) finds that the key factor influencing ghrelin levels may be the under or
overweight status (Misra et al, 2005; Tolle et al, 2003) in individuals suffering from Eating Disorders, pointing
towards the possibility that ghrelin dysregulation could be involved in the maintenance of EDs, without being
a causal factor.
Studies on Oxytocin in Anorexia Nervosa have reported lower circulating levels (Afinogenova et al, 2016;
Monteleone et al, 2016) and lower concentrations in CSF that return to normal during refeeding (Maguire et al,
2013).
Studies show that self-starvation and weight loss is followed by adaptive decline in circulating concentrations
of T3, T4 and thyroid-binding globulin (TBG) to downgrade the metabolic rate (Silva, 1995).
Anxiety Disorder
Stress is an inevitable human experience. The human body’s response to stressful events has been evolutionarily
adaptive; however, some individual’s patterns of stress responding are maladaptive.
Posttraumatic stress disorder (PTSD) affects millions of people who experience trauma in a given year and
women are twice as likely to develop PTSD. Increased estradiol levels in women are associated with increased
activations of the neural circuitry associated with fear extinction (ventromedial prefrontal cortex, hippocampus,
and amygdala) during extinction retention (Zeidan et al, 2011).

13
Moreover, women appear to be vulnerable to mood and anxiety disorders during periods of large gonadal
hormone variability, such as postpartum and menopause periods (Lokuge et al, 2011). The stress response has
been linked to the expression of anxiety and depression, but the mechanisms for these connections are unclear
and under continued consideration. A study by Raglan and colleagues (2017) explores the interactions of
glucocorticoids and corticotropin releasing hormone(CRH) in individuals with anxiety and depressive disorders
where they found individuals with PTSD seem to have lower levels of glucocorticoids, in keeping with the
results of a study by Mason and coworkers (1986), despite previous studies having shown a link between
glucocorticoid levels and high anxiety.
Individuals with PTSD also have higher levels of CRH in the cerebral spinal fluid (Bremner, 1997). Treatment
with glucocorticoid medication has been suggested as a possible intervention to reduce the presentation of
PTSD symptoms in individuals at risk.
Young shy and fearful children tend to have high cortisol levels and high reactivity to stress (Russ et al, 2012;
Schmidt et al, 2007). However, in later life socially anxious individuals may present with reduced glucocorticoid
levels and reduced reactivity (Beaton et al, 2006). As they enter their adolescence or adult phase, these children
enter a hypo-arousal phase characterised by the “shutting down”. This hypo-arousal phase is marked by
decreased energy, decreased reported anxiety, and reduced glucocorticoid levels (Beaton et al, 2006).
Symptoms of anxiety and depressive disorders have been linked to hypersecretion of corticotropin-releasing
hormone (CRH), leading to high levels of circulating glucocorticoids (Schulkin, 2011; Charney, 2004). This is
supported by studies that conclude that individuals with depression have increased startle response and may
have enhanced anxious anticipation (Grillon et al, 2013).
Obsessive Compulsive Disorder
Estradiol facilitates an upregulation of tryptophan hydroxylase (TPH), thereby increasing serotonin synthesis.
TPH is the protein responsible for catalysing the rate-limiting step in the serotonin synthesis pathway. Estradiol
also finds a role in decreasing serotonin breakdown by inhibiting the activity of monoamine oxidase A (MAO-
A) – the enzyme that degrades serotonin into the inactive 5-HIAA metabolite (Hildebrandt T, 2010). To date,
only a limited number of studies testing the relationship between estradiol and MAO activity have been
conducted in human subjects.
A study conducted in perimenopausal women, found MAO-A distribution to be higher in them compared to
women of reproductive age, and those undergoing menopause (Rekkas et al, 2014). Estradiol levels fluctuates
in the perimenopausal period with episodes of significant decline and is correlated with increased MAO-A
density (Rekkas et al, 2014). Increased MAO-A density associated with decreased estradiol may help explain the
onset or worsening of OCD during reproductive events.
As with the estrogen-dopamine relationship, the effects of progesterone on the dopaminergic system are
variable with some components being upregulated, while others are inhibited. As such, it is difficult to draw
conclusions about the role of this relationship in OCD.
The Brain and Gender
As previously mentioned, sexual differentiation of the brain occurs much later than the sexual differentiation
of the genitals (Bao & Swaab, 2011). Differences in cognition, orientation, identity are rooted in us in very early
stages of development. Contrary to popular belief, orientation and identity are not subject to changes in
14
environment, and societal pressure! The main mechanism responsible for them involves a direct effect of
testosterone on the developing brain as evidenced in different disorders. For e.g., complete androgen
insensitivity syndrome (CAIS) is caused by different mutations in the gene for the androgen receptor (AR).
Affected XY-males develop as phenotypical women and experience ‘heterosexual’ orientation and fantasies
without gender problems (Bahlburg et al, 2000). Male foetuses with a deficiency of 5α-reductase-2 or 17β-
hydroxy-steroid dehydrogenase-3 thereby preventing peripheral testosterone from being transformed into
dihydrotestosterone, appear to be a ‘girl’ with a large clitoris. Despite being raised initially as girls, puberty
heralds an increased testosterone secretion leading to the ‘clitoris’ growing to penis size, testicles descending
and the build becoming more masculinized and most of these children (60%) eventually choose to live as
heterosexual males. This is apparently due to the organizing effect of testosterone on early brain development
and the activating effect of testosterone in puberty (Garcia-Falgueras & Swaab, 2009).
The most extreme gender-identity disorder is transsexuality. It consists of the unshakeable conviction of
belonging to the opposite gender, which tends eventually to lead to a request for hormonal treatment and sex-
reassignment surgery (Cohen-Kettenis & Gooren, 1999). Postnatal social factors don’t appear to play a role for
this disorder.
Personality
A link between endogenous opioid dysfunction and borderline personality disorder has been proposed based
on multiple lines of evidence (Peciña et al., 2019); such as alterations in plasma levels of opioid peptides,
impairment in resiliency and social attachment (i.e., opioid-related behaviours), and a high incidence of opioid
dependency among individuals with borderline personality (New & Stanley, 2010; Stanley & Siever, 2009).
Furthermore, a high rate of self-injurious behaviour is noted commonly in these individuals, that is thought to
stimulate endogenous opioid release and has been associated with decreased levels of β-endorphin in
cerebrospinal fluid (Stanley et al, 2010). Using PET imaging, Prossin et al (2010) demonstrated significant
abnormalities in μ-opioid receptor levels at baseline and exaggerated endogenous opioid release following
induction of sadness in patients with borderline personality disorder, compared to controls, thereby confirming
the borderline personality—endogenous opioid hypothesis.
Very little is known of the psychobiological basis of reactive aggression which is a condition characterised by
uncontrolled outbursts of socially violent behaviour. Regardless, a number of theoretical models have been
proposed that may have complementary views about the mechanisms involved. A review paper by Jack van
Honks and colleagues (2010) compares various data to propose a Triple Imbalance Hypothesis to explain the
basis of reactive aggression. The TIH states that reactive aggression is essentially subcortically motivated by an
imbalance in steroid hormones—low cortisol levels and high testosterone levels; thereby not only predisposing
for social aggression but also down-regulates cortical-subcortical communication. This results from a lowered
activity of HPA versus the HPG systems. The reduced cortical-subcortical coupling appears to deprive the
individual of the subcortical input thought to be critical in guiding behaviour in socially and morally appropriate
fashions (Blair, 2003; Hauser, 2007). Serotonin may also play a role in the model and the notion that high
testosterone–cortisol ratios together with low central serotonin transmission predispose one toward reactive
aggression brings together several lines of animal and human research.
Substance Use Disorders

15
Information regarding the neurobiological basis of substance use disorders remain limited as are available
treatment options. Patterns of substance use intersect with appetite, sleep, stress, anxiety and sex, which are in
turn are regulated by endocrine pathways. Therefore, studies were conducted to explore a possible connection
between neuroendocrine mechanisms and substance use disorders.
A number of hormones have been studied in relation to alcohol use. Rodent studies found that exposure to
alcohol would lead to an upregulation of ghrelin receptors in the parts of the brain mediating the reward
pathway (Landgren et al, 2011). Human studies showed similar results. Alcohol consumption seemed to lower
ghrelin levels (Calissendorff et al, 2012; Leggio et al, 2013) while early abstinence from alcohol in subjects with
alcohol use disorder resulted in an increase in circulating ghrelin levels (Kim et al, 2013). Ghrelin also affected
craving where studies have found a positive correlation between plasma ghrelin concentration and urges to
drink alcohol (Kumsar et al, 2015). Craving has also found to have a significant correlation with serum leptin
levels (Hillemacher et al, 2007; Kraus et al, 2004). Human studies also found leptin to be elevated in chronic
alcohol use (Nicolas et al, 2001). Significant data coming from animal models suggests that Glucagon-like
peptide1 (GLP-1) plays an important role in the regulation of alcohol drinking. However human studies
regarding the same are limited and insufficient to establish a link between the two.
A study by Aoun et al (2017) followed up individuals with alcohol use disorder over a 3-month period after
they stopped drinking. The study found that participants who relapsed had significantly higher levels of
aldosterone as compared to those who were abstinent, and the amount of drinks consumed correlated with
circulating aldosterone concentration. They also found a significant direct correlation between aldosterone
levels and measures of alcohol craving and anxiety.
The relationship between oxytocin and substance use disorders is most likely reciprocal. Chronic drug use may
lead to down-regulation of the oxytocin system impacting tolerance and motivation for social exchange
(Buisman-Pijlman et al, 2014; McGregor et al, 2008). However, oxytocin deficiencies may have contributed to
the development of disordered substance use in the first place.
Ghrelin has also been investigated for their role in cannabis use disorder. In a study, men who smoke cannabis
to increase appetite in the context of HIV infection were found to have higher ghrelin and leptin levels (Riggs
et al, 2012). Oxytocin was found to mitigate stress cues for cannabis. A clinical study utilizing intranasal oxytocin
involving the stress response of individuals with cannabis use disorder yielded positive effects (McRae-Clark et
al, 2013).
Conclusion
Despite decades of research into neuroendocrine mechanisms and their role in mental health and disorders,
studies have hardly been conclusive. Different hormone systems may interact with each other to produce
differential expressions of symptoms, that eventually become difficult to account for. Most of the studies are
based on animal models which are tough to replicate on human subjects as hormonal manipulation in humans
are much more difficult. However, psycho-endocrine research has come a long way to suggest hormones as
treatment options in the near future considering their effects on neural circuitry and future research in this field
shows promise with the growing burden of mental disorders, and multimodal effective treatment approaches
being the need of the hour.

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DISCUSSION
WHY TALK ABOUT IT?
Over recent decades the purview of psycho-neuroendocrinology has been transformed as our understanding
of the neurobiology of behaviour has catapulted behaviour from the province of humanistic theory to the very
forefront of neuroscience.
While tremendous efforts have been made to exploit the strategy of measuring the secretion of hormones into
the plasma by the pituitary as a "window to the brain" and therefore as an insight into potential neurotransmitter
receptor lesions in patients with psychiatric disorders, a lot is left to be done in terms of translating it into
actual clinical use.” Would we still be left with nothing more than clinical and behavioural endpoints in aiding
psychiatric diagnosis and management?”, is the question to be answered.
NEUROENDOCRINOLOGY IN DEPRESSION
Expanding Views on the Neurobiology of Depression
The understanding of depression as a clinical entity has evolved radically. Research advances in the fields of
psychopharmacology and neurobiology have particularly propelled medical models for depression and mental
disorders in general, marking a transition in the understanding of these diagnoses from rather intangible, elusive
concepts, to more concrete biological terms, especially centred on the monoamine hypothesis. However, novel
approaches exceed and intertwine with this central dysfunction in monoamine neurotransmission, by involving
other neural, endocrine and metabolic pathophysiologic components.
ANDROGENS IN DEPRESSION
Androgens of both adrenal and gonadal origin can cross the blood-brain barrier, with multiple effects on the
brain, and various androgens, including testosterone, can be synthesized de novo in the brain. (Baulieu, E. E.,
& Robel, P 1990). Androgens act as allosteric modulators of GABA-A receptors, increasing the duration and
frequency of the opening of their associated chloride channel, modulating various neurotransmitter systems
and neuronal excitability, with important implications in the neurobiology of mood disorders. Interestingly,
clinical studies have failed to show effectiveness for testosterone administration as an augmentation strategy in
the management of depression in men, whereas administration of low-dose testosterone in women with
treatment-resistant MDD has been observed to significantly improve depressive symptoms in comparison to
placebo. (Pope Jr, H. G., Amiaz et al 2010) These paradoxical findings are consistent with the higher sensitivity
of females to androgens, as higher androgen exposure has been noted to exert a definite negative influence in
mood in females. (Miller, K. K., Perlis, R. et al 2009). Future studies should address these differences between
gender and their expanding comprehension of depression as a neuroendocrine disorder. Furthermore, evolving
views on the pathophysiology of depression suggest that pharmacological and nonpharmacological
interventions centred on the immunologic, metabolic, and cardiovascular aspects of this disorder may break
new ground in the field of psychiatric therapeutics in the future. Therefore, although present therapeutic
outcomes require urgent improvement, there may be enough forthcoming innovation to remain optimistic
regarding the conundrum of treatment alternatives in depression.
THYROID HORMONES IN DEPRESSION

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Thyroid hormone is notoriously involved in brain development and function, and neuropsychiatric
manifestations are hallmarks of thyroid disease. Conversely, psychiatric disorders often feature disruptions of
the hypothalamus-pituitary-thyroid axis (HPTA). On the contrary, subclinical thyroid pathology appears to be
a significant risk factor for psychiatric disorders, rather than overt thyroid pathology with multiple studies
demonstrating depressive symptoms to be significantly more frequent or severe in patients with subclinical
hypothyroidism than in age- and sex-matched controls (V. B. Chueire et al 2007). In vitro and in vivo studies
have shown T3 to stimulate microglial migration and activation, a prominent phenomenon seen in depression,
schizophrenia, and autism spectrum disorders (T. A. Kato, Y. Yamauchi, H Horikawa et al. 2013). Disruptions
in these events could contribute to the dysfunctions in neurotropism, neuroplasticity, and neurotransmission
seen in depression (R. T. Joffe 2006). Administration of thyroid hormone is a well-supported augmenting
strategy in the management of refractory depression, even in euthyroid patients (O. Agid and B. Lerer 2003).
However, hormone replacement alone may be insufficient to treat depression in hypothyroid patients, and
further research is needed to better characterize the profile of patients who would benefit most from this
intervention (B. Demartini, R. Ranieri et al 2014).
SPECIFIC TARGETS OF HPA AXIS
Fig 6- Drugs regulating the function of the HPA axis target (1) the GR, (2) the CRH1 receptors and (3) FKBP5/FKBP51
GR(GLUCOCORTICOID RECEPTOR) Antagonists Based on numerous findings of an HPA axis

hyperactivity in patients with psychotic depression open-label and double-blind trials with the GR antagonist
mifepristone were conducted (Schatzberg, A. F. 2015). The studies using dosages between 300 and 1,200 mg
/d showed mixed results, with both positive studies and failed trials. A combined analysis of similarly designed
double-blind phase 2 or 3 studies assessing the efficacy and safety of 7-day mifepristone treatment revealed a
meaningful efficacy for mifepristone in reducing psychotic symptoms, adverse events were similar in
mifepristone and placebo treated patients. (Block, T. S., Kushner, et al 2018). Interestingly, high mifepristone
plasma concentrations were associated with the strongest response, followed by changes in cortisol and ACTH.
There is also accumulating evidence that mifepristone ameliorates cognitive deficits in major depression and
bipolar disorder. (Soria V, González-Rodríguez A et al 2018). Thus, for depressed patients with psychotic features
a GR antagonist such as mifepristone may be an individualized treatment option.

18
CRH(CORTICOTROPIN RELEASING HORMONE) Receptor Antagonists CRH is a key regulator
of the stress response and controls endocrine activity by direct modulation of the HPA axis. A clinical trial
using the CRH1 receptor antagonist R121919 in the treatment of major depression revealed significant
reductions in the Hamilton Depression Rating Scale (HAMD) over the 30-day treatment period.( Zobel, A. W.,
Nickel et al 2000) The stress-elicited secretion of cortisol was reduced; however, it did not impair the CRH-
induced release of ACTH and cortisol and thus the stress hormone system responsivity to CRH remained
unchanged. The authors concluded that CRH1 receptor antagonists as a class are ineffective as monotherapy
for stress-related mental disorders.( Murrough, J. W., & Charney, D. S. 2017))Instead, patients with an
overactivity of the CRH—CRH1 receptor signalling should be identified by reliable biological measures in terms
of precision medicine, that is already well-established in other medical fields, such as oncology, and then
included in a respective trial. Thus, CRH1 receptor antagonists are still promising agents for stress-related
mental disorders, but probably only in those patients who are subject to a significant CRH signalling
dysfunction.
FKBP5 (FK506 BINDING PROTEIN) Antagonists FK506 binding protein 51/FKBP51 regulates the
responsiveness of the GR and the HPA axis and is also implicated in important gene and environment
interactions underlying stress-related mental disorders, making it a promising drug target. (Matosin, N et al
2018)). Recently with SAFit1 and SAFit2, two promising potent and highly selective inhibitors of FKBP51 were
discovered, that improved neuroendocrine feedback and stress-coping behavior in mice. Of note, co-
application of SAFit2 with the selective serotonin reuptake inhibitor escitalopram, a common antidepressant,
lowered the efficacy of escitalopram in anxiety-related tests but improved stress coping behavior in a mouse
model. (Gaali, S., Kirschner, A et al 2015)
TDO(TRYPTOPHAN 2,3 DIOXYGENASE)Inhibitors TDO inhibition by directly targeting the

kynurenine production is supposed to decrease neurotoxic metabolites and thus ameliorate depressive
symptoms. (Qin Y, Wang N et al 2018) TDO inhibition is a mechanism shared by the largest number of
antidepressants, e.g., citalopram effectively decreases TDO activity (Ara I, Bano S 2012), agents inhibiting
glucocorticoids such as RU486 showed anti-depressive properties by inhibiting TDO activity. Additionally, co-
treatment with allopurinol, also a TDO inhibitor, improved chronic stress induced depressive-like behaviour.
(Gibney SM, Fagan EM et al 2014).
NEUROENDOCRINOLOGY IN SCHIZOPHRENIA
The HPG Axis and Schizophrenia
The Hypothesis of Hypoestrogenism & Oestrogen protection hypothesis This hypothesis was first
introduced at the beginning of the 20th century. More recent work has thrown light on this early theory of
gonadal dysfunction in women with schizophrenia, with menstrual irregularities, anovulation, infertility, signs
of hyperandrogenism, and reduced circulating levels of oestradiol, progesterone, follicle stimulating hormone,
and luteinizing hormone frequently (Riecher-Rössler, A., & Kulkarni, J. 2010)However, it is still not entirely
clear whether this gonadal dysfunction precedes or follows the onset of psychosis—that is, whether it is a
causative or a resulting factor .
Oestrogen is known to have diverse neuroprotective properties that could be of particular relevance to its ability
to mediate the onset and course of neuropathology in schizophrenia. Recent in vitro and in vivo research has
confirmed that oestrogenic compounds can protect brain cells against injury from excitotoxicity, oxidative
stress, inflammation, ischaemia, and apoptosis. They can also enhance neurogenesis, angiogenesis, synaptic

19
density, plasticity and connectivity, axonal sprouting and remyelination, and expression of neurotrophic factors
(Arevalo et el. 2010)
The oestrogen protection hypothesis and hypothesis of hypoestrogenism may have important implications for
clinical practice, especially in the area of women’s mental health. To begin with, the clinician must be aware of
the possibility of an exacerbation or new onset of psychotic illness during the perimenopause, especially in
women with a history of deteriorations in mental state during the menstrual cycle or puerperium, as such women
seem to be particularly vulnerable to fluctuations in the hormonal milieu. It is these women who might benefit
most from oestrogen augmentation therapy, especially considering the additional benefits of oestrogen
replacement during the menopause. Hence recent research into SERMs is particularly important. SERMs have
been found to share the neuroprotective and neuromodulatory actions of oestradiol in the CNS but have tissue-
specific effects on peripheral oestrogen receptors
Oestradiol as Treatment
Early work in this area showed that in an open label placebo, controlled pilot study using 2 mg of adjunctive
oral estradiol valerate, the women with schizophrenia receiving estradiol had a more rapid improvement in
symptoms compared to women with schizophrenia receiving adjunctive placebo. (Kulkarni et al., 1996)
Subsequent early clinical trials including a dose-finding pilot study of transdermal estradiol and a second trial of
100 mcg transdermal estradiol (Kulkarni et al., 2001) showed efficacy of adding estradiol to antipsychotic treat-
ment in women with schizophrenia. A subsequent large clinical trial in 102 women provided further evidence
for the efficacy of adjunctive transdermal estradiol (Kulkarni et al., 2014) . Replication of these positive findings
that adjunctive estradiol is effective in improving psychotic symptoms has been provided by Akhondzadeh et
al. A meta-analysis performed in 2012 before the large trial of 102 women was published in 2014 of all estradiol
treatment trials in schizophrenia concluded “Estrogens, especially estradiol, could be an effective augmentation
strategy in the treatment of women with schizophrenia” (Begemann, Dekker, van Lunenburg, & Sommer,
2012).Estradiol treatment in men with schizophrenia is more difficult to trial with respect to the feminization
side effects for men. In a short 14-day trial of 53 men with schizophrenia, the estradiol treatment group who
had higher serum estradiol levels made a quicker recovery from psychotic symptoms(Kulkarni et al., 2011). This
suggests that estradiol has a positive impact regardless of gender.
Selective Estrogen Receptor Modulators SERMs such as raloxifene hydrochloride stimulate CNS and bone
estrogen receptors, while having an inhibitory effect on uterine, breast, and gonadal tissue. Raloxifene is a
second generation SERM that is approved for use in the treatment of osteoporosis in postmenopausal women,
and it has been shown to have a positive effect on memory.
The first dose-finding clinical trial using adjunctive raloxifene in schizophrenia (Kulkarni et al., 2010)
demonstrated that in a dose of 120 mg/day, positive and negative symptoms improved in a group of
postmenopausal women with schizophrenia.
Subsequent studies using 60 mg/day raloxifene adjunct showed some improvement in negative symptoms and
cognition but not positive psychotic symptoms in postmenopausal women with schizophrenia. (Usall et al.,
2011). Therefore, raloxifene hydrochloride 120 mg/day appears to be a useful adjunct in the treatment of older
women with schizophrenia. However, further clinical trials are required to confirm this finding.

20
Pregnenolone and its metabolites pregnenolone sulphate and allopregnanolone seem more promising. In
addition to also possessing neuromodulatory and neuroprotective properties, these neurosteroids exert positive
effects in rodent models of cognition and psychosis. Serum levels of pregnenolone have been found to be lower
in patients with schizophrenia than in healthy controls, and antipsychotic medications significantly increase
pregnenolone levels in the brain. (Ritsner, 2011).
The HPT Axis and Schizophrenia: The serum levels of T4 of acutely ill schizophrenic patients were elevated,
while those of T3, rT3, and TSH were normal. Their T4 levels showed a positive correlation with the severity
of illness and the degree of clinical response to antipsychotic treatment. There was a significant fall in serum
concentrations of T4 and rT3 during 4 weeks of drug treatment, and the decrease was significantly correlated
to clinical response. No abnormalities in the serum concentrations of any of the hormones measured were
found in schizophrenic patients in remission or in residual-type schizophrenia. (Baumgartner, Pietzcker, &
Gaebel, 2000). The authors concluded that their results indicated that elevated serum levels of T4 with normal
T3 and TSH levels may be specific for acutely ill schizophrenia patients and that antipsychotic medication may
affect thyroid hormone metabolism, this interaction being involved in the mechanism of action of these drugs.
(Baumgartner et al., 2000).
The HPA Axis and Schizophrenia Patients with psychosis, especially nonmedicated patients, have higher
baseline cortisol levels. (Garner et al., 2011) ACTH has also been found to be elevated in psychotic patients.
(Brunelin et al., 2008). In fact, both ACTH and the DA metabolite homovanillic acid (HVA) response to
metabolic stressor are also elevated in psychotic patients relative to controls. (Brunelin et al., 2008).
Antipsychotic medications reduce cortisol and ACTH secretion, in addition to decreasing positive symptoms.
The magnitude of symptom severity reduction in response to antipsychotic medications is well correlated with
a decrease in serum cortisol. (Mondelli, Dazzan, et al., 2010). Hypercortisolaemia may precipitate or exacerbate
psychotic symptoms. Warrington & Bostwick, 2006) Further evidence for this comes from studies involving
the administration of exogenous corticosteroids in high doses and causing psychotic symptoms. Symptoms of
hypercortisolaemia-induced psychosis include pressured speech, hallucinations, delusions, and disorganized
thought, which are often indistinguishable from the symptoms of psychotic disorders. (Ling, Perry, & Tsuang,
1981; Wada et al., 2001). The overall body of evidence in established schizophrenia that strongly suggests the
HPA axis plays a role in the precipitation and perpetuation of schizophrenia is a compelling area of further
investigation and underlines the impact of hormones in the development and expression of schizophrenia.
Most recently, OXYTOCIN has also emerged as possibly influencing mental state after one study found that
higher peripheral oxytocin levels were associated with decreased symptom severity in women with chronic
schizophrenia, and another study demonstrated efficacy of intranasal oxytocin as an adjunctive therapy in a
randomised, crossover sample of fifteen schizophrenia patients.
Modabbernia et al reported an 8-week double-blind, placebo-controlled study in 40 patients with schizophrenia

who had partial remission of symptoms on a stable dose of risperidone (5 or 6 mg/day). Patients were
randomized to receive intranasal oxytocin. The group receiving oxytocin had a greater response on the PANSS
total score, positive subscale, negative subscale and psychopathology score. Effect sizes ranged from 0.8 to 1.9,
indicating medium to large effects.
Overall, oxytocin shows great promise in small, preliminary studies as being a possible effective adjunctive
treatment for residual positive and negative symptoms of schizophrenia. Larger studies are needed to determine

21
the generalizability of the findings to broader populations, and to use validated measures of overall functioning
and quality of life to determine the magnitude of the clinical effect of oxytocin.
NEUROENDOCRINOLOGY OF SUBSTANCE USE DISORDERS
APPETITE REGULATING HORMONES Appetite regulating hormones include ghrelin, leptin,

glucagon-like peptide 1 (GLP-1) and insulin. The involvement between appetite regulating hormones and
substance use has been most extensively documented with alcohol. Ghrelin was also found to affect craving
for alcohol. A positive correlation has been identified in numerous studies between the urges to drink alcohol
and ghrelin plasma concentration.( Leggio L, Ferrulli A, Cardone S, et al. 2012) Research highlights a role for
ghrelin and the ghrelin receptor as potential pharmacological targets for the treatment of AUD. Ghrelin
antagonists have been developed and studied in rodent models of AUD. Early findings demonstrate a reduction
in alcohol consumption and alcohol seeking behaviors associated with the systemic administration of these
compounds. Human studies are underway. GLP-1 receptor agonists were found to reduce dopamine release
and diminish alcohol mediated rewards in mice leading to decreased spontaneous alcohol intake. (Gomez JL,
Cunningham CL, Finn DA, et al 2015) In humans, leptin levels were found to be elevated with chronic alcohol
use and correlated significantly with craving for alcohol( Kraus T, Reulbach U, Bayerlein K, et al.2004 ) In a
study of subjects with AUD, Haass-Koffler et al. demonstrated that a ghrelin infusion leads to lower leptin
levels. The change in leptin levels correlated with craving for alcohol.
VOLUME REGULATING HORMONES Volume regulating hormones include renin, angiotensin,

aldosterone, vasopressin, and some other natriuretic peptides such as atrial natriuretic peptide (ANP) Available
research supports a role for aldosterone in alcohol drinking behaviors . (Edwards S, Koob 2015) In the subset
of patients who developed severe withdrawal including delirium tremens, investigators identified elevated ANP
levels in early abstinence that did not normalize until 2 weeks later. Similarly, in that subgroup, the renin activity
was noted to start higher than the general sample of adults with AUD in acute withdrawal, but dips to
significantly lower activity by 10 days compared to those who do not develop DT. Such findings support a
possible protective role against severe withdrawal for these volume regulating hormones. (Bezzegh A, Nyuli L,
Kovács GL 1991) As such, renin and aldosterone could be viewed as compensating mechanisms for the
physiological stress associated with withdrawal by conserving sodium. Adults with AUD were followed for 3
months after they stopped drinking. Study participants who relapsed were found to have significantly higher
aldosterone levels that those who were abstinent and the amount of drinks consumed correlated with circulating
aldosterone concentration. A significant direct correlation was also identified between aldosterone levels and
measures of alcohol craving and anxiety. (Aoun EG, Jimenez VA, Vendruscolo LF, et al 2017)
STRESS HORMONES Any clinician who has worked with individuals with SUD can appreciate the
significant relationship between stress and substance use. Elevated basal levels of CRF, ACTH, and cortisol
were demonstrated in early withdrawal from alcohol along with a blunted response to stressful experimental
designs. This blunted HPA response to stress-cues, along with negative mood and stress-induced craving have
been shown in numerous studies to be associated with drinking outcomes such as relapse. Nicotine delivery to
individuals without a tobacco use disorder was found to stimulate the HPA axis resulting in increased levels of
cortisol and ACTH. (Sinha R 2008 ) This in turn triggers inhibition of the production of these hormones by
way of a negative feedback loop. Early withdrawal from nicotine is also associated with elevated basal levels of
CRF, ACTH, and cortisol along with a suppressed ACTH and cortisol response to stressful experimental

22
designs. These markers of abnormal stress response were identified as predictors of nicotine relapse (Lemieux
AM, Al’Absi M 2016).
REPRODUCTIVE HORMONES Sex differences in substance use disorders exist. Clinically, it has been
observed that females achieve disordered substance use faster than males. Females also suffer physiologic
consequences like end-organ damage at a quicker pace. While some sex variance may be mediated by culture,
preclinical studies have consistently demonstrated differences between male and female substance use in
multiple domains. ESTROGEN’S relationship to substance use is modulated by its influence on GABA,
dopamine, and glutamate. Estrogen increases dopamine both directly and indirectly by: 1. Inducing dopamine
gene transcription 2. Decreasing inhibitory GABA firing and GABA-B receptor stimulation 3. Downregulating
D2 auto-receptors with consequential dopamine enhancement. Estrogen is the reproductive hormone
primarily responsible for increased drug seeking and relapse found preferentially in females. Through its
alpha receptor, estrogen is associated with the glutamatergic system in the striatum and the prefrontal cortex,
both known to play a role in craving. If estrogen can be thought of as the hormonal “gas pedal” for disordered
substance use, then PROGESTERONE serves as a homeostatic “break.” On a neurobiological level,
progesterone and its metabolites demonstrate pro-striatal GABA activity and dopamine reduction.
(Mermelestein PG, Becker DJ 1996).
A randomized double-blind, placebo-controlled trial demonstrated that subjects receiving a 24 IU dose of

OXYTOCIN required nearly five times less total lorazepam to complete detoxification than controls(
Pedersen CA, Smedley KL, Leserman J, et al 2013) Substance self-administration is significantly reduced with
oxytocin intervention for most drugs of abuse in animal models. Recently, it was shown that voluntary ethanol
consumption was inhibited by oxytocin and that oxytocin completely blocked alcohol-induced dopamine
release in the nucleus accumbens following acute and chronic alcohol exposure.
NEUROENDOCRINOLOGY IN PTSD
Posttraumatic stress disorder (PTSD), is one of the most sex-polarized psychiatric illnesses, with women having
more than twice the prevalence than men. While there is much debate about what factors contribute to these
disparities –from sociocultural and environmental influences to sexual dimorphisms in physiology – there is,
surprisingly, very little known about the biological mechanisms that underlie sex differences in PTSD. Recently,
however, a few studies have linked the cyclical release of ovarian hormones to PTSD vulnerability in women.
(Lebron-Milad K, Milad MR 2012) These findings are particularly important given that anxiety disorders tend
to emerge around puberty, when sex organs begin to release hormones that have activational effects on brain
activity. A notable observation is that individuals with PTSD show deficits in their ability to inhibit
conditioned fear responding after extinction training.( Inagaki T et al 2010)Given that extinction
procedures, via exposure-based cognitive behavioural therapy, make up one of the predominant modes of
treatment in PTSD, there is a critical need for more research on sex interactions in this form of fear regulation.
An emerging hypothesis is that fluctuating gonadal hormones, especially estrogen, in the menstrual
cycle may play a critical role in fear extinction and, hence, PTSD vulnerability and symptom severity
in women. It has been established that PTSD is a disorder of the fear memory circuitry and that individuals
with PTSD show deficits in extinction. (Milad MG, Quirk GJ 2002 )By establishing a role of estrogen in this
neural circuitry and in extinction function, there is a unique opportunity to pharmacologically target this
behavioural phenotype in women with PTSD. Estrogen receptors, both ERα and ERβ, are densely expressed
in the amygdala, hypothalamus, and hippocampal cortical regions, and express sexually dimorphic intracellular
processing, suggesting sex-specific estrogen modulation of emotion and cognition. (Kruijver FP et al 2002)
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Estrogen may influence extinction via genomic mechanisms by binding to classical nuclear receptors and
initiating long-lasting transcription-related events. However, recent advances suggest that estrogen may also act
at membrane receptors (which are similar or identical to classical receptors) to initiate rapid effects via signal
transduction pathways. The fact that acute estrogen administration induces rapid and reversible changes in
synaptic plasticity within the extinction network and in extinction memory suggests that non-genomic estrogen
activity at membrane receptors may largely mediate these facilitatory effects. A number of candidate cellular
and molecular markers have been linked to estrogen activity within the extinction network, nevertheless, a great
deal of research is needed to delineate the precise mechanisms underlying estrogen modulation of fear
extinction. (Phelps EA et al 2004)
Fig 7 Schematic summarizing risk factors related to oestrogen levels in PTSD vulnerability and severity based
on preclinical and clinical investigations. Although not depicted in the figure, it is understood that these factors
operate within the context of a larger gene by environment perspective and that the beneficial “dose” range of
oestrogen must be further explored.
NEUROENDOCRINOLOGY IN OCD
Current lines of evidence suggest a role for gonadal hormones in OCD pathology. It has been observed that
in some cases, obsessive-compulsive (OC) symptoms worsen or first appear during reproductive milestones
such as pregnancy, and the postpartum period. A 2013 meta-analysis revealed that pregnant and postpartum
women had a 45 and 138% increased risk of developing OCD, respectively (Uguz F, Kaya V 2011). The
regulation of OC symptoms by reproductive hormones is thought to be mediated by 3 neurotransmitter
systems: the serotonergic, dopaminergic, and glutamatergic systems. Generally, impaired serotonergic signalling,
and enhanced neurotransmission by dopamine and glutamate have been associated with worsened OCD. These
neurotransmitter systems can be modified by hormones including estrogens, progesterone, and oxytocin, and
are speculated to be the link between fluctuating hormone level and altered OCD course during reproductive
events in these patients. Further investigation into this relationship is warranted. Future studies should
prospectively evaluate OC symptom severity along the course of female reproductive events, with concurrent
measurements of hormone levels.

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TABLES 1, 2 & 3 - Effects of gonadal hormones on neurotransmitter systems and OCD symptoms
NEUROENDOCRINOLOGY IN EATING DISORDERS
Data from preclinical and human research suggest that neuroendocrine signals that regulate both homeostatic
and hedonic eating may serve as useful novel targets for the treatment of AN and BN. Although many
neuroendocrine alterations in eating disorders are illness state-dependent to some degree, evidence suggests
they may maintain eating disorder symptoms. Future, longitudinal research in larger samples is necessary to
determine whether neuroendocrine alterations may impact the development of dopaminergic reward systems
in humans and precipitate the development of AN and BN symptoms. Such studies will be particularly helpful
in disentangling the effects of altered gonadal hormones on the risk for and maintenance of eating disorders,
and potential sex differences in these effects. In addition, as most research has focused on AN and BN,
additional research on neuroendocrine interactions with reward among individuals with binge eating disorder
are needed. As more data become available, future meta-analyses will be helpful in evaluating the relative impact
of neuroendocrines on eating disorder symptoms. Further, additional research is needed to clarify the potentially
interacting roles of neuroendocrine signals on altered reward circuitry in eating disorder populations. For
example ghrelin has been shown to interact with orexins and leptin to alter food intake (Perello and Dickson,
2015; Perello et al, 2010) and orexin-A may mediate the effects of leptin and insulin (Figlewicz and Benoit,
2009a). In addition, estrogen alters sensitivity to the anorexigenic effects of leptin and insulin (Clegg et al, 2006)
and is thought to be a protective factor against insulin insensitivity (Hong et al, 2009). Research with
adrenalectomized rodents has supported a role for corticosterone’s interactions with insulin function in
overeating and obesity (Chavez et al, 1997; la Fleur et al, 2004). Given the complex interplay of these
neuroendocrines, future neuroimaging studies of food reward in eating disorders should be carefully controlled.

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The preference for and nutritional composition of food stimuli presented, the method of presentation, how
recently participants have eaten, and menstrual status, phase, and pubertal age of participants may all impact
reward-related findings via neuroendocrine effects. As neuroendocrines affect distinct reward-related processes,
future eating disorder imaging studies should measure valuation of food palatability, food reward consumption,
other rewarding sensory aspects of eating including smell, and effort exerted to obtain food (e.g., Bragulat et al,
2010; Fernández-Aranda et al, 2016). Studying neuroendocrines in conjunction with fMRI (e.g., via
pharmacological neuroimaging) could improve characterization of aspects of reward circuitry that play key roles
in eating disorder pathophysiology. As current human imaging technologies cannot distinguish some small,
reward-related regions with distinct neuroendocrine-mediated responses, conducting pharmacological fMRI
research in concert with parallel preclinical studies will be particularly valuable.
NEUROENDOCRINOLOGY IN EXERCISE AND MENTAL WELL-BEING
Chekroud et al. 2015, included more than 1 million members of the U.S. population in their study, which
investigated the relationship between physical exercise and mental health burden. A very interesting aspect of
the study of Chekroud et al. is that it contributes to our knowledge about the optimal range for frequency and
duration of physical exercise and that it is not a “the more, the better” relationship. Chekroud et al. show that
the correlation with mental health burden was lowest when individuals engage in about 45 min of exercise 3–5 days per week. This
is in close agreement with the recommendation of 150 min per week of moderate-to-vigorous physical activity
from the World Health Organization. Evidence has indicated that the practice of physical exercise has antidepressant effects
that might be associated with Irisin release and BDNF signalling. Central administration of irisin and BNDF elicited
antidepressant-like behaviour C. Bjorkholm, L.M. Monteggia, 2016).
METABOLIC SYNDROME AND MENTAL DISORDERS
Schizophrenia Metabolic syndrome is common among people with schizophrenia, although the estimated
prevalence varies widely, from 8.9 to 68%. The prevalence of metabolic syndrome in people with schizophrenia
is still around 5 times higher than that in the general population. Schizophrenia is also associated with a greater
risk of diabetes mellitus, with a two- to threefold higher prevalence compared with the general population. This
increase is independent of the use of antipsychotic drugs. (de Hert 2009). Antipsychotic-naive patients were
found to have higher insulin resistance, impaired glucose tolerance and increased intra-abdominal fat deposition
compared with normal controls. (Papanastasiou 2012). In addition, siblings of individuals with schizophrenia
were found to have increased glucose intolerance (Fernandez-Egea 2008),, while parents of those with non-
affective psychosis had increased prevalence of type 2 diabetes. (Fernandez-Egea 2008). These findings suggest
that metabolic abnormality is probably an intrinsic component of schizophrenia, with biological and genetic
predisposing factors.
Mood Disorders Metabolic syndrome is associated with increased prevalence of depressive disorder and
depressive symptoms, ranging from 36 to 50%. First, people with depression are less likely to abide by dietary
restrictions and more likely to be physically inactive. The lack of exercise may also reduce serotonin synthesis,
thus worsening depression (Attvall 1993; Wojciech 2007).. Second, the activation of the HPA axis increases
plasma cortisol levels (Bjomtorp 2000). Third, the chronic increase of insulin and leptin may activate the
sympathetic nervous system leading to faulty glucose metabolism and blood pressure regulation, and
accumulation of abdominal fat (Musselman 1998; Anagnostis 2009). Fourth, the increased levels of
proinflammatory cytokines and leptin resistance (Howren 2009) found in patients with metabolic syndrome
have been shown to be involved in depressive disorder. Several studies have reported that metabolic syndrome

26
tends to be associated with certain characteristics of bipolar disorder such as (Chang 2009; McIntyre 2010):: •
longer duration of bipolar disorder, especially type I • more lifetime manic and depressive episodes • more
severe first affective episode • late onset of first manic episode • late age at first treatment for manic or
depressive episode.
Cognitive decline, dementia Elderly people with metabolic syndrome are more likely to develop cognitive
impairment than those without the syndrome. (Yaffe 2004) Common cognitive deficits that are linked to
metabolic syndrome involve memory, visuospatial abilities, executive functioning, processing speed and overall
intellectual functioning. (Yates 2012). The effects of metabolic syndrome on the brain, and thus on cognitive
decline, include neuroinflammation, oxidative stress, impaired glucose metabolism and impairment of vascular
reactivity. Interestingly, adiponectin, which is released from adipose tissue, has also been found to be related to
cognitive function in several studies (Une et al 2011). These findings contradict the commonly accepted belief
that a high level of plasma adiponectin is protective of metabolic and cardiovascular functioning. Nevertheless,
it is important to note that the renal clearance of adiponectin in the elderly is lower than in younger adults.
Thus, plasma adiponectin levels in elderly people should be interpreted with caution.
Post-traumatic stress disorder (PTSD) is associated with cardiovascular risk factors such as hypertension,
diabetes and obesity, and chronic and more severe PTSD may be associated with higher risk of metabolic
syndrome. Stress-related dysregulation of glucose and lipid metabolism in PTSD can also lead to the
development of metabolic syndrome.
Borderline personality disorder-The prevalence of metabolic syndrome among people with borderline
personality disorder is twice that in primary care patients (Une et al 2011). The increased rate is associated with
older age, higher BMI, second-generation antipsychotics, benzodiazepine dependency and binge eating
behaviour.
Hyperprolactinemia and antipsychotics
Dopamine acts on the pituitary as an inhibitor of prolactin secretion. Blockade of dopamine D2 receptors by
typical antipsychotics and risperidone can cause hyperprolactinaemia in males and females. Other atypical
antipsychotics do not cause sustained hyperprolactinaemia because of their lower affinity for D2 receptors.
Symptoms of hyperprolactinaemia include amenorrhoea, galactorrhoea, infertility, loss of libido and erectile
dysfunction. Resulting hypogonadism may cause osteoporosis. Treat symptomatic antipsychotic-induced
hyperprolactinaemia by dose reduction or change to an antipsychotic with less effect on prolactin. Also consider
endocrinological consultation. Warn women that menstruation and fertility will return as their prolactin levels
normalise, therefore contraceptive advice may be needed.
PCOS AND MENTAL DISORDERS Little research exists regarding psychiatric disorders apart from
depression and anxiety in women with PCOS. Recent studies show increased rates of obsessive-compulsive
disorder and somatization in women with PCOS. As with depression and anxiety, no guidelines exist regarding
screening for or treatment of these disorders in women with PCOS. ( R.S. Legro, S.A. Arslanian, D.A. Ehrmann
et al 2013) Further research is necessary to bolster the validity of these findings. The increase seen in
somatization disorders in women with PCOS is particularly interesting given the physical symptoms that are
seen with this syndrome. In the setting of diagnostic criteria including hyperandrogenism, anovulation, an d
polycystic ovaries, physical manifestations of PCOS often include hirsutism and obesity. ( S.M. Sirmans, K.A.
Pate 2014) Past research has demonstrated that hirsutism, low self-esteem, and poor body image are associated
with psychological distress and decreased health-related quality of life in women with PCOS. (L. Borghi, D.

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Leone, E. Vegni et al. 2018) More research on the prevalence of somatization disorders in this population could
involve investigation of the role of common physical manifestations of PCOS.
ENDOCRINOLOGY OF TRANSGENDER MEDICINE
Transgender people before gender-affirming treatment present with higher levels of mental health problems,
particularly depression, anxiety, and self-harm, than do cisgender people. Gender-affirming treatment has been
found to reduce mental health problems in transgender people (Hoshiai M et al, 2010) Long-term estrogen and
androgen-lowering medications may be associated with increased risk of thromboembolism, which can be
mitigated by changing the formulation and route of estrogen therapy. Testosterone treatment in transgender
men I s seen as safe regarding cardiovascular and oncological disease in the short-term and mid-term, but long-
term effects need to be elucidated. (Quirós C et al 2015) The few somatic data available in adolescents are
favourable and hitherto support the fact that the proven psychological benefits of early medical intervention
outweigh the potential medical risks. In well-informed transgender people regrets of gender-confirming
treatment are very rare. (Dhejne C et al.2016)
MELATONIN IN MENTAL DISORDERS
Although melatonin has been found and widely used since as early as 50 years ago, relationship between
melatonin and mental disorders are still quite unclear, and there is little research on melatonin treatment of
mental diseases. With the results from biochemical measurements in melatonin treatment of mental disorders
showed that melatonin treatment of mental disorders did not have serious negative consequences melatonin
will likely be widely used in the treatment of mental disorders in clinical practice. At the same time, the
measurements of the effects of melatonin treatments will become more standardized and effective. We believe
that in the coming years, we might have breakthrough progress in the treatment of mental disorders field by
using melatonin.
Figure 8 MELATONIN IN ANXIETY AND DEPRESSION
Figure 9- MELATONIN IN SCHIZOPHRENIA, AUTISM AND ADHD
ACKNOWLEDGING THE IMMUNE-ENDOCRINE INTERACTION
In the last two decades, numerous investigations have revealed that the immune and the neuroendocrine
functions amply interrelate in regulating the mechanisms of adaptation to internal and external stimuli. More
recently, the CNS has been observed to be part of a triangle that includes the neuroendocrine and the immune

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systems, each of which maintains a strict control of the function of the others. In particular, the effects of the
immune system, modulated by the neuroendocrine activity in the brain centres higher than the hypothalamus,
are still poorly understood and are being debated. Some data obtained in experimental animals suggest that
concomitant immune and neuroendocrine dysfunctions during prenatal and postnatal life can result in
anatomical alterations in the CNS, with ensuing behavioural impairments. The same phenomenon could occur
in humans and be the basis of mental or neurological disease. For humans, very few studies of the effects of
cytokines on behaviour and mentation have been reported. However, alterations of secretion of cytokines in
parallel with multiple hormonal impairments have been found in affective disorders, anxiety disorders, and in
schizophrenia, suggesting they are possibly involved in the modulation of the mental disorders. Something that
really spiked the interest in autoimmunity as a player in mental illness, was the discovery of autoimmune
encephalitis
Figure 10- THE NEURO-IMMUNO-ENDOCRINE TRIANGLE
Fig 11 Mechanisms through which TNF-α could contribute to the emergence of a depression: activation of the
hypothalamus-pituitary-adrenal (HPA) axis, induction of apoptosis, stimulation of the serotonin reuptake and
induction of the IDO. For details see text. Abbreviations: tryptophan hydroxylase (TPH), aromatic L-amino
acid decarboxylase (AAAD), indoleamine (2,3-) dioxygenase (IDO), tumor necrosis factor-α (TNF-α).

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Table 4 - summary of important autoimmune disorders presenting with psychiatric symptoms
MICROBIOME
The gastro-intestinal tract of humans contains vast amounts of bacteria, phyla and other microorganisms, their
genes collectively known as the microbiome, containing at least 100 times more genetic material than the human
genome. (Gill SR, Pop M et al 2006). This area has received great attention in the research of many different
illnesses in the last years and have been implicated as a possible etiological factor in both neuropsychiatric
illnesses and autoimmune diseases. An important function of the microbiome, seems to be its effect on the
epithelial cells in the GI wall, with evidence implicating that the composition of the microbiome is important
for the tightness of the gut-blood barrier. (Burger-van Paassen N et al 2009) Severance et al. found markers in the
serum of patients with schizophrenia indicating increased permeability, also known as “leaky gut.” A leaky gut

30
allows the entrance of foreign pathogens and antigens into the blood. It has been suspected to induce systemic
inflammation, and in mice it has been found to even result in neuroinflammation, both of which might increase
the risk of mental illness and autoimmune diseases. (Alhasson F, Das S, Seth R et al, 2017) Interestingly, both
infections and the treatment hereof with antibiotics can modulate the microbiome, linking the previously
mentioned epidemiological findings of the influence of infections with the microbiome theory. Additionally, it
has been theorized that maternal infection might alter both the maternal and foetal microbiome, ( -Keeler J,
Weitkamp JH et al 2015) possibly impacting the immune system and neuropsychiatric development of the
offspring. A few studies have tried probiotic treatment in patients with schizophrenia, but no evidence of effect
hereof on psychopathology has yet been found. (Severance EG, Gressitt KL et al 2017)However, further research
on the actual composition of the microbiome in patients with mental illness as well as the possibility of using
probiotics as treatment hereof is warranted.
WHAT ABOUT ESTROGEN? WHY IS IT IMPORTANT?
Everyone knows estrogen has something to do with mood, right? It’s amazing how little we know. At this point
these are only “very suggestive” studies, not “tells you what to do” research, except for one conclusion at the
bottom( Soares CN, Almeida OP, Joffe H, Cohen LS 2016).
Estrogen’s effects are complex!
In a recent review on of the brain chemistry of reproductive hormones in women, the following estrogen effects
were described:
• an increase in brain norepinephrine levels;
• a decrease in dopamine release;
• multiple effects on serotonin, and even an effect on blood tryptophan levels (the amino acid from which
serotonin is made);
• protective effects on acetylcholine systems (possibly thereby protecting against Alzheimer’s disease);
• effects on the production of neurotrophic factors, the brain’s own cell fertilizers, now known to be very directly
involved in the mechanism of depression;
• an increase in endorphin levels in the brain as well as the bloodstream;
• a possible relationship with melatonin, the sleep-regulating hormone (complex relationship, different in
different animal species);
• promotion of the production of allopregnanolone, a “neurosteroid” with strong antianxiety effects; and
• a complex relationship, but clearly affecting the levels of DHEA, another neurosteroid with mood effects.(
Morgan ML, Cook IA, Rapkin AJ, Leuchter AF 2017)
The moral of the story: there is no simple way to explain “here’s how estrogen affects mood”. While you will
often see the implication “too little estrogen leads to depression”, and the related claim “estrogen can be a
treatment for depression”, you should keep in mind that this is a dramatic simplification of a complex
relationship, most of which we don’t understand.
SLEEP- IS IT A CONNECTING LINK?
Several hormones are involved in sleep and circadian rhythmicity. Evidence suggests that various hormones
and metabolic processes are affected by sleep quality and circadian rhythms; such interactions are mediated by
numerous clock genes. Hormones such as growth hormone, melatonin, cortisol, leptin, and ghrelin are closely
associated with sleep and circadian rhythmicity, and endogenous circadian-regulating mechanisms play an

31
important role in glucose and lipid homeostasis. Sleep disturbances and, particularly, deprivation is associated
with an increased risk of obesity, diabetes and insulin insensitivity, and dysregulation of leptin and ghrelin,
increased risk of mental disorders which negatively impact human health.
Growth hormone levels are increased during sleep and peak immediately subsequent to sleep onset. In a
previous study, growth hormone levels, measured every 30 s during sleep, increased significantly during slow-
wave sleep (SWS) compared with stages 1 and 2 and REM sleep. Growth hormone is intermittently secreted
during sleep, which could relate to the cyclic nature of SWS.( L. Weibel, M. Follenius et al 1997) Posttraumatic
stress disorder patients characterized by frequently disturbed sleep exhibited lower night-time growth hormone
plasma levels compared with healthy subjects.( S. van Liempt, E. Vermetten et al 2011) Growth hormone
replacement therapy, for growth hormone-deficient paediatric patients, enhanced EEG slow oscillation.
Melatonin exhibits robust circadian rhythmicity. Studies using constant routine and forced desynchrony
protocols demonstrate that melatonin levels are high during the biological night versus day. Administration of
sustained-release or transdermal formulation melatonin reduces sleep latency, increases total sleep time, and
improves sleep maintenance. (H. J. et al 2010) Melatonin administration increases sleep spindle frequency on
EEG. Beta-blockers possess melatonin-suppressing properties; in patients taking atenolol in conjunction with
melatonin, total wake time and sleep were improved Melatonin also confers a chrono-biotic effect and can
facilitate maintenance of an optimal sleep wake cycle. Blind subjects with free-running circadian rhythm
disorder were entrained to a 24 h rhythm following melatonin administration. ( S. W. Cain, C. F. Dennison, J.
M. Zeitzer et al. 2010).
Cortisol exhibits circadian rhythmicity; its level rises rapidly in the middle of the biological night and peaks
during the biological morning. Cortisol is released in a pulsatile manner throughout the 24 h with a circhoral
ultradian rhythm. The pulsatile secretion of gonadotropin releasing hormone prevents the receptor
desensitization. The SCN is at the centre of this rhythm regulation spectrum. Intravenous infusion of cortisol
increased SWS and decreased REM sleep; concerning the mechanism underlying this effect, Steiger reported
that cortisol infusion suppresses CRH, thereby decreasing SWS in accordance with a negative feedback
mechanism. (F. A. J. L. Scheer, M. F. Hilton 2009)
Ghrelin and leptin promote and suppress food intake, respectively. Ghrelin levels increase prior to habitual
meal times and decrease thereafter. Several studies have evaluated the relationship between sleep and hormone
levels. Increased growth hormone levels and proportion of SWS and decreased REM sleep were observed
following intravenous injection of ghrelin. (M. Kluge, M. Gazea, P. Schüssler et al. 2010) In a rodent study,
SWS increased and REM sleep decreased following leptin infusion( C. M. , T. E. Fitch, and H. K. Gershenfeld
1999) Elderly males administered ghrelin were subsequently characterized by an increased proportion of stage
2 and SWS sleep and decreased stage 1 and REM sleep. Increased ghrelin levels during early-stage sleep and a
blunted ghrelin response during sleep deprivation were also reported. (A. Dzaja, M. A. Dalal et al 2004)
FUTURE
So, what are we looking at in the possible future?
It is undeniable that the neuroendocrine strategy can characterize the hypothalamic-pituitary and pineal
dysfunction of certain clinical entities, and evaluate the functionality of some neurotransmitter systems by using
appropriate pharmacological stimuli, however, it appears necessary, in order to generate and validate new
pathophysiological hypotheses, to associate neuroendocrine investigations to other paraclinical approaches

32
(e.g., neurochemistry, neuroimmunology, genetics, molecular biology, neurophysiology, nuclear magnetic
resonance spectroscopy, other types of neuroimaging, etc). Indeed, most psychiatric diseases do not have
defined single causes, and it is believed that multiple genes or gene families may trigger disease manifestations
while non-genetic factors may play a key role in the development and progression of the illness. Endocrine
secretions represent one of the principal links between the environment and the genes, and it has been suggested
that endocrine alterations in psychiatric patients could be linked to genetic polymorphisms Among the other
paraclinical approaches, neuroimaging, despite promising structural and functional findings in patient groups,
has currently provided no valuable biomarkers for a given psychiatric patient. Thus, using information in
conjunction with genetics and brain imaging data is expected to significantly improve our understanding of
both normal and pathological variability of brain organization. This multivariate approach should lead to the
development of biomarkers most relevant in view of a future personalized medicine.
LIMITING FACTORS
Although much has been learned about hormonal dysfunctions in major psychiatric diseases for the past 50
years, it is clear that there is no simple answer to the question as to whether altered endocrine activity is directly
related to the pathophysiology of the psychiatric illness, or acts as a vulnerability factor or may even represent
a compensatory mechanism. Furthermore, a number of factors may compromise the reliable and valid
assessment of hormones in psychiatric conditions.
--Unreliable clinical diagnosis considering subjective nature of clinical endpoints
-- Non- specific effects of stress or hospitalization
--Extraneous variables like Age, sex, menstrual status etc
-- Confounding effects of intercurrent medical illness
--Direct biological effects of medications
--Treatment or withdrawal from drugs or alcohol.
--Paucity of human studies and interventions
--Ethical issues when hormonal biomarkers used in conjunction with genetic testing- should be resolved with
collaborative efforts.
Given the difficulty to control all these factors, it is not surprising that so many false leads and unreplicated
findings continue to plague psychoneuroendocrinology.
Another important issue, is the lack of strict standardization of the challenge tests (e.g., with regard to the dose
of the compound administered, assay used to measure hormones, threshold for abnormal response, and the
moment in the day when the test is performed) that limit the comparability of results from different studies. At
present, it seems hardly possible to create international databases in psychiatry from the results of
neuroendocrine tests, contrary to what is achieved in other branches of medicine. This explains why the
introduction of endocrine parameters in diagnostic algorithms, although theoretically desirable, is not feasible
because of methodological obstacles inherent to these investigations.
However, the neuroendocrine strategy still offers new insight in biology and treatment by delineating more
homogeneous subgroups from a bio-clinical and therapeutic viewpoint. However, its possible expansion
depends in part on the development of specific pharmacologic tools in order to better investigate the activity
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of neuroreceptors and receptors for the endocrine target hormones. These advances will consolidate the
strengths of the neuroendocrine strategy in elucidating the specific mechanisms by which hormones affect brain
function, as well as mechanisms underlying hormone changes during psychiatric states in a diachronic
perspective.
CONCLUSION
By leaps, steps, and stumbles, science progresses. Its seemingly inexorable advance promotes a sense that
everything can be known and will be known. Through observation and experiment and lots of hard thinking,
we will come to explain even the murkiest and most complicated of nature’s secrets: consciousness, dark matter,
time, the full story of the universe etc. But what if our faith in nature’s knowability is just an illusion, a trick of
the overconfident human mind?
And with the years of research on hormones in psychiatry not leading us to a concrete safe haven in terms of
disease diagnosis and treatment, should our perspective about hormones radically change?
As hormones as investigative and prognostic markers are not always feasible and specific, can we have more
specific BEHAVIOURAL TOOLS to aid in our diagnosis? Can we refine our list of symptoms/syndromes/
behavioural patterns to something highly specific, reliable for the psychiatric disease we see in practice, as for
instance, IN a patient with a complaint of chest pain, a set of specific characters are highly specific for the pain
being of cardiac origin? Do we see hormones as a valuable supplement or as a radical replacement altogether?
Or do we become too myopic in our view that we start ignoring the mutually inclusive psychological,
psychosocial and cultural aspects of the disease process, which is clearly the essence of Psychiatry, on our way
ahead towards an exclusively biological basis?
OTHER INTERESTING STUDIES!!
In the clinical area, an interesting study assesses the plasma levels of the muscle-derived hormone irisin in
anorexic women, without finding any significant correlation between irisin level and physical exercise.
(Hofmann T, Elbelt U et al 2014).
Another fascinating study analyses the complexity of psychiatric and personality disorders in women with
polycystic ovary syndrome, highlighting the issue of psychological distress in this patient group ( Scaruffi E,
Gambineri A et al 2014).
A comprehensive picture of gender dysphoria, a psychiatric condition, which requires endocrine management,
in Ireland is presented. (Judge C, O’Donovan C et al 2014).
In a short review, the most relevant reproductive, neurodevelopmental, and genetic aspects of
hypogonadotropic hypogonadal syndromes are outlined. (Valdes-Socin H, Rubio Almanza M et al 2014).
A German study indicates that psychopathology significantly predicts quality of life in patients with acromegaly
and suggests that depressive symptoms and anxiety, being modifiable factors, may represent relevant targets for
a broad treatment intervention in acromegalic patients. (Geraedts VJ, Dimopoulou C et al 2015).
In a concise review, the psychiatric alterations, the neurocognitive impairment, and the altered quality of life
affecting at some extent the majority of the patients with Cushing’s syndrome are summarized, and the authors
highlight that resolution of hypercortisolism, a challenging and non-granted achievement, does not always lead
to the complete remission of the neuropsychiatric changes or restore the quality of life . (Pivonello R, Simeoli
C et al 2015).
34
Studies have addressed the complex interactions between metabolism and neuropsychiatric symptoms. The
first one focuses on biological differences between restrictive anorexia nervosa and constitutional thinness, a
controversial concept to describe young girls who follow a normal diet and differ from restrictive anorexia
nervosa on a number of endocrine parameters. At the opposite of the spectrum, the second one reviews the
role of inflammatory processes in the neuropsychiatric comorbidity associated with obesity. Finally, the last one
summarizes the fascinating link through ghrelin peptides between appetite/reward/growth hormone axis and
psychiatric disorders ( Estour, Castanon, Labarthe et al 2014).
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CIP STUDIES EXPLORING THE RELATION BETWEEN HORMONES AND PSYCHIATRY
TITLE NAME AND GUIDE & KEY FINDINGS

YEAR CO-GUIDE
Metabolic Syndrome in Schizophrenia : the role of Dr Archana Singh Prof (Dr) C.R.J No statistically significant
illness and atypical antipsychotic drugs (2011) Khess difference even after treatment
Prolactin levels before and after ECT and its Dr Shalini Bijali Prof (Dr) D. No significant correlation between
correlation with clinical improvement in (2014-2016) Ram prolactin changes and improvement
psychopathology in psychopathology.
Thyroid indices in children and adolescents with Dr Sanjoy Roy Prof (Dr) B. No significant finding in
OCD : effects of pharmacological treatment (2013-2015) Das comparison of baseline thyroid
function between patients and
control group
Gender difference in phenomenology of Dr Partha Sarathi Prof (Dr) C.R.J Males were associated with younger
Depression Biswas (2001- Khess age of onset , greater family history
2003) and more number of episodes of
affective disorder as compared to
females.
Suicidality in post-partum onset psychiatric Dr Avinash Shukla Prof (Dr) B. Women with post-partum onset
disorders (2011-2013) Das psychiatric disorders had more
severe disorders and higher
suicidality
Effect of Vitamin D supplementation in treatment Dr Satytam Prof(Dr) B. Although both groups of patients
of first episode psychosis- a randomized double Kishore Das showed improvement in clinical
blind, placebo controlled study parameters with time, this was
irrespective of whether they
received vitamin D
supplementation or not
Prevalence of thyroid dysfunction in psychiatric Dr Rajeev Ranjan Prof (Dr) Frequency of thyroid dysfunction
inpatients Raj Arunlata was almost similar among major
Agarwal psychiatric disorders. The
frequency was found to be 42.74%
Change in thyroid status in lithium treated adult Dr Sekh Afrar Prof (Dr)Vinod Patients on long term lithium were
patients with mood disorders Alam (2008-10) K Sinha found to have increased thyroid
volume and trend towards
hyperthyroidism, starting lithium at
a later age is a major risk factor for
increased thyroid volume

44

10-17-2019 Neuroendocrinology in Mental Health An Update

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10-17-2019 Neuroendocrinology in Mental Health An Update

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GOVERNMENT OF INDIA

CENTRAL INSTITUTE OF PSYCHIATRY

SEMINAR: NEUROENDOCRINOLOGY IN MENTAL HEALTH: AN UPDATE

Chairperson: Dr. K.K. Kshitiz

Venue: R.B. Davis Hall Plagiarism: 9% Date: 17th October 2019

• Introduction • Why talk about it?

ENDOCRINE SYSTEM: A QUICK GLANCE

Following is a table of some of the endocrine glands and their functions:

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

Group Structure Examples Storage Lipid Soluble

Mechanism of action of hormones:

Hormones act via two main mechanisms:

Figure 1: Diagrammatic representation of steroid hormone action

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

Figure 2: Diagrammatic representation of mechanism of protein hormone action

Quite naturally, the question arises: “Does hormone affect behaviour?”

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

Serotonergic and cholinergic inputs have been shown to amplify

A number of psychiatric disorders have been associated with the

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

Figure 4: Representation of HPG axis

Thyroid hormones are involved in the regulation of

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

POSTERIOR PITUITARY HORMONES

DOES VITAMIN D PLAY A ROLE IN PSYCHIATRIC ILLNESSES?

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

HORMONES AND THEIR ROLE IN MENTAL DISORDERS

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

Obsessive Compulsive Disorder

The Brain and Gender

Substance Use Disorders

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

WHY TALK ABOUT IT?

Expanding Views on the Neurobiology of Depression

THYROID HORMONES IN DEPRESSION

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

SPECIFIC TARGETS OF HPA AXIS

GR(GLUCOCORTICOID RECEPTOR) Antagonists Based on numerous findings of an HPA axis

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

TDO(TRYPTOPHAN 2,3 DIOXYGENASE)Inhibitors TDO inhibition by directly targeting the

The HPG Axis and Schizophrenia

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

Modabbernia et al reported an 8-week double-blind, placebo-controlled study in 40 patients with schizophrenia

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

NEUROENDOCRINOLOGY OF SUBSTANCE USE DISORDERS

APPETITE REGULATING HORMONES Appetite regulating hormones include ghrelin, leptin,

VOLUME REGULATING HORMONES Volume regulating hormones include renin, angiotensin,

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

A randomized double-blind, placebo-controlled trial demonstrated that subjects receiving a 24 IU dose of

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

NEUROENDOCRINOLOGY IN EATING DISORDERS

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

NEUROENDOCRINOLOGY IN EXERCISE AND MENTAL WELL-BEING

METABOLIC SYNDROME AND MENTAL DISORDERS

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

Hyperprolactinemia and antipsychotics

Neuroendocrinology in Mental Health: An Update Kshitiz, K.K, Bhakta, S, Rajamani, V.M

ENDOCRINOLOGY OF TRANSGENDER MEDICINE