Neurosteroids in Psychiatry – Pharmacology | Mechanisms of Action | Clinical Application

BIOSYNTHESIS OF NEUROSTEROIDS

Neurosteroids are synthesised in the periphery and the central nervous system in
the mitochondria of glial cells and neurons, mainly glutamatergic neurons in the
hippocampus and amygdala.
[Schumacher et al 2000] ,[Mellon and Vaudy 2001]

Allopregnanolone-type neurosteroids are acute, “on-demand” stress
modulators.
[Zorumski et al., 2019]

• ACTH stimulates the conversion of cholesterol to pregnenolone, which is then
  either hydroxylated into DHEA and its sulfate ester metabolite, DHEA-S, or
  is converted into progesterone.
• Progesterone can then be either hydroxylated into deoxycorticosterone (DOC),
  which is converted to 5a-dihydrodeoxycorticosterone (5α-DH DOC) or is
  converted to 5α-dihydroprogesterone (5α-DH PROG), which is also known as
  allopregnanedione.
• 5α-DH DOC and 5α-DH PROG are then converted into 3α,5α-TH-DOC (AlloTHDOC)
  and 3α,5α-TH PROG (also known as Allopregnanolone), respectively.
• DOC is synthesised in the periphery, and most 3α,5α-TH DOC is known to come
  from the adrenal gland, although some 3α,5α-TH DOC is produced in the brain from its precursor, 5α-DH DOC.
  [Purdy et al. 1990]
• In addition to the gonads and adrenal glands, active biosynthesis of
  testosterone occurs in the brain. This can be de novo synthesis from
  cholesterol or conversion from dehydroepiandrosterone (DHEA) or
  progesterone.
• DHEA and its sulfate ester, DHEA-S, are among the most abundant steroid
  hormones in the human body. They are produced in the adrenal cortex and the
  gonads as well as the brain.

MECHANISM OF ACTION OF NEUROSTEROIDS

Other Mechanisms of Action: 

Much of the research into neurosteroids have concentrated on the potentiation of GABA_A receptor function by AlloP and AlloTHDOC. The levels of these neurosteroids mainly differ between healthy individuals and those with mood disorders. However, neurosteroids can affect several neuronal receptors, not just GABA_A receptors. [Perkins and Newport 2018]

Sigma-1 receptor: 

• Sigma-1 receptor activation fosters neuronal homeostasis and is neuroprotective. [Ryskamp et al.,2019]
• PregNENolone, pregNENolone sulfate, DHEA, and DHEA sulfate act as sigma1 agonists

Glutamate receptors: 

• NMDA receptors have two distinct neurosteroid binding sites. Sulfated neurosteroids, such as PS and DHEAS, appear potent allosteric agonists on the NMDA receptor complex.

T-channel effects: 

• T Channels modulate hypnotic/anaesthetic activity.

Toll-Like Receptor (TLR-4): 

• Neurosteroids may act via TLR-4, which plays an essential role in regulating the function of monocytes and microglia and contributes to NAS’s anti-inflammatory effects.

Modulation of Mesolimbic Activity

• Neurosteroids may inhibit the stress response by modulating mesolimbic activity via GABA inhibitory action on DA release. [Motzo et al, 1996].

NEUROSTEROIDS AND MOOD DISORDERS

Cortisol is the dominant stress steroid; however, AlloTHDOC is released from the adrenals during the stress response while AlloP is synthesised in the adrenals, ovaries, and the brain.

Stress increases the release of neuroactive steroids in the periphery through HPA axis activation. Activation of the HPA axis is beneficial during acute stress; however, chronic activation can result in a dysregulated HPA axis and reduced neurosteroid biosynthesis. [Crowley and Girdler 2014]

Both  AlloTHDOC and AlloP pass through the BBB to act on the GABA-A receptor sites, the main stress-sensitive GABA receptors. [Crowley and Girdler 2014]

Thus, both AlloTHDOC and AlloP represent an allostatic mechanism that limits the duration of stress-induced HPA axis activation. [Crowley and Girdler 2014]

Current clinical data suggest that dysregulation of neurosteroids and GABAergic neurotransmission is, therefore, a potential mechanism underlying the aetiology of stress-related mood disorders [Luscher et al. 2011]. [Crowley and Girdler 2014]. 

Depression and anxiety

• Reduction in the level of AlloP and higher cortisol to DHEA ratio has previously been suggested to be an aetiopathological link between neurosteroid-mediated HPA-axis dysregulation and affective mood disorders. [Eser et al 2006]; [Markopoulou et al 2009]
• Decreases in AlloP levels in cerebrospinal fluid (CSF) and blood are found in patients with major depression
• Low levels of pregnenolone sulfate (GABA_A antagonist) are found in the plasma of patients with a generalised anxiety disorder or generalised social phobia. [Seminiuk et al 2001]; [Heydari et al 2002]
• In men, low PROG levels were predictive of depression or anxiety, whereas lower levels of sulfated neurosteroids were predictive of depression. [Šrámková et al. 2017]

Clinical Application: 

DHEA: 

• In a small (n=22) randomised clinical trial of DHEA for major depression, DHEA (up to 90 mg/day) showed a 45% response rate vs 0% for placebo. [Wolkowitz et al., 1999]
• However, long term use of DHEA can potentially exacerbate hormone-sensitive tumours.

Testosterone:

• Mirtazapine, fluvoxamine and fluoxetine increased neurosteroid levels. Fluvoxamine or fluoxetine treatment was associated with increased CSF AlloP, with a significant positive correlation between AlloP level and depression symptom scores. While fluoxetine increases AlloP levels (deceased in depression), it reduces AlloTHDOC levels which are elevated in depression. [Ströhle et al., 2000]
• Low serum allopregnanolone and pregNANolone and high serum isopregNANolone reverted to normal in depressed patients following fluoxetine, amitriptyline, clomipramine, nortriptyline, viloxazine, or lithium treatment. [Romeo et al., 1998]

ECT and TMS have shown no effect on neurosteroid levels.

PREMENSTRUAL MOOD DISORDERS

The mood disturbances associated with PMS and PMDD occur 7 to 10 days before menses, which is when Progesterone (PROG) levels decline. Symptoms resolve a few days after the onset of menses when PROG levels recover. [Lovick 2013]

Women with PMDD have a more rapid late luteal phase drop in PROG.

However, the hormonal fluctuations in PROG and estrogen may not be causally related to PMS and PMDD. Instead, the reduced GABA-A receptor sensitivity to AlloP during the luteal phase and receptor subunit alterations (upregulation of the α4, β, δ subunits) may be responsible. [Schmidt et al 1998]; [Backstrom et al 2011]

Furthermore, women with PMS have low GABA-A  receptor sensitivity to the PROG metabolite, pregNANolone, and the efficacy of citalopram is related to its ability to restore GABA-A receptor sensitivity. [Sundstrom and Backstrom 1998]. 

PMDD’s characteristic waxing and waning symptoms (mood lability, anxiety and irritability) reflect suboptimal GABA-A response to fluctuating levels of AlloP across the menstrual cycle resulting in paradoxical anxiogenic activating effects. [Hantsoo & Epperson, 2020.]

Clinical Application: 

Sepranolone (IsoallopregNANolone) :

• IsoallopregNANolone (UC1010) is an isomer of allopregnanolone and an allopregnanolone antagonist.
• A study showed that it significantly decreased depressive symptoms in women with premenstrual dysphoric disorder comparable to serotonin reuptake inhibitors and oral contraceptives. [Bixo et al., 2018]

Dutasteride: 

• Dutasteride is a 5α-reductase inhibitor that prevents the conversion of PROG to AlloP.
• It has been shown to decrease symptoms of PMDD.
• Dutasteride was well tolerated, and while it prevented the luteal phase increase in plasma allopregnanolone, it did not significantly change luteal plasma progesterone levels. Stabilisation of AlloP levels from the follicular to the luteal phase of the menstrual cycle by blocking progesterone conversion mitigates PMDD symptoms. [Martinez et al., 2016]

Read more on the diagnosis and management of PMDD. 

POSTPARTUM DEPRESSION

• During pregnancy, neurosteroids such as AlloP increase dramatically and rapidly decline following the baby’s birth. This change in AlloP levels can affect GABA-A receptor plasticity resulting in an imbalance between excitatory and inhibitory GABAergic circuits. [Gilbert Evans et al. 2005]
• Lower levels of allopregnanolone during the later stages of pregnancy (weeks 37 to 40) has previously been observed in women at risk of postpartum depression. [Hellgren et al. 2014]
• The severity of postpartum depression is positively correlated to progesterone and pregNANolone concentrations (positive correlation) and negatively correlated to GABA concentrations.  [Deligiannidis K et al 2017]

Clinical Application: 

Hormonal Treatment: 

• In women experiencing the onset of depression within 3 months of delivery and persisting for up to 18 months postnatally, transdermal estrogen effectively reduced depressive symptoms. [Gregoire et al., 1996].
• A small study of high dose oral estrogen was effective in relapse prevention of depression in women with prior postpartum depression. [Sichel et al., 1995] 

Brexanolone: 

• Brexanolone is an intravenous stabilised form of AlloP, which the FDA recently approved to treat postpartum depression. [Faden & Citrome,2020]
• Brexanolone produces a stable serum level of AlloP, thus potentially mitigating the steep decline that occurs following childbirth postulated to cause postnatal depression.
• Studies have shown rapid remission, with the effect of a single treatment sustained up to 30 days.
• However, some limitations include cost, the need for administration in a supervised inpatient setting for the entire 60-hour infusion, and the lack of availability of an oral formulation.

Zuranolone: 

• Zuranolone is an oral medication which has a similar molecular profile to brexanolone.
• Zuranolone has better oral bioavailability and thus does not have to be administered intravenously.
• Zuranolone showed improvements in both depressive and anxiety symptoms in postpartum depression (PPD), with a higher rate of concurrent remission at days 3, 15, and 45 compared than placebo. [Deligiannidis et al, 2023]
• Zuranolone also improved insomnia and patient-reported functional health and well-being. [Deligiannidis et al, 2023]

ZURANOLONE (ZURZUVAE)

Zurzuvae (zuranolone) has been approved by the U.S. Food and
Drug Administration as the first oral medication indicated
for the treatment of postpartum depression (PPD) in adults.

Dosing: 

• 50mg taken orally once daily, preferably in the evening,
  for 14 days.
• Advised to take with fat-containing food for improved
  absorption and efficacy.
• If CNS depressant effects occur within the 14-day period,
  consider lowering the dosage to 40mg once daily in the
  evening.
• Zuranolone can be used alone or alongside oral
  antidepressant therapy, providing clinical decision
  flexibility.

Side Effects and Interactions: 

• Drowsiness, dizziness, diarrhoea, fatigue,
  nasopharyngitis, and urinary tract infections.
• A boxed warning highlights ZURZUVAE’s impact on cognition,
  emphasizing its potential to impair driving and hazardous
  activities.
• Patients are advised to refrain from driving or operating
  heavy machinery for at least 12 hours after taking the
  medication.
• Zurzuvae can also cause fetal harm, and women should use
  effective contraception while taking the medication and
  for one week after stopping the treatment.
• Risk of suicidal thoughts and behaviours necessitates
  monitoring.

Pharmacokinetics and Interactions: 

• The terminal half-life of zuranolone is approximately 19.7
  to 24.6 hours
• The Cmax increased approximately 4.3-fold when taken with
  a high-fat meal (800 to 1,000 calories, 50% fat), thus
  prompting the recommendation to consume it alongside a
  high-fat meal.
• Zuranolone is predominantly metabolised by CYP3A4, and
  therefore, administration with a strong CYP3A4 inhibitor
  increases zuranolone exposure.
• Reduce Zuranolone dosage with a strong CYP3A4 inhibitor.
• A CYP3A4 inducer decreases zuranolone exposure.

Boxed Warning: 

Advise patients not to drive or engage in other
potentially hazardous activities until at least 12 hours
after ZURZUVAE administration for the duration of the
14-day treatment course. Inform patients that they may
not be able to assess their own driving competence, or
the degree of driving impairment caused by
ZURZUVAE. </em ></strong >

PERI AND POSTMENOPAUSAL DEPRESSION

• Women experiencing their first lifetime episode of depression during perimenopause reported lower DHEA and DHEA sulfate levels but not estradiol compared to perimenopausal women without depression.
• A study comparing depressed postmenopausal women to non-depressed age-matched controls reported significantly lower allopregnanolone and DHEA amongst depressed patients with symptoms improving following treatment with sertraline; however, allopregnanolone and DHEA remained low compared to controls.
• Estradiol and progesterone hormone therapy have significant antidepressant properties against perimenopausal depression and early euthymic postmenopausal depression. [Rubinow et al 2015]; [Gordon et al 2018]
• Initiation of estrogen replacement therapy for euthymic perimenopausal and early postmenopausal women was more effective than placebo at preventing the emergence of depression. [Maki et al., 2019]

Read more on Diagnosis and Management of Perimenopausal Depression.

PTSD

• The cortisol/DHEA ratio is a marker of PTSD symptom severity and the severity of childhood trauma. Elevated DHEA and DHEA-S are associated with symptom improvement in PTSD, indicating a compensatory mechanism – as it is neuroprotective and neurotrophic.
• The CSF AlloP/DHEA ratio was negatively correlated with the severity of PTSD re-experiencing symptoms and depression. CSF AlloP levels in men and women with PTSD are decreased compared to controls. Low CSF AlloP levels in PTSD might contribute to an imbalance in inhibitory versus excitatory neurotransmission, resulting in increased PTSD re-experiencing and depressive symptoms. [Rasmusson et al., 2006]
• Following a traumatic event, women are more susceptible to developing PTSD, with many studies suggesting that oestrogen is an important mediator of this. Sex differences in AlloP may play a role in the PTSD gender differences.
• AlloP is an integral component of fear extinction and retention, which may be dysregulated in PTSD. Women with PTSD have more significant fear extinction deficits at the mid-luteal phase when estradiol and progesterone are highest. [Bryant et al.,  2011]

BIPOLAR DISORDER

• Women with BD or MDD in a state of well-being showed higher plasma concentrations of progesterone and 3alpha,5alpha-THPROG in the luteal phase than did healthy controls and even higher in bipolar disorder than major depression patients.
• PregNENolone for depressive episodes of bipolar disorder, depressive symptoms significantly improved as rated by the Inventory of Depressive Symptomatology-Self-Report but not the Hamilton Rating Scale for Depression in depressive episodes of bipolar disorder. [Brown et al, 2014]
• Olanzapine, clozapine and lithium increase neurosteroids. [Carta et al, 2012]

NEUROSTEROIDS IN SCHIZOPHRENIA

• Schizophrenia is associated with abnormalities in several key neurosteroids, including PREG. PS, DHEA, DHEA -S, PROG, and AlloP. These abnormalities signal dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and aggravate anxiety, negative symptoms, and cognitive impairment. [Cai et al., 2018]
• PREG and its metabolites exhibit antipsychotic and cognitive enhancing properties.
• There is some evidence that DHEA improves negative symptoms and EPSEs.
• PREG exhibited higher therapeutic efficacy than DHEA for psychotic and cognitive symptoms in chronic schizophrenia and schizoaffective disorder at 30 mg/day doses.
• A higher add-on dose of PREG ( 500 mg/day) showed benefits for negative symptoms in schizophrenia and schizoaffective disorder.
• Estradiol and raloxifene, a selective estrogen receptor modulator (SERM) are effective and safe adjunctive treatments that improve schizophrenia symptoms in women. [Li et al, 2022].
• Schizophrenia in Women – Role of Estrogen and Novel Treatments- Prof Jayashri Kulkarni

SUMMARY

Neurosteroids are a family of endogenous steroids synthesised from cholesterol.

Neurosteroids have been reported to act on many neuronal receptors, including GABA-A, sigma1, glutamate, glycine, serotonin, and acetylcholine receptors.

Neuroactive steroids are implicated in the pathophysiology of mood disorders, including depression, generalised anxiety disorder, bipolar disorder, PTSD, and panic disorder.

Furthermore, female reproductive mood disorders such as premenstrual dysphoria (PMD) and postpartum depression (PPD) are characterised by changes in endocrine function and neurosteroid dysregulation.

Due to their highly lipophilic nature, neurosteroids can readily cross the blood-brain barrier and modulate the HPA axis to reduce stress activation. Furthermore, consistent with their GABAergic activity, research indicates that neurosteroids have anaesthetic, anticonvulsant, sedative, and anxiolytic effects.

Further understanding of their biosynthesis, mechanism of action, and often paradoxical effects will enable the development of personalised synthetic neurosteroid treatments.