Navigating Female-Specific Complexities in Psychiatry: Clinical and Psychopharmacological Implications

Pre-clinical psychiatric research is primarily based on male-animal models due to the unknown effect the oestrous cycle may have on behaviour. The scarcity of pre-clinical stage data results in an insufficient understanding of how to modulate behavioural expression concerning experimental outcomes.

Women were only allowed to be enrolled in clinical trials as of 1993. The main concerns were around the impact of drug trials on pregnant women of childbearing age.

Furthermore, a significant proportion of women of childbearing age are on hormonal contraceptives, and therefore, there is the possibility of an unknown, possibly harmful interaction between an experimental drug and a hormonal contraceptive.

However, once a drug is commercialised and sold, details of its interactions with hormonal contraceptives are necessary in the real world, given the proportion of women on prescription contraceptives.

The primary contraceptive effect of the oral contraceptive (OC) pill is attributed to the progestin component.

Interactions between medications and OC pills form an important part of clinical practice.

Medications like Carbamazepine, Topiramate, and Armodafinil can diminish the effectiveness of hormonal contraceptives by CYP3A4 enzyme induction. [Johannessen et al., 2010]

A survey looking at pregnancy and contraception experiences in women with narcolepsy revealed that a substantial portion of survey participants, including half of modafinil/armodafinil users, lacked awareness of the interaction between oral contraceptives and these medications.

Conversely, oral contraceptive pills (OCPs) can impact Lamotrigine excretion, potentially reducing its effectiveness, which is important in bipolar disorder and epilepsy management. [Pascoe et al., 2019]

Lamotrigine and the Oral Contraceptive Pill – Are Dose Adjustments Needed?

Furthermore, it is an important ethical debate to discuss female participation in clinical research for illnesses that have the same or greater prevalence in women as in men.

The NICE guidelines recognise the importance of accurately assessing and treating women who have, or are at risk of, psychiatric disorders during the perinatal period. [NICE, 2014]

This includes mental health issues such as depression, anxiety, eating disorders, and severe mental illness such as bipolar disorder and schizophrenia. But for other areas, the development of a female-focused branch of psychiatry and psychopharmacology does not exist.

Women are twice as likely to grapple with depression and anxiety disorders and face higher rates of attempted suicide. [Nestler et al., 2002]

In contrast, men confront a higher risk of substance use disorders, certain neurodevelopmental conditions, and death by suicide.

In bipolar disorders, females show a clear predominance in both manic and depressive phases throughout their lives. Additionally, there is a notable overrepresentation of women diagnosed with Bipolar Type 2, which can be linked to misdiagnosing some females with borderline personality disorders as Bipolar Type 2 patients. This misdiagnosis often leads to treatments involving mood stabilisers, antidepressants, and antipsychotics.

Current studies investigating gender differences in Borderline Personality Disorder (BPD) are limited, with the majority focusing on female populations. Some research suggests certain BPD features are more prevalent in women, while other studies report no significant gender differences. A minority of studies indicate that some clinical manifestations are more common in men. [Bozzatello, 2024].

Borderline Personality Disorder – Deconstructing the Diagnosis from a Neurobiological and Psychodynamic Lens

Stress-related disorders such as PTSD and depression are clinically very different. Still, they share several features, notably the dysregulation of the HPA axis and functional changes to hormones and other neuropeptides important in the stress responsiveness network.

The stress response regulates arousal and cognitive responses and primarily involves the activation of the neuropeptide, corticotrophin-releasing factor (CRF). Together with noradrenaline (NA) systems, these coordinate the behavioural response to stress.

CRF is the primary physiological activator of the HPA axis and acts on the pituitary to initiate the mammalian stress response. The stress response is essential for adaptation and survival. Still, chronic stress can increase disease predisposition and cause changes to homeostatic balance and various critical neural circuits associated with psychiatric illness.

The amygdala & hypothalamus are connected with the LC, where corticotrophin-releasing hormone and noradrenaline interact to increase fear conditioning, encoding of emotional memories and enhance arousal and vigilance. [Weathington and Cooke, 2012]

Hypersecretion of CRF is maladaptive, and evidence from research and clinical investigations shows:

• Increased CRF levels in the cerebrospinal fluid positively correlated with symptom severity. [Baker et al., 2005], [Sautter et al., 2003]
• Single nucleotide polymorphisms in the CRF-1 receptor gene have been reported in patients with PTSD and depression. [Amstadter et al., 2011], [Polanczyk et al., 2009], [Liu et al., 2006]
• Post-mortem studies show that there is altered CRF receptor expression in depressed patients. [Wang et al., 2008], [Bissette et al., 2003]

Differences in the Female Stress Response

Although there are reliable epidemiological data on sex differences in susceptibility to stress-related psychiatric illness, the exact neurobiological basis for this is unknown. Preclinical research has focussed on the CRF system and how this may play a critical role in sex-specific susceptibility to stress. [Bangasser and Valentino, 2012], [Bangasser, 2013], [Valentino et al., 2012]

Under the circumstances characterised by the heightened release of CRF (corticotropin-releasing factor), these gender-based distinctions are expected to be accentuated.

This phenomenon is particularly relevant in stress-related psychiatric disorders that exhibit a higher incidence among females, such as depression and post-traumatic stress disorder (PTSD).

The sex-specific differences in the stress response include:

1. HPA activation – A female’s endocrine system responds differently to perceived threats and is highly influenced by CRF neurons in key stress-related brain regions, independent of circulating sex steroids. [Babb et al., 2013], [Iwasaki-Sekino et al., 2009]

2. CRF receptors – Females have a higher expression of CRF receptors in the CE and BLA regions of the amygdala, which may increase fear consolidation and impair extinction. [Weathington and Cooke, 2012] Sex differences in the corticotropin-releasing factor 1 receptor (CRF1) make noradrenergic neurons in the LC more sensitive in females.

3. Oestrogen and NA – Oestrogen increases NA in LC target regions by enhancing its synthesis and reducing its breakdown. The resulting increased sensitivity of the noradrenergic system underlies hyperarousal. [Weathington and Cooke, 2012]

4. CRF receptor binding – CRF receptor binding is increased in the CA3 region of a female’s hippocampus, which could impair declarative memory and make females more vulnerable to adverse memory effects. [Weathington et al., 2014]

5. CRF-induced changes – Cortical CRF receptors in females are more highly coupled to G-proteins, which activate a cAMP and protein kinase A signalling cascade, leading to many downstream cellular changes. [Iwasaki-Sekino et al., 2009]

6. Amygdala Response: Women show a stronger amygdala response to negative emotions and stress processing. During fear conditioning, there were significantly more significant BOLD-signal changes in the right amygdala, right rostral anterior cingulate (rACC) and dorsal anterior cingulate cortex (dACC) in women compared with men. [Kogler et al., 2016] [Lebron-Milad et al., 2012]

7. Oxytocin (OXT): OXT may also play a role in the stress response and the development of PTSD. OXT increases the amygdala’s reaction to fearful faces and aversive scenes in healthy women. Conversely, it diminishes the amygdala’s responses to infant crying in healthy women. It can alleviate amygdala responses to fearful faces, even in male and female PTSD patients, particularly at higher doses. [Bolea et al., 2018]

Both Estrogen and Progesterone are neurosteroids (neuroactive steroids). there is increasing evidence of the role of neurosteroids in the pathophysiology of mood disorders, including depression, generalised anxiety disorder, bipolar disorder, PTSD, and panic disorder.

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

Zuranolone Improved Depression, Anxiety and Insomnia in Postpartum Depression

Recent evidence also suggests that menstrual cycle-driven hormonal changes impact white matter microstructure and cortical thickness across the entire brain, extending beyond traditional receptor-rich areas. [Rizor et al., 2023]

17 β-estradiol and Luteinising hormone (LH) are linked to diffusion anisotropy (μFA) (Diffusional anisotropy of water protons, induced by nonrandom, directional barriers which hinder or retard water motion) while FSH correlated with cortical thickness.

FSH and progesterone displayed opposing associations with mean diffusivity and cortical thickness in specific regions within the temporal and occipital lobes, affecting the limbic and visual systems.

Progesterone also influences brain tissue and cerebrospinal fluid volumes without altering total brain volume.

Effect of Oestrogen and Progesterone on The Brain:

• Oestrogen receptors ERα and ERβ are widely distributed in the brain, with ERα situated in the hippocampus, hypothalamus, amygdala and brain stem.
• Oestrogen facilitates glutamate transmission and suppresses GABA inhibitory input. This facilitatory effect of estrogen at glutamate NMDA receptors is responsible for plasticity, learning and memory.
• Oestrogen can increase serotonin levels and decrease 5-HT reuptake. Estrogen and progesterone are also known to modify serotonergic responsivity to SSRI administration.
• Oestrogen increases dopamine release in the striatum by reducing the GABAergic inhibitory tone.
• Progesterone, as well as allopregnanolone, interacts with dopaminergic systems. In the striatum, progesterone can stimulate dopamine release only if there has been a preexposure to oestrogen, which could be associated with the observed improvement in sensorimotor functions during phases of the menstrual cycle when progesterone is elevated. [Del Rio, 2018]
• Progesterone suppresses the glutamate response and facilitates GABAergic neurotransmission and, therefore, plays an important part in anxiety and sleep.
• Progesterone can stimulate dopamine release in the striatum but only after prior exposure to oestrogen.
• Progesterone increases serotonergic neurotransmission via the regulation of the expression of serotonin-related genes and proteins.
• Progestogen-only contraceptives are known to reduce oestrogen levels in premenopausal women, which can be associated with depressive symptoms in the general population. In order to preserve and protect natural estrogen levels, estrogenic contraceptives should be preferred over progestogen-only contraceptives.

Evidence indicates that oestrogens have neuroprotective effects relevant to Alzheimer’s Disease (AD) prevention, such as promoting neuron viability and reducing beta-amyloid accumulation, a key factor in AD progression. However, age-related changes may diminish estrogen’s neuroprotective effects, potentially limiting hormone therapy’s utility in older women. Progestogens can modulate estrogen’s effects, with continuous exposure inhibiting estrogen’s effects and cyclic delivery enhancing neuroprotection. [Barron & Pike, 2012]

Is the Oral Contraceptive Pill Associated with Depression?- A Synopsis of The Impact of OC Pills on Mood

Following a traumatic event, women are more susceptible to developing PTSD. Evidence suggests that oestrogen influences the formation and retrieval of fear-related memories, which mediates this risk rather than the type of event, its frequency, or the higher rates of comorbid psychiatric disorders [Olff et al., 2007] [Maddox et al., 2018]

Specific observations include:

• Studies in humans and animals show that oestrogen modulates the expression of fear of extinction. [Milad et al., 2009], [Zeidan et al., 2011], [Milad et al., 2010]
• Women with low oestrogen levels were shown to have impaired fear inhibition compared to women with high oestrogen levels. [Glover et al., 2015]
• Female patients with PTSD were shown to have a correlation between low oestrogen levels and deficits in extinction. [Milad et al., 2010]
• In both healthy women and those with PTSD, low oestrogen has been linked to fear inhibition with the inability to discriminate between danger and safety. [Glover et al., 2013]
• Furthermore, if these women were administered synthetic oestrogen, they had an increase in extinction recall. [Graham and Milad, 2013]
• Oestrogen can increase NA levels by increasing NA synthesis within the LC and reducing NA degradation. As a compensatory mechanism, oestrogen also reduces postsynaptic adrenergic receptors in parallel, thus decreasing the ability of NA to affect downstream structures, thus preventing hyperarousal.
• In PTSD, it is postulated that oestrogen in females may shift the balance towards a high NA state, increasing hyperarousal.

The menstrual phase status of a woman appears to play an important role in the severity of symptoms after trauma. [Nillni et al., 2015]

Since the amygdala and hippocampus contain a significant number of oestrogen (and progesterone receptors), they are susceptible to variations in function and volume across the female menstrual cycle. [Eder-Moreau et al., 2022]

If a female is in the mid-luteal phase during a traumatic event, then they are more likely to experience more trauma-related flashbacks. [Bryant et al., 2011]

We have provided more comprehensive coverage of PMDD and Perimenopausal Depression previously.

Premenstrual dysphoric disorder (PMDD):

Approximately 20% of females are affected by premenstrual syndrome (PMS), which describes a cluster of affective and somatic symptoms that occurs during the luteal phase and then decreases as menstruation begins.

PMDD is a more severe form of PMS that results in significant distress and affects approximately 3-8% of females. Symptoms include a more defined set of physical and psychological symptoms, including anger, irritability, fatigue, sleep disturbances, and mood swings.

One of the postulated pathophysiological mechanisms of PMDD is related to cyclical changes in gonadal hormone secretion during the menstrual cycle. [Lovick et al., 2017]

In PMDD, a recent study found that SERT density was significantly increased in the midbrain dorsal raphe nucleus (DRN), a critical brain region involved in regulating mood and emotion, compared to controls.

The increase in midbrain SERT density with increased central serotonergic uptake followed by extracellular serotonin loss was correlated with depressive symptom severity across the menstrual cycle. [Sacher et al., 2023]

This suggests that the brain’s response to endogenous hormonal changes rather than the dysregulated hormones in the periphery is the underlying aetiological factor of the disorder.

This increase in SERT density was only observed in the menstrual cycle’s late luteal phase, when oestradiol and progesterone are decreasing, and not in the periovulatory phase when oestradiol levels are high. [Sacher et al., 2023]

Diagnosis and Management of Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD)- A Synopsis

Perimenopausal Depression:

Women experiencing menopause are at greater risk of developing depression and major depressive episodes.

Problematic menopause affects approximately 1.5 million women every year, and symptoms often overlap with psychiatric symptoms, making accurate diagnosis and treatment difficult. [Cohen et al., 2006], [Maki et al., 2018]

Important Points: 

• Women experiencing perimenopausal depression complain about physical symptoms more than cognitive symptoms, which are not typically included in scales assessing for major depressive disorder, leading to an underdiagnosis or missed diagnosis.
• Most women do not experience significant mental ill health during the transition to menopause. Nonetheless, an estimated 20% of perimenopausal women will present to their primary healthcare physicians with depressive symptoms that may not be explicitly recognised as ‘perimenopausal depression’.
• The most common perimenopausal physical complaints are irritability (45%), headache (39.8%), body aches (34.3%), sleep disturbance (33.3%) and joint pains (35%). [Jagtap et al., 2016]

Perimenopausal Depression – A Review of Diagnosis and Management

BPAD and Female expression:

Dell’Osso et al. investigated gender-related differences in the prevalence of bipolar disorder. They consistently found a higher preponderance of female patients in every sample and sub-sample of both BD-I and BD-II, which supported their hypothesis of an increased diagnosis of bipolar disorder in women.

Furthermore, their analysis revealed that women with bipolar disorder displayed higher rates of rapid cycling, depressive episodes, and suicide attempts, highlighting the distinct clinical features of bipolar disorder in females. [Dell’Osso et al., 2021] [Arnold, 2003]

Essential points for Clinicians:

• Women with bipolar disorder frequently experience depressive episodes, mixed mania, and rapid cycling.
• Comorbid medical and psychiatric disorders are more common in women, which can impact their recovery.
• Specific comorbidities like thyroid disease, migraine, obesity, and anxiety disorders are more prevalent in women, while substance use disorders are more common in men.
• There’s no evidence suggesting that gender affects treatment response to mood stabilisers in bipolar disorder.
• Clinicians should be vigilant about the possibility of a bipolar diathesis in women presenting with their first depressive episode.

Another study showed notable sex differences include a higher severity of mania in women and a greater likelihood of men experiencing affective episodes with mixed features. Contrary to the previous evidence, no significant sex differences were observed in suicidality, comorbid substance use disorders, rapid cycling, polarity, and age at onset. [Menculini et al., 2022]

PCOS is a common endocrine disorder, affecting 5.6–21.3% of women of reproductive age globally.

Women with PCOS are at increased risk for various health issues, including hypertension, dyslipidaemia, insulin resistance, type 2 diabetes, coagulation disorders, and cardiovascular problems.

Patients with PCOS show a greater incidence of hypothyroidism and a higher level of anti-thyroid peroxidase antibodies compared to women without PCOS. High-density lipoprotein (HDL) cholesterol was substantially higher in hypothyroid PCOS patients than in non-hypothyroid individuals, although no significant changes were observed in other metabolic markers. [Bonakdaran et al, 2023].

According to previous studies, 56.9% of women with PCOS have at least one psychiatric disorder. [Hung et al., 2014]

PCOS is highly comorbid with the following conditions:

• Depression
• Anxiety
• Bipolar disorder
• Schizophrenia spectrum disorder
• Eating disorders
• OCD
• Personality disorders
• Sleep disorders

It is also associated with worse symptoms of depression, anxiety, OCD, and somatisation. [Brutocao et al., 2018]

While studies have shown women with PCOS have higher ADHD symptoms, no correlations between ADHD symptoms and serum hormone levels, including testosterone in women with PCOS, have been identified. [Hergüner et al, 2015]

Emerging evidence suggests an increased risk of ADHD in offspring, especially boys with maternal PCOS. [Zhang et al., 2023]

Another nationwide cohort study reinforced the increased risk of depressive, anxiety, and sleep disorders among PCOS patients, but the risk of newly diagnosed bipolar disorders was not significantly elevated.

PCOS patients have a heightened risk of developing new-onset sleep disorders, potentially due to two key factors:

• Higher prevalence of obstructive sleep apnoea (OSA)
• Elevated night-time urinary melatonin levels (irrespective of OSA) can negatively impact sleep quality. [Hung et al., 2014]
• Elevated melatonin levels in females with PCOS may result from androgen excess, and the administration of supraphysiological melatonin levels (2 mg/day for six months) has been shown to reduce testosterone levels and improve menstrual irregularities. [Fernandez et al., 2018]
• Additionally, HPA axis dysfunction affects sleep quality, leading to increased fragmentation, decreased slow-wave sleep, and shorter sleep duration. [Buckley and Schatzberg, 2005]
• However, sleep dysfunction itself leads to elevated cortisol, underpinning a bi-directional relationship. [Garde et al., 2012]
• Psychosocial and lifestyle factors.
• Adolescent girls receiving metformin treatment for PCOS reported a decrease in sleep disturbances and daytime sleepiness. However, it remains challenging to differentiate the impact of improved insulin resistance from the simultaneous reductions in BMI and hyperandrogenemia on these outcomes. [El-Sharkawy et al., 2014]

Multidimensional treatment, including treatment to improve sleep, may improve metabolic function and could potentially prevent long-term cardiometabolic sequelae for these women.

Depression and the Female Expression: [Romanescu et al., 2022]

Evidence from both preclinical and clinical studies indicates that the presentation and response to depression treatment may differ based on gender, with differences in the serotonin, dopamine, and noradrenaline systems.

Females tend to respond better to serotonergic antidepressants than males, and postmenopausal females may have a diminished response to antidepressants compared to premenopausal females.

Following are the neurobiological findings in females with depression:

• Positron Emission Tomography (PET) shows that females show a more significant reduction in serotonin synthesis after tryptophan depletion.
• Women tend to have higher levels of serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), which may be attributed to the greater availability of the serotonin transporter.
• The serotonin 5-HT1A receptor subtype exhibits reduced binding potential with age in men but not women. This receptor subtype has been linked to the pathogenesis of depression.
• Age-related changes in brain levels of serotonin and norepinephrine appear to be more pronounced in females when compared to males.
• Research into monoamine oxidase, specifically platelet monoamine oxidase, indicates a significant increase in females compared to males. [Veral et al., 1997]
• Women tend to exhibit a higher concentration of synaptic dopamine in the striatum than men, with age-related decreases in synaptic dopamine levels appearing more prominent in men.
• Differences between the D1-D2 heteromer function within the NAc and striatum may increase female vulnerability to developing depression- and/or anxiety-like behaviour. [Williams et al., 2021]

Clinical differences: [Sloan and Sandt, 2006]

• Women are more likely to experience atypical depression symptoms, greater severity, earlier onset, and longer-lasting depressive episodes.
• Atypical symptoms correlate with increased depression severity and comorbidity, particularly a higher likelihood of comorbid anxiety in women.
• Women are also more likely to exhibit prototypical depressive symptoms, such as depressed mood, feelings of guilt or worthlessness, anxiety, psychomotor retardation, somatic concerns, and increased crying. At the same time, men are more likely to manifest depression with symptoms of anger.
• Women are more likely to experience increased appetite and weight gain (cf., Men are more likely to report decreased appetite, weight loss, and insomnia).
• Depressed women have a higher likelihood of comorbidities like anxiety and eating disorders, whereas depressed men are more prone to alcohol and substance abuse disorders.
• Regarding medical comorbidity, depressed women are more likely to present with conditions such as thyroid disease, migraine headaches, chronic fatigue syndrome, and fibromyalgia compared to depressed men.

BPAD and Female expression:

There is a higher preponderance of female patients in samples of Bipolar Disorder I and II (BDI and BDII), pointing to an increased diagnosis of bipolar disorder in women. [Dell’Osso et al., 2021]

Clinical Differences: 

• Women with bipolar disorder show higher rates of rapid cycling, mixed mania, depressive episodes, and suicide attempts. [Dell’Osso et al., 2021] [Arnold, 2003]
• Another study, however, showed no significant sex differences related to suicidality, comorbid substance use disorders, rapid cycling, polarity, and age at onset in bipolar disorder. [Menculini et al., 2022]
• Women experience a higher severity of mania ( cf. men experiencing affective episodes with mixed features). [Menculini et al., 2022]
• Comorbid medical and psychiatric disorders are more common in women.
• Specific comorbidities like thyroid disease, migraine, obesity, and anxiety disorders are more prevalent in women, while substance use disorders are more common in men.
• Clinicians should be vigilant about the possibility of a bipolar diathesis in women presenting with their first depressive episode.
• Current evidence also suggests a worse treatment response to anticonvulsants in bipolar disorder in females. [Menculini et al., 2022]

Schizophrenia displays gender differences, with a higher incidence in men at around a 1.4:1 ratio compared to women, although some studies don’t find significant lifetime prevalence variations. [Li et al., 2022]

Onset typically occurs earlier in males, with symptoms emerging 3.2–4.1 years before females. Different susceptibility patterns are observed across life stages:

• Men under 40 show a higher prevalence, peaking between 20 and 29 years.
• Women exhibit increased prevalence after 40, with two peaks between 20-39 years and during perimenopause.

Women’s physiologically higher oestrogen levels, while potentially leading to a slightly lower overall incidence of schizophrenia, also delay the age of onset.

The increased prevalence in older women may be linked to declining oestrogen levels, which are considered protective against schizophrenia development.

Oestrogens and Schizophrenia Spectrum Disorders:

The role of oestrogens, notably 17-β-oestradiol, in schizophrenia spectrum disorders is increasingly recognised. These hormones influence brain development and functioning, contributing to the gender-related disparities observed.

Oestrogens have direct neuroprotective actions by decreasing neuro-inflammation, promoting synaptic plasticity, and influencing dopamine signalling.

Oestrogens play an essential role in the pathophysiology of schizophrenia by:

• Modulating dopamine sensitivity of dopamine D2/D3 receptors in the ventral tegmental area (VTA), which is part of the mesolimbic (associated with positive symptoms) and the mesocortical pathway (associated with negative and cognitive symptoms)
• Modulating COMT expression: Since oestrogens inhibit COMT gene transcription, oestrogen deficiency can increase COMT activity and decrease dopaminergic functioning. [Brand et al., 2021]
• Promoting synaptic plasticity
• Decreasing neuroinflammation

After menopause, when oestrogen levels decline, a second peak of onset is observed, accompanied by more severe symptomatology in women. [Riecher-Rössler et al., 2018]

The fluctuation in oestrogen levels further complicates the symptom profile in women with conditions like polycystic ovary syndrome (PCOS), rendering them more susceptible to psychosis.

Recent studies underscore the role of time since menopause in influencing antipsychotic response, emphasising the significance of hormonal fluctuations. [González-Rodríguez et al., 2020]

Gender-Based Symptomatology in Schizophrenia:

Women often experience affective symptoms, including depression, and exhibit specific psychotic symptoms like paranoia, while men show more significant negative symptoms, such as social withdrawal and blunted affect.  [Riecher-Rössler et al, 2018]

Women have more frequent comorbid depression, more frequent mania, more self-harm and more suicide attempts, together with the higher use of antidepressants, mood stabilisers and sedatives, indicating that the female trajectory of schizophrenia is, on average, more towards the bipolar spectrum as compared to men. [Sommer et al., 2020]

Some consider schizoaffective disorder to represent ‘the more female form of schizophrenia’. [Sommer et al., 2020]

An intriguing aspect of gender-based differences is the variation in self-perceived signs of the disease.

Men typically report noticing negative and cognitive symptoms initially, while women more frequently detect subthreshold positive and affective symptoms at the onset.

Moreover, studies have illuminated alterations in the sexual dimorphism of the healthy brain in the context of schizophrenic psychoses, further underscoring the intricate interplay between gender and symptomatology. [Riecher-Rössler et al, 2018]

Given the prevalent affective symptoms in women with schizophrenia, oestrogenic contraceptives (e.g. ethinylestradiol) or combined contraceptives (e.g. ethinylestradiol/levonorgestrel) should be preferred over progestogen-only contraception until further research has been done regarding the potential risks and benefits of contraceptive use in schizophrenia. [Brand et al., 2021]

Comorbidities and Treatment Response: 

• Women exhibit a distinct pattern of comorbidities in the context of schizophrenia.
• Depression, anxiety, and eating disorders are more common among women, while men tend to have higher rates of alcohol and substance abuse disorders. This comorbidity profile profoundly impacts treatment approaches, with women more frequently utilising antidepressants, mood stabilisers, and sedatives. [Sloan and Sandt, 2006]
• The odds of using antidepressants and mood-stabilising medication were about 40% higher in women.
• The use of benzodiazepine and zopiclone/zolpidem was significantly higher in women. [Sloan and Sandt, 2006]

Impact of Antipsychotic Medications:

• Antipsychotic medications introduce unique challenges for women with schizophrenia.
• These medications can contribute to menstrual irregularities and amenorrhea, primarily through hyperprolactinemia.
• The associated fertility implications further underscore the need for gender-tailored approaches in treatment. [Riecher-Rössler et al, 2018]
• Side effects of antipsychotic medications can affect personal appearance. Weight gain, hirsutism, acne, dental issues, and other adverse effects can further complicate their mental health journey. [González-Rodríguez et al., 2020]
• Estrogens directly impact antipsychotic drugs, particularly clozapine and olanzapine, by inhibiting the activity of CYP1A2, resulting in higher drug levels in the bloodstream.
• Due to sex differences in CYP enzyme activity and D2 receptor occupancy, women, on average, require lower doses of olanzapine (approximately half) and clozapine than men to achieve equal occupancy of the dopamine D2 receptor. [Sommer et al., 2020]

Specific Considerations in Treatment :

Oestrogens increase the sensitivity of dopamine D2 receptors, and thus, they augment the efficacy of (D2-receptor binding) antipsychotics.

To minimise the risk of oestrogen deficiency, prolactin-sparing antipsychotics (e.g., partial agonists aripiprazole, brexpiprazole, cariprazine) are preferred, especially in premenopausal women, as they are more susceptible to oestrogen deficiency following hyperprolactinemia.

Premenopausal women generally require lower drug dosages than men and postmenopausal women, whereas women may require slight increases in their dose to prevent relapse of symptoms during low estrogenic phases. [Brzezinski-Sinai & Brzezinski, 2020]

Selective estrogen receptor modulators (SERM), such as raloxifene, have been effectively added to standard treatment to reduce symptom severity. [Huerta-Ramos et al., 2019]

There is evidence for the efficacy of raloxifene in reducing symptoms in postmenopausal women with schizophrenia. [Brand et al., 2020]

A meta-analysis showed that oestradiol and raloxifene are effective and safe adjunctive treatments that improve schizophrenia symptoms in women with specific benefits on negative symptoms and working memory. [Bodyl et al., 2023]

Moreover, the effects of oestradiol and raloxifene differed in timing and dosage. [Li et al., 2023]

A recent study supports the identification of hormonal phenotypes among women with schizophrenia, suggesting that it may help to improve existing treatments and implement personalised medicine strategies that address the heterogeneity seen in schizophrenia. [Thomas et al., 2019]

Elevated prolactin (PRL) is common in individuals undergoing treatment with antipsychotic medications, with a higher prevalence among women.

84% of patients experiencing prolactin-related adverse effects are women. [Brugnoli et al., 2012]

PRL responses to antipsychotics are greater in females than in males due to the ability of estrogens to elevate serum PRL levels and enhance responsiveness to PRL-releasing stimuli.

Oestrogens increase the number of lactotrophic cells in the anterior pituitary and act on the hypothalamus to decrease dopamine. [Peuskens et al., 2014]

Thus, post-pubertal girls may be more sensitive to hyperprolactinemia.

Effects of Hyperprolactinaemia: 

Elevated prolactin levels are associated with various adverse effects, including amenorrhea, oligomenorrhea, galactorrhea, and gynecomastia in females, as well as sexual dysfunction and increased risk of bone loss. These side effects not only raise the risk of nonadherence to antipsychotic treatment but also contribute to a heightened risk of suicide. [Kelly et al., 2013]

Psychiatric impact of hyperprolactinaemia: 

• Exacerbation of psychosis
• Impulse control disorders
• Sleep attacks
• Metabolic effects
• Valvular heart disease

Recent research has shed light on the relationship between prolactin-related effects and an increased risk of suicide. [Brugnoli et al., 2012]

• Amenorrhea elevates the risk of suicide by 64%
• Galactorrhea and gynecomastia increase the risk by 163% and 200%, respectively.

Reference Serum Prolactin Levels: [Conversion: ng/ml × 21.2 converts to mIU/l; ng/ml × 43.478 converts to pmol/l.  ng/ml × 0.043 converts to nmol/l]

• Men: 210–420 mIU/L (approximately 10–20 ng/mL)
• Women: 210–530 mIU/L (approximately 10–25 ng/mL)

1. Prolactin levels between 657 and 1060 mIU/L (30.9–49.8 ng/mL): Reduced libido.
2. Prolactin Levels between 1081 and 1590 mIU/L (50.8–74.7 ng/mL): Oligomenorrhea
3. Prolactin levels >2120 mIU/L (99.6 ng/mL): Hypogonadism and menstrual dysfunction, including amenorrhea and galactorrhea.

Elevated prolactin (PRL) levels are linked to D2 receptor (D2R) antagonism in the anterior pituitary lactotroph cells.

Since the pituitary gland is located outside the blood-brain barrier (BBB), antipsychotic medications, such as amisulpride, risperidone, and paliperidone, have a limited ability to penetrate the BBB barrier, leading to a higher occupancy of D2R in the pituitary region at therapeutic doses.

Consequently, this increased D2R occupancy results in a more significant increase in PRL levels.

Amisulpride, in particular, exhibits a marked tendency to raise PRL values due to its reduced penetration of the blood-brain barrier. [Peuskens et al., 2014]

Antipsychotics with the highest risk of elevating PRL: 

• Paliperidone
• Risperidone
• Amisulpride
• Haloperidol

Prolactin Sparing Antipsychotics: 

• Aripiprazole
• Brexpiprazole
• Cariprazine
• Quetiapine

Recent pharmacovigilance studies have shown a higher proportion of pituitary tumours associated with risperidone compared to other available antipsychotics. [Szarfman et al., 2006]

Two epidemiological studies have found an association between the use of prolactin-elevating antipsychotics and breast cancer in women with schizophrenia and other psychotic disorders.

While the risk of breast cancer with prolactin-elevating antipsychotics reported in these studies varies, with some indicating disconcertingly high risks of up to 62%, further research is needed to clarify the true risk of breast cancer with prolactin-elevating antipsychotics.  [Hope et al.,  2023 ]

[Bölte et al., 2023]

Sex hormones play a significant role in shaping neurodevelopment. They impact neurotransmitter systems, neural differentiation, and synapse formation during critical developmental windows, including mid-gestation, shortly after birth, and around puberty.

In conditions like ADHD, sex hormones can alter intracellular signalling pathways. Furthermore, these hormones impact hypothalamic structure and function, which exhibit sex differences and may hold importance in conditions like Tourette syndrome.

Some of the essential differences identified are:

• Variations in dopamine receptor distributions
• Distinct regional glutamate levels in various brain regions in females
• Females may need to reach a higher threshold of genetic and environmental exposures for ADHD to be expressed (Female Protective Hypothesis)

Read the summary of the gender differences in neurodevelopment.

Attention Deficit Hyperactivity Disorder (ADHD) in Females – Gender Differences in Neurobiology, Assessment & Management

In children and adolescents with ADHD, girls responded less favourably to dexamphetamine than boys (51% favourable response in females vs 78.8% in males). [Kok et al., 2020]

Higher oestrogen and lower levels of progesterone are associated with greater subjective stimulation after amphetamine in women, and these hormonal influences contribute to sex differences in response to amphetamine. Thus, dose adjustments may be needed depending on the phases of the menstrual cycle. [White et al., 2002]

Women exhibit a more significant reduction in striatal dopamine release in response to amphetamines compared to men. [Del Río et al., 2018]

Anecdotal accounts of ADHD symptom exacerbation in women during the post-menopausal period have been reported, and the use of hormone replacement therapy may be beneficial. [Young et al., 2020]

Females exhibited more significant dopamine increases in the ventral striatum (Nucleus Accumbens (NAc)) in response to methylphenidate, suggesting that females are more sensitive to the dopamine reward system than males.

This discrepancy in methylphenidate-induced dopamine increases in the Nucleus Accumbens (NAc) may contribute to females’ increased susceptibility to drug conditioning and addiction. [Manza et al., 2022]

[Sramek et al., 2022]

Women exhibit adverse reactions to medications almost twice as frequently as men do, and adverse reactions are often more intense in women than in men. This phenomenon can be attributed to differences in pharmacokinetics, which sometimes result in the inadvertent overmedication of women.

Differential effects between the sexes have been found in the effectiveness, side effect profile and pharmacokinetics of psychotropic drugs.

As an example, zolpidem, one of the most widely prescribed drugs for insomnia, is known to have lower clearance in women, and the Food and Drug Administration (FDA) recommends different doses for men and women.

Pharmacokinetic Gender Disparities: [Soldin et al., 2011]

Gastric and Intestinal Factors on Drug Absorption:

• Gastric acidity levels are generally lower in women compared to men.
• Gastric emptying time and intestinal transit time tend to be slower in women.
• The composition of bile acid, influencing drug solubility, exhibits gender-based variations.
• When these combined effects are considered, women tend to show more thorough drug absorption compared to men.

Lipophilic Drug Accumulation:

• Women’s bodies contain a higher proportion of adipose tissue than men, leading to a longer half-life for these drugs and an increased risk of elevated drug concentrations if significant weight loss occurs.
• Ceasing lipophilic drugs, such as antipsychotics (APs), may result in a more rapid symptom relapse in men due to their smaller adipose tissue stores, as opposed to women.
• For individuals receiving depot injections, the intervals between injections can be safely extended.
• Evidence suggests extending intervals between depot injections is safe and offers several potential benefits. These include reduced injection frequency for patients, lessening the physical health burdens of antipsychotics, and granting clinicians more control over dosing and frequency adaptability. [O’Neill et al., 2023]
• Reducing antipsychotic doses by 25% to 40% of the most recent dosage every six months in stable, chronic psychotic disorder patients generally does not lead to relapse, as per recent studies. [Liu & Takeuchi, 2020]. 

Plasma Protein Binding:

• Women generally exhibit a lower capacity for plasma protein binding, resulting in a higher fraction of free drug circulating in their bloodstream.
• This increased availability of free drugs can lead to greater drug interactions at relevant neuroreceptor sites.

Renal Excretion:

• Glomerular filtration is slower in women than in men.

Hepatic Clearance:

• Women have lower hepatic blood flow.
• P-glycoprotein, regulating the biliary excretion of certain drugs, is present in lower amounts in women than in men.

Cytochrome P450 (CYP) Enzymes:

• CYP3A4 exhibits higher activity in women of reproductive age.
• This higher activity can lead to potentially lower drug concentrations in women than in men when prescribed the same dose.
• Additionally, CYP3A4 activity differs across ethnicities and within different female populations.
• CYP1A2 activity may be lower in women compared to men.

Oestrogen and Phase 2 Glucuronidation:

• Oestrogen influences phase 2 glucuronidation and UDP glucuronosyl transferases (UGTs), which are involved in drug metabolism.
• Since lamotrigine excretion is influenced by phase 2 glucuronidation, OCPs can interfere with lamotrigine excretion. Dose adjustments may be needed.
• Lamotrigine and the Oral Contraceptive Pill – Are Dose Adjustments Needed?
• The net effect of oestrogen-related influences is an increase in the amount of free drug that reaches the brain in women compared to men.

[Sommer et al., 2025].

Menopause introduces a distinct phase in a woman’s life where oestrogen and progesterone levels drop significantly, contributing to complex changes in pharmacokinetics and drug response. These hormonal shifts may interact with previously established sex-based pharmacokinetic patterns, requiring nuanced adjustments in prescribing practice.

Impact on Drug Absorption and Transport

• Decreased oestrogen levels can reduce gastric acid production and alter p-glycoprotein activity, both of which influence drug absorption and efflux.
• Changes in plasma protein levels may further affect the free fraction of drugs.

Cytochrome P450 Enzymes

CYP3A4:

• Oestrogen upregulates CYP3A4.
• Postmenopausal decline in oestrogen is associated with reduced CYP3A4 activity, potentially resulting in higher plasma levels and increased risk of toxicity for medications metabolised by this enzyme (e.g., quetiapine, tacrolimus, midazolam).

CYP1A2:

• Activity increases post-menopause due to the removal of oestrogenic inhibition, potentially reducing the efficacy of medications metabolised by this pathway (e.g., olanzapine).

Phase II Metabolism (UGT Enzymes)

• Reduced oestrogen levels may lower UGT activity, leading to decreased clearance of drugs like lamotrigine, increasing the potential for toxicity.

Empirical Evidence of Menopausal Impact

Postmenopausal women exhibit:

• Reduced clearance of CYP3A4 substrates (e.g., alfentanil, midazolam, tacrolimus).
• Increased plasma concentrations of psychotropics and other commonly prescribed agents.
• Altered lamotrigine metabolism through glucuronidation, even in the absence of OCPs.

Clinical Implications

• Menopausal status should be considered independently from chronological age when making pharmacotherapy decisions.
• Drug levels may either increase (due to reduced metabolism) or decrease (due to enzyme disinhibition), depending on the metabolic pathway involved.
• Regular monitoring, dose reassessment, and awareness of hormonal transitions are critical to optimising treatment in midlife and older women.

This article highlights the complex landscape of female-specific psychiatric factors and their vital impact on clinical practice and psychopharmacology.

Understanding the interplay of hormonal influences, drug metabolism, and pharmacological factors is crucial for tailoring treatments to women’s unique needs.

This underscores the importance of gender-sensitive approaches in psychiatric practice and the need for further research to advance personalised treatments, ultimately improving women’s mental well-being.

Clinicians and researchers armed with these insights are better equipped to navigate the dynamic field of women’s psychiatric health, benefiting countless individuals.