This report highlights the potential role of psychotropic medications in contributing to the development of gender dysphoric delusions. In our case, the patient experienced side effects—specifically amenorrhea and hirsutism—linked to treatment with paliperidone and sodium valproate. These adverse effects led her to discontinue the medications, which precipitated a manic relapse with psychotic features. Following this relapse, she developed a gender dysphoric delusion, believing herself to be half female and half male. She used the physical changes from the medications as evidence to support and reinforce this belief. Additional psychotic symptoms subsequently emerged, including delusions of reference and religious delusions of being a religious prophet. Her behaviour also shifted significantly: she responded only to the name associated with her delusional gender identity, dressed in male clothing, adopted a male voice, and requested gender affirming surgery.

However, alternative explanations should also be considered. Gender dysphoric delusions may arise as part of broader psychopathology associated with psychiatric disorders such as bipolar disorder or schizophrenia. It is possible that the delusions observed in this case were intrinsic to the patient’s underlying illness and would have emerged independently of treatment with paliperidone and sodium valproate. The discontinuation of medication may have simply triggered a sixth manic episode, within which these new symptoms manifested. Additionally, the gender dysphoric delusion may represent a systematization of earlier grandiose or religious delusions—features present in her previous episodes. Notably, she did not merely identify as a generic male but as a powerful religious entity and responded only to that figure’s name. This supports an interpretation of the gender dysphoric delusion as part of a larger grandiose delusional framework. It is also possible that these symptoms were resistant to her prior treatments and only responded to clozapine. Alternatively, had the original psychotropics been continued, the symptoms might have resolved—though this was not a viable option due to the emergence of significant adverse effects.

Possible mechanisms for the association between gender identity and psychosis

At least five mechanisms have been proposed to explain the association between gender identity and psychosis: (1) Identity problems acting as a stressor triggering the onset of psychotic symptoms: This can be explained within the framework of the ‘diathesis-stress’ model, where identity problems resulting from the negative impact of the family environment constitute a stressor that triggers symptoms in vulnerable individuals [6]; (2) Identity problems occurring because of psychosis: here the individual with psychosis perceives reality in a distorted way, including for their own self-image [6]. (3) A common neurobiological basis for both psychosis and gender dysphoria: here both conditions are considered neurodevelopmental disorders in which there are reduced levels of brain-derived neurotrophic factor, along with changes in brain lateralization, gender dimorphism and levels of sex hormones in the prenatal period [18, 19]; (4) The influence of psychosis-specific deficits on gender identity: where gender identity problems in psychosis may be affected by cognitive, emotional and social deficits in the pre-psychotic stage, influencing construction of the self-image, including for the individual’s gender identity [6, 18]. (5) Sexual dimorphism in schizophrenia: where sex differences in brain function in schizophrenia have found disturbances of normal sexual dimorphism during emotional and cognitive processing which can be partly accounted for by altered levels of sex steroid hormones such as estrogen and testosterone [20,21,22]. In the case of our patient, the second association seems to be the most likely mechanism where due to the development of psychosis, her perception of her reality became distorted, including for her own gender-identity.

Psychosis-associated gender change and its implications

Gender dysphoric delusions are reported to occur in about 20–25% of patients with schizophrenia with four possible variants having been identified [9]: (1) delusions of not belonging to one’s own gender; (2) delusions of not belonging to either gender; (3) delusions of simultaneously belonging to both genders; and (4) delusions of belonging to the opposite gender, which has received the most attention and been the focus of controversies about the relationship between gender dysphoria and psychosis, partly due to the issue of gender affirming surgery. Our case seems to have experienced the third and fourth variants at chronologically different times. In the case of our patient, her gender dysphoric delusion initially conformed to the third variant (delusions of simultaneously belonging to both genders), yet as her symptoms progressed, they seemed to transform towards the fourth variant (delusions of belonging to the opposite gender) as evidenced by her adopting a male name, voice, clothes and request for reassignment surgery to be changed into a male.

Symptoms of gender dysphoric delusions are more frequently reported during periods of exacerbation of the illness in unmarried males, but do not seem to be related to age, duration of illness or the type of schizophrenia and may be accompanied by genital sensory hallucinations in the form of simple burning sensations or the feeling that people are invisibly masturbating or intending intercourse with the patient [9]. It is estimated that between 30 and 36% of patients with schizophrenia report experiencing hallucinations related to their genitals [6], and in chronic patients hospitalized with schizophrenia-spectrum disorders, lifetime prevalences of sexual hallucinations reach up to 44%, where hallucinations may occur in any sensory modality either separately or concurrently, ranging from hallucinatory whispers with a sexual content to compound personifications carrying out sexual acts. Alternatively, the hallucinations may constitute “projections” perceived outside oneself, either in three-dimensional space or as if projected on a screen [23]. In the case of our patient, delusions seemed to have occurred without any associated genital/sexual hallucinations or somatic delusions of transformation of her internal or external organs.

While gender dysphoric delusions are most frequently associated with psychiatric disorders, they have also been reported in neurological disorders such as epilepsy [23] and even in cases where there are underlying structural abnormalities of the brain. For example, Kasper et al. [24] described the case of a woman who experienced an ego-dystonic gender transformation concomitant with epileptic seizures secondary to a cystic lesion in the right nucleus amygdalae. The alterations described by this woman entailed hairy arms, a deep voice, the conviction that she had turned into a man (with coenesthetic sexual hallucinations).

The implications of failing to distinguish between psychosis and actual gender dysphoria can have serious consequences. In an analysis of individuals mutilating their peri-genital areas, it was found that 49% of them were diagnosed as having a psychotic-spectrum disorder such as schizophrenia and more frequently performed penile self-amputation in comparison to subjects with non-psychotic disorders [25]. The failure of proper differentiation may also expose patients with psychosis to far-reaching and irreversible changes. There have been reports of misdiagnoses of gender dysphoria in men with psychosis, resulting in inappropriate administration of sex hormones causing, among other things, genital atrophy and breast growth [8], and even undergoing gender affirming surgery with one patient later regretting having undergone surgery and expressing a desire to become a man again [9]. This differentiation should not only be restricted to individuals with schizophrenia. Gender dysphoria beliefs in the context of bipolar disorder are far less frequently described in the literature than in schizophrenia-spectrum disorders and may be missed or overlooked, which can also have a significant bearing on outcomes. Zahoor et al. [26] described three cases of bipolar patients reporting gender dysphoric beliefs of wanting to be of the opposite gender occurring in the context of mania, and which improved on treatment of the manic episode, stressing the need for proper assessment of gender dysphoria beliefs and not merely brushing aside them as “just another symptom” [26]. Similarly, delays in correctly diagnosing actual gender dysphoria can lead to delays in accessing treatments with every year of delay in accessing gender-affirming care increasing the risk of suicidal ideation and suicide attempts [27], while gender-affirming treatment with hormones and surgery is associated with reduced suicide attempts over time [28, 29].

Role of psychotropics in gender delusions

Jakubowski [5] summarized the impact of antipsychotics on patients with gender delusions, as following one of three trajectories. First, is the disappearance of gender incongruence, suggesting that it is a true delusion. Second, is the partial reduction of gender incongruence, suggesting that it is either gender dysphoria co-occurring with psychosis or a true delusion that has been partially responsive to antipsychotic treatment. Third, is the maintenance of gender incongruence at a constant level, suggesting that it is either gender dysphoria co-occurring with psychosis or a true delusion that has been non-responsive to antipsychotic treatment. Our case might have followed any of these three trajectories. Given the eventual resolution of symptoms on clozapine, the first trajectory is a possibility, while the use of clozapine suggests treatment-resistant delusions, and the possibility of the second or third trajectories.

Regarding the role of sodium valproate in the development of these side effects, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) reported that within the first year of treatment, 10.5% of women taking sodium valproate manifest hirsutism, acne, or elevated testosterone as a result of developing oligomenorrhea accompanied by hyperandrogenism, compared to only 1.4% of women on other mood stabilizers, such as lithium or lamotrigine [30].

Amenorrhea due to paliperidone develops mainly because of paliperidone-induced hyperprolactinemia, which was evident in our patient who had elevated serum prolactin. The incidence of amenorrhea among patients receiving paliperidone varies across studies ranging from as low as 0.9% in chronically ill subjects and 3.2% of recently diagnosed subjects receiving once-monthly injections [31, 32], to 4% in a long-term 52-week open label study of oral paliperidone extended release [33], to as high as 15.6% in a short-term 8-week open label study also involving oral paliperidone extended release [34]. However, it should be noted that not every elevated prolactin reading is an indication that it is a persistent problem or will lead to clinical signs and symptoms (including menstrual disturbances), and may just be an elevated reading measured during a peak because of the pulsatile manner in which prolactin is normally secreted, leading to diurnal fluctuations in prolactin levels [35].

The primary mechanism by which antipsychotics affect the release of prolactin is by acting as an inhibitor of prolactin secretion via dopamine D2 antagonism in a dose-dependent manner [36]. An additional mechanism for increased prolactin is possibly hypothalamic serotonin 5-HT-2 agonism [37]. Regarding the role of prolactin in the development of delusions, Ali et al. [38] suggest that the association between elevated prolactin and the occurrence of delusions is not necessarily a cause-and-effect relationship, as there is no increase in the incidence of psychotic symptoms in psychiatrically healthy pregnant women who have naturally occurring elevated prolactin in their pregnant state. Some authors even contend that pregnancy may be protective in certain psychiatric disorders [39].

In conclusion, our case was unique for two reasons. First, it is the first to report on the role of psychotropic-associated side effects in the development of gender dysphoric delusions. Second, the patient initially presented with delusions of belonging to both genders and then transformed into delusions of belonging to the opposite gender, which is the first report of the same patient experiencing two different types of gender dysphoric delusions at different times. This adds to the literature on gender identity in schizophrenia and highlights the importance of monitoring reproductive endocrine function in women of reproductive age who are prescribed psychotropics.