Gender Trends in Psychotropic Medication Use in Autism

Autism is a neurodevelopmental condition that includes differences in social communication and restrictive, repetitive behavior. Its diagnosis is far more common in men than women. Therefore, a female phenotype of autism might not concern caregivers or be detected early by clinical assessments. Given that medications address problematic behaviors rather than autism, different problems associated with autism necessitate other treatments. We reviewed existing literature on gender differences in psychotropic drug usage in autism patients and found that antidepressants, anticonvulsants, and mood stabilizers were more common in females, while stimulants and antipsychotics were predominant in males. This review highlights that autistic men and women receive different pharmacologic agents, likely attributable to gender-specific trends in presenting problematic behaviors.


Introduction And Background
Autism is a neurodevelopmental condition that includes differences in social communication and restrictive, repetitive behavior. According to the Centers for Disease Control and Prevention, one in 54 children has autism. Moreover, it is 4.3 times more prevalent in males than females [1]. Although the complete explanation for the male predominance is unclear, the difference may be partly due to innate physiologic sex differences. A complementary reason for the male predominance is that autistic women present differently than autistic men. Autistic women are more likely to have an intellectual disability (intelligence quotient (IQ) ≤70) compared to their male counterparts, 39% versus 32%, respectively [1].
prescribing a wide range of psychotropic medications. Understanding these prescription patterns can advance our understanding of these different patterns of autism and lead to better treatment and symptom management. Therefore, this review aimed to identify the gender-specific trends in psychotropic medication usage in autism management. We primarily focused on evaluating whether autistic men and women are recipients of different psychotropic medications and whether this gender difference in using specific categories of medicines sheds light on the female phenotype of autism.

Literature search and study selection
We conducted a literature search from July 2021 through January 2022, following the evidence-based guidelines for systematic reviews described in the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) [6]. We used PubMed and a PRISMA checklist. As illustrated in Figure 1, the search strategy included articles written in English and published between 2000 and 2021 and excluded systematic reviews, meta-analyses, case reports, and editorials. Search terms included "autism" AND "prescription use" OR "prescription trend" OR "prescription pattern" OR "prescription management" OR "medication use" OR "medication trend" OR "medication pattern" OR "medication management" OR "pharmacologic use" OR "pharmacologic management" OR "psychotropic use" OR "psychotropic management" OR "pharmacy use" OR "pharmacy management" OR "psychiatric use" OR "psychiatric management" OR "prescribing pattern" OR "prescribing trend" OR "psychotropic medication" OR "psychotropic drug" OR "prescription rate" OR "drug use." Of the 167 studies screened, we excluded 111 and retrieved 80. We did not include studies examining complementary or alternative health medicine because this review focused only on psychotropic medications. Of the 80 articles retrieved, 30 met the inclusion criteria.

FIGURE 1: Literature search and study selection.
This review utilized PubMed and followed PRISMA guidelines to search for clinical studies on the use of psychotropic substances in autistic patients. The search strategy involved using specific search terms in different combinations. The keywords were limited to "Autism," "Prescription Use," "Prescription Trend," "Prescription Pattern," "Prescription Management," "Medication Use," "Medication Trend," "Medication Pattern," "Medication Management," "Pharmacologic Use," "Pharmacologic Management," "Psychotropic Use," "Psychotropic Management," "Pharmacy Use," "Pharmacy Management," "Psychiatric Use," "Psychiatric Management," "Prescribing Pattern," "Prescribing Trend," "Psychotropic Medication," "Psychotropic Drug," "Prescription Rate," and "Drug Use." By using filters and inclusion criteria, including articles written in English, and complete clinical studies focused on psychotropic medications in autistic males and females, the number of studies was narrowed down to 30.
ASD: autism spectrum disorder; MEDLINE: Medical Literature Analysis and Retrieval System Online; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Use of psychotropic medications
Of the 30 studies reviewed, 25 assessed the male versus female usage of any psychotropic medication ( Table  1). Of these 25 studies, six reported only crude percentages and did not assess statistical significance. In the other 19 studies that analyzed the statistical significance, 13 did not perform statistical analysis, while six showed a difference between psychotropic medication use between male and female autistic patients. Four of the six studies found that males were significantly more likely to take any psychotropic medication, while two found that females were significantly more likely to take any psychotropic medication.

Use of antidepressants
Of the 30 studies included, nine reported antidepressant use in males and females ( Table 2). Two studies reporting only a crude percentage found a greater likelihood of females receiving antidepressants, although statistical significance was not assessed. Five separate studies found no significant difference. Two studies detailed that females used significantly more antidepressants than males.

Use of stimulants and other ADHD drugs
Of the 30 clinical studies analyzed, 13 estimated the use of stimulants and other ADHD drug prescriptions ( Table 3). Two studies reported only crude percentages and did not perform statistical analysis, though both demonstrated a more significant share of males who received ADHD medications than females. Three studies found no statistical difference between usage. Eight studies found that males were prescribed considerably more stimulants or other ADHD drugs than females.

Use of antipsychotics (neuroleptics)
Of the 30 studies reviewed, 10 reported usage of antipsychotics (neuroleptics) ( Table 4). Three of the 10 studies determined crude percentages and did not report statistical significance. Five studies found no statistically significant impact of gender on antipsychotic usage. However, two studies reported that males received significantly more neuroleptics than females.

Use of mood stabilizers or anticonvulsants
Of the 30 clinical studies, 10 investigated mood stabilizers or anticonvulsant use ( Table 5). Two studies presented only a raw percentage of medication usage. Both found that females were more likely to use anticonvulsants or mood stabilizers, although investigators did not perform statistical analysis. In addition, Croteau et al. (2017) [7] reported that gender impacted the use of anticonvulsants but did not specify the nature of the relationship. However, three studies showed no significant impact of gender on mood stabilizer usage. On the contrary, four studies found that females were significantly more likely to use mood stabilizers or anticonvulsants than males.

Use of anxiolytics, hypnotics, and sedatives
A total of eight studies examined the use of anxiolytics, hypnotics, and sedatives (  [22] reported only crude statistics. Two studies found no significant difference, while four studies showed a substantial impact of gender on the prescription patterns of these drugs. Croteau et al. (2017) [7] demonstrated that gender impacted the use of anxiolytics but did not specify the nature of the relationship. The remaining three studies found that females used significantly more anxiolytics, hypnotics, and/or sedatives than males.   Significant results are highlighted in bold.
a The category was anxiolytics. Although the direction was not specific, gender impacted the use of anxiolytics; b Statistics were not reported but noted significant (specific for anxiolytics). The category was anxiolytics; c p = 0.025. Study category was sedatives/hypnotics; d χ2 = 97.92; p < 0.001. The category was anxiolytics; e It reported data on anxiolytics and hypnotics; f Category was anxiolytics; g Category was hypnotics; h Study category was anxiolytics; i It addressed data on anxiolytics and sedatives; j The category was anxiolytics; k Category was sedatives; l Category was anxiolytics/hypnotics/sedatives.

Use of other drugs
In total, five clinical studies investigated the use of "other" subsets of medications ( Table 7). One study reported only crude statistics. The second study found that females were more commonly prescribed antianxiety (tranquilizers) and non-barbiturates than males. While a third study found that melatonin was prescribed more frequently to females. However, the other two did not observe any statistical difference in the use of metformin, gastrointestinal-related, or sleep-related medications between autistic men and women.   In autistic patients, a gender-specific difference in psychotropic medication use can be explained by one of the following: (1) the different prescription trends mimic gender-specific trends that also exist in the nonautistic population, or (2) the prescription patterns are due to different comorbidities that autistic males and females experience. In a large cohort (n = 20,194) of autistic patients in the United Kingdom, the three most common neuropsychiatric comorbidities across all patients included behavioral and conduct disorders, anxiety, and ADHD. Behavioral and conduct disorders and ADHD were more common in males, while anxiety and depression were more common in females [17]. It follows suit that prescription patterns would likely differ under these comorbidities. The limitations can partly explain the breadth of data and lack of homogeneity between studies in the present review. Assessing the prevalence of psychotropic medication can be misleading because this analysis limits the visibility into medication trends within specific classes of drugs.
This review highlights the lack of uniformity between studies as the primary limitation. Although several studies overlapped, their inclusion criteria varied (age, IQ, psychiatric comorbidities). Further, medications in some studies were reported from caregivers, while in others, they were directly from electronic medical records. The setting or location also varied, as some studies focused on in-patient and acute care settings. In addition, it was worth considering that geography and health care varied in different countries and regions.
Another drawback is the variability in categorizing drug classes. For example, stimulants were generally thought of as being employed to improve measures of impulsivity and hyperactivity. Still, some stimulants, such as extended-release guanfacine, were also efficacious in a randomized, placebo-controlled trial in reducing oppositional and repetitive behaviors in children with autism and ADHD [36]. Therefore, it must be considered that some stimulant medications might be prescribed to manage symptoms more consistent with mood disorders (such as opposition behavior) than their typical use as attention-related symptoms (hyperactivity).
In general, the lack of efficacious medications for the core symptoms of autism made it challenging to identify trends between sexes. Nonetheless, several studies found substantial differences in prescription patterns and specific classes of drugs. For example, antidepressants, anticonvulsants, and mood stabilizers were more commonly used in females, while stimulants and other ADHD drugs and antipsychotics were more frequently used in males. This review highlights prescription differences between autistic men and women. Such differences in drug use support the idea that autism manifests differently in women than men, so it should not be equated. The evidence presented in this review warrants further investigation to adequately address and compare patterns in psychotropic drug usage by gender, age, IQ, and comorbidity to draw more definitive conclusions in autistic patients.
Another crucial factor, although not within the scope of this review, is the pharmacogenetic testing of autistic males and females to maximize the treatment benefits of psychotropic drugs administered to such patients. The most commonly prescribed psychotropics used in treating autistic patients are metabolized by cytochrome 2D6, an isoenzyme of cytochrome P 450. Depending upon the genetic or chromosomal abnormality, a patient may be a slow or fast metabolizer of psychotropics [37], directly affecting the plasma concentration of these medications and, consequently, their benefits and adverse effects. An improved understanding of the male and female autistic phenotypes and the gender trends of psychotropic prescription based on the genetic profile would help tailor the treatment plan to the specific needs of autistic patients and will lead to better patient outcomes.

Conclusions
This review highlights the trend of psychotropic drug use in autistic men and women. By reviewing the existing literature and focusing on a symptom-focused model of pharmacologic treatments, we identified a difference in the use of psychotropics among autistic men and women. Autistic women are most likely to consume antidepressants, anticonvulsants, and mood stabilizers. In comparison, autistic men are more likely to use stimulants and ADHD drugs. Moreover, based on the clinical evidence, it is clear that psychiatric comorbidity alone does not entirely explain the differences in these medication usages between genders. Recognizing a female phenotype of autism may partly contribute to this difference but merits further clinical investigation. Understanding the gender trends in psychotropics use by autistic patients is critical as gender-related differences can impact a wide range of pharmacokinetic and pharmacodynamic parameters. These differences may influence the diagnosis and ultimately affect the recommendation for initial dosing and titration of these drugs.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.