Neuropharmacology and gender
There is a growing interest in examining differences in pharmacological responses among different genders. This gender-related discrepancy in the administration of pharmaceutical drugs has influenced that success of the treatment of specific medical disorders. Several research investigations have been conducted in the last ten years in order to better understand any underlying gender-related mechanisms that influence factors related to particular diseases. The factors that are swayed by gender include prevalence, disease symptoms, behavior of the patient during treatment and reaction to pharmacological treatment.
Several analyses have suggested that gender-related differences in pharmacology induce different levels of sensitivity to drug medications. In the field of neuropharmacology, a significant number of pharmaceuticals have already been reported to illicit gender-related differences in the reaction and response to specific neuropharmacologic reagents. The differences include delayed reaction time or even a lowered sensitivity to the administered drug. The opposite scenario has also been observed with other medications, wherein a specific gender is more responsive to the drug treatment due to the elevated sensitivity to the medication. It has also been suggested that gonadal hormones may play a role in the reaction of specific genders to particular drugs.
Pharmacological research has recently focused on determining the factors that influence the effects of prescription drugs on the treatment of neurological disorders. One factor that has been of great concern is gender. There are critical differences based on sex that have been determined to influence neurological disease prevalence. In addition, gender has also swayed the presentation of symptoms among patients as well as the behavior of the patient himself in terms of seeking treatment.
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Another influence of gender-based neuropharmacological treatment is the response of the patient to psychotropic medication. It has been observed that females tend to undergo a less serious course of schizophrenia than males. This condition is characterized by less frequent negative symptoms and a greater chance for the females to adapt to her social environment. Females have also been determined to response faster to an administered low dose of antipsychotic drug regimen, thus resulting in fewer cases of hospital admissions and hospitalization.
It has been estimated that approximately 5% of all hospital cases are due to adverse drug reactions. This significant number of death due to adverse drug reactions thus makes it essential to identify the factors that are strongly associated with risk management. Case studies have shown that the increasing age of a patient poses a higher risk for adverse drug reactions. In addition, the employment of several pharmaceutical drugs at the same time influences a patient to experience adverse drug reactions. Liver and kidney diseases are also correlated with adverse drug reactions. Interestingly, gender has also been determined to be a factor for adverse drug reactions, wherein females are more prone to experience such deleterious side effects.
The main mechanism behind the connection between gender and adverse drug reactions still remains unclear but it has been suggested that pharmacological concepts play a major role in this reaction. Pharmacokinetics or the dynamics of drug interactions in the human body is one of the areas of pharmacology that integrates the aspect of gender-related differences (Meibohm et al., 2002). The concept of pharmacogenetics or the inter-individual differences in drug response also provides some kind of influence of gender-related pharmacological issues. Hormonal factors have also been suggested to cause some effect of the response of different genders to pharmacological reagents.
Classical pharmacological studies have generally under-represented females in clinical trials for neuropharmacological drugs and this has resulted in an insufficiency of information with regards to any gender differences in drug efficiency and side effects (Aichhorn et al., 2005). The major reason behind the under-representation of females in clinical trials is that there is a general fear that the drug being tested may be a potential teratogen which may cause mutations and eventually cancer to females.
The fear is also associated in generating offspring that may carry multiple congenital anomalies due to the exposure of a neuropharmacological drug that is still being investigated. Today, the principles of registration of a new drug require more stringent criteria for approval for clinical trials. Amongst the requirements are the guidelines that indicate the need for gender-specific testing.
Both males and females should thus participate in a clinical trial, with equal numbers of females and males in the entire study population so that bias can be avoided. In addition to sex-matching in clinical trials, each gender is age-matched, meaning that every age group within the female category of participants should have an equivalent male of the same age group. The new guidelines with regards to registration of a new drug have thus facilitated the inclusion of females in clinical trials.
One neuropharmacological drug that has been extensively studied in terms of pharmacokinetics and pharmacogenetics are the second generation anti-psychotic drugs. Clinical investigations have reported that different anti-psychotic drugs have different efficacies. In turn, there anti-psychotic drugs also exert variable side effects among the patients that have been administered with this drug. Anti-psychotics are generally given to patients suffering from schizophrenia and bipolar or manic-depressive disorders.
Other mental health illnesses that are associated with the use of anti-psychotic drugs include dementia, delirium, depression and autism. Anti-psychotics drugs are prescribed to the patient in order to control any untoward behavior that the patient may perform in the near future, such as aggression, violence and suicide. These drugs are effective enough in lowering the chances of performing these untoward actions without affecting their normal motor functions, yet there are particular side effects that have been noted in relation to the use of anti-psychotic drugs.
One side effect is weight gain which is determined by the increase in weight as well as the change in body mass index of the patient. Abnormalities in glucose and lipid metabolic pathways are also affected by the intake of anti-psychotic drugs. There have also been reports with regards to side effects related to cardiac and sexual functioning of the patient. Gender-based differences in side effects have been implicated to these observations.
For the case of schizophrenia, gender-related differences have been observed in relation to the cumulative lifetime risk. The initial expectation for the risk of schizophrenia among males and females was classically determined to be the same. However, there is an accumulation of clinical reports that show that males generally experience schizophrenia at a younger age than females.
There is an average difference of 3 to 5 years between males and females with schizophrenia. More importantly, this gender-related difference also affects the patients’ behavior in terms of seeking medical attention. Negative symptoms associated with schizophrenia have also been observed to be higher frequency among males. The prevalence of cognitive deficiencies has een reported to be greater among males. Any related structural brain and neurophysiological dysfunctions and abnormalities are also more frequent among male schizophrenia patients than among female schizophrenia patients.
Oppositely, female schizophrenia patients have been reported to more frequently show affective symptoms related to this psychological disorder. Females are also more prone to experience auditory hallucinations as well as delusions that result in self-persecution. However, it is interesting to know that females respond to anti-psychotic medications at a faster rate than male patients. This quick response, unfortunately, is strongly correlated to more severe drug-related side effects. Clinicians have observed that the course of schizophrenia is less destructive among female patients. Also, female schizophrenia patients are associated to fewer incidents with smoking and substance abuse, unlike male patients who generally perform both heavy smoking and drug and alcohol abuse during their entire illness.
The gender-related issues that were observed with schizophrenia are strongly associated to neuroanatomic sexual differences among males and females. For example, research has shown that the temporolimbic abnormalities are present among male schizophrenia patients. These abnormalities involve a significant change in the volume of the left temporal lobe of male schizophrenia patients. The volume was observed to be much smaller as compared to the left temporal lobe of female schizophrenia patients. Comparison of the volume of the left temporal lobes of schizophrenia patients with that of normal healthy individuals has shown that the volume of the left temporal lobe of female schizophrenia patients is the same as that of normal healthy males and females.
Another difference that relates to gender differences and neuropharmacology is the variation in the volume of the grey matter of the brain. It has been reported that male schizophrenia patients showed a significant decrease in the volume of their grey matter (Leung and Chue, 2000). On the other hand, female schizophrenia patients show a smaller volume in their hippocampal region, while the volume of their amygdala had increased. Magnetic resonance imaging studies have indicated that male and female schizophrenia patients show great differences in the volume of their corpus callosum.
The differences in volume of several regions of the brain among male and female schizophrenia patients may possibly influence the variations in response to pharmacological treatment of schizophrenia. Initial pharmacological studies with regards to psychopharmaceuticals mainly focused on the treatment of the disorder itself and gender differences were not investigated until a significant number of cases reports were issued describing specific adverse drug reactions to anti-psychotic drugs. It has been generally observed that female schizophrenia patients improve at a faster rate than their counterpart male schizophrenia patients. This positive response, unfortunately, is coupled with the occurrence of extrapyramidal symptoms among female schizophrenia patients.
Aside from gender differences in neuropharmacological treatment, differences among female schizophrenia patients have also been observed. Research investigations have observed that pre-menopausal female schizophrenia patients show a faster and better response to pharmacological treatment than post-menopausal female schizophrenia patients. This observation suggests that female younger than 40 years old only need a minimal amount of anti-psychotic pharmacological treatment than male schizophrenia patients. This pharmacological treatment advantage is lost when the female schizophrenia patient is above 40 years of age.
Differences in neuropharmacological treatment response, clinical course and treatment outcome among males and females may also be due to variations in the cerebrum. An example that could be employed to this notion is that the volume of the caudate nucleus changes over time after treatment of the patient with anti-psychotic drugs. These changes in volume of the caudate nucleus are also influenced by the gender of the schizophrenia patient. In terms of male schizophrenia patients, treatment with neuropharmacologic reagents generally results in an increase in the volume of the caudate nucleus. On the other hand, this volume was observed to increase among female schizophrenia patients after treatment with anti-psychotic drugs.
It should be noted that not all components of the brain show gender-related differences in terms of neurological disorders and neuropharmacological treatment and response. The striatal dopamine D2 receptor binding activity among male and female schizophrenia patients were determined to be the same, suggesting that the left striatus of both male and female schizophrenia patients are similar before and after neuropharmacological treatment for schizophrenia.
Cognitive functions have also been observed to be different among male and female schizophrenia patients. It is a common observation that male schizophrenia patients perform in a poorer fashion than female schizophrenia patients. Other research groups have observed the opposite result, wherein female schizophrenia patients showed a lower degree of performance in cognitive functions.
One explanation for such variations among genders is that some particular research groups only reported these differences as a side-observation while conducting an investigation that focus on another aspect of neuropharmacological research. It would thus be more reliable if a research study was performed solely in identifying gender-related differences associated with neurological disorders and their response to pharmacological treatment. It has been postulated that the discrepancies among male and female schizophrenia patients may eventually lead to major variations in the cognitive functions of males and females.
It is therefore imperative that gender differences be comprehensively analyzed in terms of cognitive functions. Another interesting research would involve drug responses among males and females of different neurological disorders. There is also a great need to determine whether there exists a difference between males and females in terms of neurocognitive outcome after pharmacologic treatment for a neurological disorder.
There is also a need to examine differences between gender and ethnicity in terms of neurological disorders, treatment and response. Case reports have described that African-American male and female patients diagnosed with psychoses showed a unique neurological profile and treatment response from that of the general human population. This observation resulted in a faster rate for hospital discharge after administration of a relatively higher dose of anti-psychotic pharmaceutical drug.
The comprehensive investigation of gender-related differences among neuropharmacological treatments would provide a better understanding of the pharmacokinetics of drugs. In addition, future research efforts on this area would also provide more information that may be used in designing safe, effective and personalized drug treatment plans for patients suffering from neurological disorders.
Reference
Aichhorn W, Gasser M, Weiss EM, Adlassnig C and Marksteiner J (2005): Gender differences in pharmacokinetics and side effects of second generation antipsychotic drugs. Current Neuropharmacology 3:73-85.
Leung A and Chue P (2000): Sex differences in schizophrenia, a review of the literature. Acta Psychiatrica Scandinavica Suppl. 401:3-38.
Meibohm B, Beierle I and Derendorf H (2002): How important are gender differences in pharmacokinetics? Clinical Pharmacokinetics 41:329-342.
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