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administration of concomitant drugs. There are sex differences in all of these factors and taken together, these factors are estimated to contribute to a tenfold variability in responses to medication.

Sex differences in response to ► antipsychotic agents have been reported in both animals and humans. In drug-naive subjects, response to antipsychotic drugs is reported to be superior in women. In chronically ill patients with ► schizophrenia or related psychoses, men require twice as high a dose as women for effective maintenance. Recommendations for prescribing antipsychotic medication to women include using lower doses for women than men, longer intervals for women when depot doses are used, and careful modulation of drug dose in aging women. In general, schizophrenic women have higher degree of symptom improvement, but also of ► extrapyramidal symptoms.

Until recently, women have been underrepresented in clinical trials of ► second generation antipsychotics, and therefore, there are limited data on possible sex differences in drug efficacy and side effects. A main reason for this underrepresentation was the fear of potential ► tera-togenicity. Currently, sex-specific analysis of efficacy and safety data is a requirement and therefore an increasing number of studies are now available concerning sex differences in pharmacokinetics or ► pharmacodynamics of second generation antipsychotics.

There are reported sex differences in pharmacokinet-ics for second generation antipsychotics ► clozapine, ► olanzapine and ► sertindole, and CYP1A2 activity has been implicated in these differences. Women have higher plasma levels of all these second generation antipsycho-tics than men. On the other hand, no sex differences were observed for ► quetiapine. However, as the studies involve relatively small number of patients, larger samples are required before generalizations can be made on sex differences in responses to novel antipsychotics.

Recent reports suggest that women on olanzapine have a significantly better treatment response than men, and pre-menopausal women have a better treatment response than postmenopausal women. Overall, schizophrenic women under 40 years of age require lower antipsychotic doses than men regarding both acute response and maintenance.

Because of important side effects of antipsychotic medication, regular monitoring of weight gain and body mass index, plasma glucose level, lipid profiles, signs of prolactin elevation and ► hyperprolactinemia, or sexual dysfunction are recommended. Cardiac side effects and extrapyramidal symptoms should be considered as well. However, despite established sex differences in response to antipsychotic medication, these effects do not receive much emphasis in prescribing these drugs to men or women. Women, perhaps because of the influence of sex hormones, have a lower risk of sudden cardiac death, but a higher risk of acquired ► long QT syndrome from antiarrhythmic drugs. Estrogens may facilitate bradycardia-induced prolongation of the QT interval. Patent antipsychotic drugs were likely to block cardiac voltage-gated potassium channels, prolong the QT interval, and result in ventricular arrhythmias. Subsequently, women may be at a higher risk of cardiac side effects of antipsychotic medication. Older antipsychotics like ► butyrophenone and ► pheno-thiazine derivatives, and some of the second generation antipsychotics elevate prolactin levels (hyperprolactine-mia) and result in sexual dysfunction, which in turn results in non-compliance with treatment, particularly in men. In the long run, hyperprolactinemia also causes galactorrhoea, amenorrhea, breast engorgement, and osteoporosis. In women, the elevation of prolactin concentrations is generally noted to be higher than in men. On the other hand,

► aripiprazole which has a different profile from second generation antipsychotics by being a partial D2 receptor agonist is reported to lower prolactin levels.

Antidepressants

Although, the prevelance of major depression is twice as much in women than men, sex differences observed in

► antidepressant medication is not overwhelming. Women experience more vegetative and atypical symptoms, ► anxiety, and anger than men, and report higher severity of depression on self-report measures; however, no significant sex differences are observed in the course of the illness and treatment response. The efficacy of ► bupro-pion and ► selective serotonin reuptake inhibitors (► SSRI), appear to be equally effective in treating depression, anxious/somatic symptoms, and ► insomnia; there is a slight sex difference as greater improvement was seen in women during SSRI treatment regarding anxious/somatic symptoms of depression. Additionally, the efficacy of antidepressants is more pronounced in younger patients. On the other hand, a recent study suggests that women with ► generalized anxiety disorder, particularly those with a later age of onset, may have a poorer response to the SSRI ► fluoxetine compared to men. Although women have higher plasma levels than men, no sex differences are reported in response to ► tricyclic antidepressants.

Analgesics

Pain management by pharmacotherapy is another important medical problem where sex differences are noted. Furthermore, there may be gender differences in pain tolerance. Women report suffering from migraine and arthritis, more intensely than men do. Men have a better response to non-steroidal anti-inflammatory analgesics (NSAIDS) than women, and women benefit more from narcotics than men do. Therefore, over-the-counter analgesics do not help women as much as men, and lower doses of narcotics which are effective on women are not as effective on men.

Males and females respond differently to drugs acting at ► opioid receptors; these quantitative and qualitative differences are not restricted to the ► analgesic and anti-nociceptive properties of opioids, but are also present in opioid-induced side effects (i.e., effects on respiration, locomotor activity, learning/memory, addiction, and cardiovascular system). However, the direction and magnitude of sex differences regarding the potency of opioids depend on the interacting variables which are specific to the drug (i.e., dose, pharmacokinetics and pharmacodynamics, route and time of administration) or to the subject (i.e., species, type of pain, genetics, age, gonadal/ hormonal status, and psychological factors). The differential organizational and/or ► activational effects of go-nadal steroid hormones in males versus females have received emphasis in explaining sex differences in opioid antinociception. There are sex differences in response to drugs acting on ► kappa-opioid receptors: Women respond more robustly than men to ► kappa-opioid agonists and antagonists with analgesic and hyperalgesic properties, respectively. When drugs acting at different receptors are compared, women have better pain scores with kappa-opioid agonists (butorphanol) than mu-opioid agonists (morphine). However, rodent data from laboratory pain models contrast with human data.

Conclusion

Recent studies on both animals and humans clearly indicate that many normal physiological and pathological functions are influenced by sex-based differences in biology, either directly or indirectly. Males and females are not only different regarding reproductive function, but sex differences exist in brain and behavior, including emotion, memory, vision, hearing, processing faces, pain perception, navigation, neurotransmitter levels, stress hormone action on the brain, and disease states. Sexual dimorphisms are observed in many neurotransmitter systems, including monoamines, serotonin, GABA (gama-aminobutyric acid), acetylcholine, vasopressin, and opioids. Furthermore, dynamic factors that influence the bioavailability of drugs, body composition, gastrointestinal, renal and liver function, hormonal status, and activity of enzymes involved in drug metabolism, are not the same in males and females. Subsequently, it is clear that there are sex and gender differences in response to neuropsychopharmacological treatments. Sex is an important variable that should be considered when designing and analyzing studies in all areas of biomedical and health related research.

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