While simvastatin inhibited the enzyme HMGCoA-reductase, punicalagin, β-sitosterol, and PJ inhibited macrophage cholesterol biosynthesis downstream to mevalonate. Simvastatin (15μg/mL) also modestly decreased macrophage ROS formation by 11%. In the presence of punicalagin (15 or 30μM), however, a remarkable further inhibition was noted (by 61% or 79%, respectively).Although β-sitosterol alone showed some pro-oxidant activity, the combination of simvastatin, β-sitosterol, and punicalagin clearly demonstrated

a remarkable 73% reduction in ROS production. Similarly, simvastatin + PJ decreased the extent of ROS formation by up to 63%. These results suggest that PJ consumption Inhibitors,research,lifescience,medical by hypercholesterolemic patients together with treatment Inhibitors,research,lifescience,medical with a low dose of statins could lead to attenuation of macrophage foam cell formation and atherogenesis in these patients. CONCLUSIONS Pomegranate fruit click here polyphenols protect against lipid peroxidation in serum by direct interaction of pomegranate polyphenols with LDL, or indirectly by increasing serum PON1 stability (HDL association), as well as its catalytic activities, resulting in the hydrolysis of lipid peroxides. Moreover, PJ has a remarkable effect on macrophage Inhibitors,research,lifescience,medical and lesion atherogenicity. Pomegranate juice consumption decreased oxidative stress in macrophages and in atherosclerotic lesions,

and the extent of Ox-LDL uptake by macrophages. This could be a direct antioxidant effect of PJ, or an indirect effect, by increasing HDL-associated PON1 as well as cellular PON2. Interestingly, Inhibitors,research,lifescience,medical the lesion cholesterol levels were decreased after PJ consumption. This could be related to the reduction in Ox-LDL uptake by macrophages, to PJ/PON1-induced inhibition of cholesterol biosynthesis, and to PON1 stimulation of HDL-mediated Inhibitors,research,lifescience,medical cholesterol efflux from arterial macrophages. All these antioxidative and anti-atherogenic effects of pomegranate polyphenols were clearly demonstrated

in vivo, in humans (healthy subjects, CAS patients, as well as diabetic patients).The preferred pomegranate product in terms of biological potency and consequent health benefits is PJ from the whole fruit (including the peel). Since the combination of antioxidants that exists in PJ can provide a wider most range of free radical scavenging capacities than an individual antioxidant, clinical and nutritional studies in humans should be directed towards the use of combinations of several types of dietary antioxidants, as well as combinations of flavonoids together with other nutritional antioxidants, such as vitamin E or carotenoids. In addition, PJ can be beneficially used in combination with low-dose statins in hypercholesterolemic patients. Finally, it is also important to identify populations suitable for antioxidant treatment, as antioxidants treatment may be beneficial only in subjects who are under excess oxidative stress.

We will examine blood markers from different distinct biologic pathways as candidate biomarkers. Thus, we will assess markers of infection, inflammation, organ dysfunction, endothelial dysfunction, vasodilation / infection-control, stress hormones, cardiac dysfunction, nutrition, and kidney function, which all have been shown to predict adverse outcomes in different types of medical conditions (Table  1). Depending on the HA-1077 molecular weight expected

benefit from a literature research, the available funding and logistic support, we will decide which markers should be analyzed in the stored aliquots. Table 1 Candidate Inhibitors,research,lifescience,medical parameters for improved diagnostic and prognostic patient assessment Ancillary projects Within this study, we have several ancillary projects focusing on different aspects of patient care in this medical population. First, we will look at costs from Inhibitors,research,lifescience,medical different perspectives, i.e. patient, society perspective, insurance perspective and hospital perspective. We will collect detailed

cost data as well as resource use data. Based on the daily clinical assessment we will have good estimates how length of stay (LOS) could be reduced in patients without increasing their risk, i.e. at the time patients are classified as “medically stable” by the treating physician Inhibitors,research,lifescience,medical team. We will develop cost models using DRG reimbursements Inhibitors,research,lifescience,medical to evaluate the potential in savings. Second, within a subset of patients we will focus on psychological distress defined as negative psychological reaction which may pre-exist

or develop in the context of an acute disease potentially involving a variety of affective, cognitive, and behavioral reactions, such as fear, sadness, Inhibitors,research,lifescience,medical anxiety, frustration, or non-compliance. In this ancillary project we aim to explore the prevalence and course of patients’ psychological distress on ED the admission and within the hospital stay. To measure psychological distress we will use several validated instruments including the Distress Thermometer (DT) [68,69] and the positive and negative affect schedule (PANAS) [70]. Beside general distress our focus will particularly lie on anxiety and depression assessed with the Patient Health Questionnaire-4 (PHQ-4) [71]. Additionally we will explore the relation of psychological distress with health outcomes (mortality, comorbidity, health-related quality of life, LOS among other) 30 days after admission. Finally, we aim to further delineate the role of specific patient’s psycho-social resources (personality, social support, age, sex, SES, medical diagnosis) with regard to distress and health outcomes.

28 Alterations in the AZD5363 migration and integration of GABAergic interneurons in cortical circuits have emerged as key processes involved in the susceptibility to psychiatric disorders.29,30 In addition to genetic alterations, early-life stress affects the migration of cortical interneurons.31 Recent work using time-lapse imaging of cortical slices has revealed that excess serotonin decreases the migration speed of cortical interneurons as well as the velocity of the pyramidal neuron in the superficial layer.32,33 Furthermore, the

distribution Inhibitors,research,lifescience,medical of both cortical interneurons and projection neurons was altered in the somatosensory cortex of neonatal SERT KO mice.32,33 Alterations in neuronal migration due to a developmental excess of serotonin could contribute to the subtle changes in the thickness of cortical layers observed in different cortical regions of SERT KO mice.34 In vitro studies combined with pharmacological approaches using time-lapse imaging revealed that serotonin receptor 6 (5-HT6R) Inhibitors,research,lifescience,medical is involved in regulating cortical neuronal migration.32,33 Interestingly, proteomic approaches indicate that 5-HT6R forms a complex with a set of proteins involved in regulating developmental processes such as the mTOR pathway,35 and 5-HT6R-mediated mTOR Inhibitors,research,lifescience,medical signaling is affected in the medial frontal cortex of mice exposed to postweaning social isolation,

a developmental model that induces schizophrenia-like phenotypes.35 The mTOR pathway has been shown to be an important signaling hub involved in autism spectrum disorders.36 Following their migration to specific cortical layers, pyramidal neurons progressively Inhibitors,research,lifescience,medical develop a dendritic arborization and receive synaptic inputs. Morphological

investigation of pyramidal neurons in the ventromedial infralimbic prefrontal cortex of SERT KO mice has revealed conflicting results with either decreased37 or increased38 apical dendritic morphologies in SERT KO mice. More studies are clearly necessary to understand these dendritic Inhibitors,research,lifescience,medical structural changes, which have been shown to be very sensitive to stress.39 Dendritic growth of cortical neurons has been shown to be regulated by serotonin fibers, creating synapses on CR cells.40 Genetically deleting the 5-HT3A receptor increases unless apical dendritic arborization of upper layer pyramidal neurons in the somatosensory cortex, whereas pharmacologically blocking SERT during pregnancy decreases their dendritic complexity.40,41 In CR neurons lacking 5-HT3A, serotonin is unable to stimulate the secretion of reelin, a glycoprotein that helps regulate neuronal migration and inhibits the growth of apical dendrites. Therefore, a reduction in reelin secretion has been proposed to lead to an abnormal hypercomplexity of apical dendrites.

31) In addition to the use of standard therapy for heart failure (diuretics, vasodilators and digoxin), prolactin inhibition32) may provide potential benefit to patients with peripartum cardiomyopathy. Careful attention must be paid to select drugs relatively safe for mother and fetus and to exclude those that can evoke fetal abnormalities. The duration of treatment is still unknown. Though the majority of peripartum cardiomyopathy patients recover partially or are completely improved with treatment, the reported mortality rates lie between 18% and 56%.26),33)

Inhibitors,research,lifescience,medical Moreover, subsequent pregnancy in these patients can be associated with a recurrence of peripartum cardiomyopathy and can result in death.33) Stress-induced cardiomyopathy Inhibitors,research,lifescience,medical SCMP is a syndrome of VE-821 chemical structure reversible LV systolic dysfunction with characteristic apical ballooning in patients without significant epicardial coronary artery stenosis.10),34) This syndrome, also known as Takotsubo cardiomyopathy, is believed to be associated Inhibitors,research,lifescience,medical with various clinical scenarios, especially with intense mental or emotional stress.35) However, physical stress can cause this kind of cardiomyopathy. Park et al.35) reported their data of patients admitted to the medical intensive care unit.

They reported 28% of patients showed apical ballooning and they were usually Inhibitors,research,lifescience,medical associated with hypotension, sepsis, cardiomegaly and use of inotropic agents. SCMP occurs usually in

women over 50 years of age, and the typical features include profound mental stress immediately preceding and triggering the cardiac events, acute retrosternal chest pain with ST-segment change and/or T-wave inversion, absence of significant coronary artery stenosis by coronary angiography, and LV systolic dysfunction with abnormal wall motion of Inhibitors,research,lifescience,medical apex (apical ballooning).11) There is a variant of apical ballooning syndrome. Transient mid- and basal-ventricular ballooning is a new variant of the transient LV apical ballooning syndrome. The involvement of the LV’s mid- and basal-ventricle with sparing Digestive enzyme of the apical segment is the unique finding of this variant.36) Because the guideline excludes the presence of pheochromocytoma in the diagnosis of SCMP, the presence of a specific pattern with pheochromocytoma should be classified as catecholamine-induced cardiomyopathy.37) Echocardiography is a useful method to diagnose this type of cardiomyopathy. Transthoracic echocardiography usually demonstrates LV systolic dysfunction with typical apical ballooning and/or midventricular hypokinesia, and the wall-motion abnormality extends beyond the distribution of any of one single coronary artery.10),11) Transient LV hypokinesia can be restricted to the midventricular segment and/or basal segment without involvement of the apical segment in a minor population.

72,78,86 pH-selleck compound sensitive intracellular signaling molecules include Pyk2 and soluble adenlyl cyclase (sAC).72 All of these molecules are sensitive enough to detect pH changes that occur during physiology or pathophysiology. Further, all of these molecules have been suggested as candidates for pH chemosensitivity.72,86

Though more investigation is needed, some of these molecules have already Inhibitors,research,lifescience,medical been implicated in pH sensing. For example, voltage-dependent Ca2+ channels and NMDA receptors modulate synaptic plasticity in response to changes in extracellular pH.80,81 Adenosine Al receptors, adenosine triphosphate (ATP) receptors (P2X and P2Y), and ASIC1a have been implicated in the ability of CO2 and low pH to inhibit seizure activity.32,78 Recent studies also investigated the potential role in the inward rectifier K+ channel Kir5.1, which is highly sensitive to extracellular pH when heteromerically coupled to Kir4.1. Disrupting Kir5.1 produced abnormal respiration and metabolic acidosis in mice, however central hypercapnic ventilatory responses remained Inhibitors,research,lifescience,medical intact. Instead, impaired sensory afferent nerve conduction was thought to be responsible for the abnormal respiratory phenotype.85 Effects of chemosensation

on arousal and emotion circuits pH-sensitive respiratory Inhibitors,research,lifescience,medical chemosensors in the brain stem medulla and pons comprise a powerful mechanism for controlling systemic CO2 and pH. Slow or shallow breathing acidifies systemic pH, while fast or deeper breathing raises systemic pH, making it more alkaline. There may also be a need for higher level (more rostral) brain structures to monitor pH, for example to produce Inhibitors,research,lifescience,medical appropriate cognitive or behavioral responses to rising CO2. Rising CO2 heralds the potential threat of suffocation, a terrifying situation that demands immediate Inhibitors,research,lifescience,medical detection and action to ensure survival. The clusters of pH-sensitive neurons in the medulla and pons that stimulate breathing might communicate this need for action to higher level structures. Alternatively, it might be advantageous if sites above the medulla and pons sensed pH more directly.68,69 A prominent example is midbrain serotonergic

neurons. Midbrain raphe neurons are highly pH-sensitive and increase firing when CO2 rises and pH falls.87 These neurons are well positioned to deliver serotonin out (5-HT) to forebrain, cortical, and subcortical structures and thus alter mood and cognition in response to CO2 and low pH. In sleep, a rising CO2 and falling pH might signal the need to reposition the airway or to relieve an obstruction. During sleep CO2 inhalation causes wild-type mice to wake up, whereas CO2 fails to wake mice lacking pH-sensitive serotonin neurons.88 Thus, dysfunction of these neurons might play a critical role in sudden infant death syndrome,89 where a failure to wake may lead to suffocation. Neurons in even higher order brain areas are also activated by low pH, including orexin-expressing neurons in the hypothalamus.

Synaptic transmission and plasticity: mechanisms of selleck antidepressants Synaptic plasticity encompasses all forms of neuroplasticity that specifically occur at synapses; both functional and structural forms of plasticity have been described (Table II). In many cases this term is referred to activity -dependent modifications of the strength or efficacy of synaptic transmission at glutamate synapses; the most common forms Inhibitors,research,lifescience,medical of long-lasting activity-dependent changes in synaptic strength are long-term potentiation (LTP) and longterm depression (LTD).56 It has been repeatedly shown

that, both stress and antidepressant treatments change synaptic plasticity (reviewed in refs 3,18,57,58). Beyond the monoamine hypothesis: the role of glutamate Recent, neuroimaging Inhibitors,research,lifescience,medical and histopathological studies in brain of depressed and bipolar patients revealed the presence of morphometric/functional modifications, including ventricular enlargement, hippocampal and cortical volumetric reduction, and of reduced neurons and glial density.59-61 In many of the areas implicated, glutamatergic neurons and synapses predominate, suggesting Inhibitors,research,lifescience,medical an involvement. of glutamate neurotransmission

in the pathophysiology of mood disorders. Indeed, in the last few years numerous lines of evidence have accumulated in favor of a role for glutamate in psychiatric pathophysiology, including the following: (i) higher levels of glutamate in plasma and brain of patients with mood disorders62-63; (ii) abnormal elevation of glutamate neurotransmission and glutamate levels in cortical/limbic brain areas of depressed patients16,64; (iii) atrophy of apical dendrites in Inhibitors,research,lifescience,medical CA3 hippocampal neurons induced by chronic stress, a major factor in pathogenesis of mood disorders17; (iv) increased amplitude

and reduced decay kinetics of NMDA current, induced by chronic stress65; (v) impaired long-term potentiation (ITP) and facilitated depression (LTD) induced by stress.66 Conversely, antidepressant treatments were also shown Inhibitors,research,lifescience,medical to affect glutamate neurotransmission: ADP ribosylation factor (i) antidepressants downregulate NMDA receptor subunits and dampen NMDA function67; (ii) antidepressants may overcome the effects of stress on LTP68-69; (iii) chronic antidepressants reduce depolarization-evoked release of glutamate in hippocampus by modifying presynaptic protein interactions regulating exocytotic release.70 Several compounds that modulate glutamate receptors or glutamate neurotransmission at various levels are under development for the treatment of mood disorders (depression, bipolar disorder, anxiety).71 Some of these putative drugs may work by stabilizing glutamate release when its synaptic level becomes too high, a feature that, is now considered as part of the pathophysiology of mood disorders.3,15,58,72,73 Recently, it.

2012), and no studies have investigated the neural basis of patients’ loss of self-awareness regarding a complex socioemotional characteristic such as their

capacity to behave empathically toward others. Empathy is a well-characterized, complex social behavior, involving the subjective emotional feelings induced by others’ emotions, the ability to differentiate between the feelings one experiences and the feelings Go 6983 clinical trial expressed by others, and mental flexibility (Decety and Jackson 2004). Inhibitors,research,lifescience,medical Despite this complexity, healthy individuals are able to represent their own level of empathy fairly accurately, indicating that this information is normally accessible to awareness. Examining the neural substrates of self-awareness for this type of complex behavioral trait could provide information to better dissociate modality-specific from supramodal neural processes underlying self-awareness. Previous neuroimaging studies have

examined impaired self-awareness independent of its directionality, despite the fact that patients can show highly divergent patterns (Michon Inhibitors,research,lifescience,medical et al. 1994; Rankin et al. 2005; Tranel et al. 2010; Zamboni et al. 2010), with some patients overestimating their level of functioning Inhibitors,research,lifescience,medical (“polishers”) and others underestimating it (“tarnishers”). Rather than reflecting a continuum, being overcritical or under critical may reflect divergent pathophysiological processes, thus this should be investigated independently. In this study, we asked whether either overestimation or underestimation of one’s capacity for empathic concern predict specific patterns of focal brain damage in a large sample of neurodegenerative disease patients and healthy older adults. To answer this question, we separated the sample into “polisher” and “tarnisher” Inhibitors,research,lifescience,medical subsamples based on the Inhibitors,research,lifescience,medical subject-informant discrepancy method, using

the Interpersonal Reactivity Index (IRI) (Davis 1983). Within each of these two subsamples, discrepancy measures were then correlated with structural MR images using voxel-based morphometry (VBM) across the whole brain. We also examined the degree to which the anatomy underlying self-awareness of empathic concern corresponds to the neural correlates of empathic concern itself and the neural correlates of affective perspective taking (Davis 1983), a cognitive capacity related why to empathic concern (Davis 1983; Sollberger et al. 2012). Materials and Methods Subjects We studied 102 subjects, including 83 patients diagnosed with one of five neurodegenerative diseases and 19 healthy normal controls. Of the 83 patients, 28 patients met the research diagnostic criteria for behavioral variant frontotemporal dementia (bvFTD) (Rascovsky et al. 2011), 16 met criteria for semantic variant primary progressive aphasia (svPPA) (Gorno-Tempini et al. 2011), 4 met criteria for nonfluent variant primary progressive aphasia (nfvPPA) (Gorno-Tempini et al. 2011), 23 met criteria for AD (McKhann et al.

Head growth is one of the first features to fail to proceed with a normal velocity, and careful measurements can identify this as early as 2 months of life.21 A combination of decreased head growth velocity and developmental delay in girls is currently the most likely way that affected individuals are identified prior to regression. Gastrointestinal problems Nearly all affected

individuals have significant gastrointestinal problems. Motility and coordination are disrupted throughout the entire gastrointestinal tract, leading to chewing and swallowing problems, gastroesophageal reflux, delayed stomach emptying,22 bloating, #VRT752271 purchase keyword# and constipation.17 These gastrointestinal issues can have a significant impact on quality of life in affected people. Seizures and nonepileptic spells The majority of affected people have seizures during their lives; however a significant percentage (up to 40%) of people do not have seizures.23 Inhibitors,research,lifescience,medical This is somewhat surprising given the markedly abnormal electroencephalogram (EECj) present in all affected people.24 The EEG abnormalities include frequent multifocal epileptiform discharges, which can Inhibitors,research,lifescience,medical become nearly continuous during sleep, and slow background activity.24 A wide variety

of antiseizure medications have been used to control seizures in RTT, and no clinical trials have been performed to indicate improved efficacy with any particular agent. Some people have medically intractable epilepsy requiring either vagal nerve stimulator placement25 or ketogenic Inhibitors,research,lifescience,medical diet,26 both of which have some efficacy in RTT. In addition to epileptic seizures, people with RTT also commonly have nonepileptic paroxysmal events. The events are often associated with

breathing abnormalities and can clinically appear to be seizures, even to trained clinical observers. During these events, the patient may have tonic extension of limbs with a vacant look, often with breath-holding. Occasionally the nonepileptic paroxysms can Inhibitors,research,lifescience,medical include high-amplitude irregular movement of limbs more akin to a paroxysmal dyskinesia. The events are more common at sleep/wake transitions. Because the semiology of these events can be consistent with true epileptic events, it is important to consider evaluation with video EEG to confirm the epileptic nature of paroxysmal events in RTT. Unfortunately, no medical therapy has proven beneficial for treatment of these nonepileptic events in RTT. Breathing abnormalities Nearly all during people with RTT have some degree of breathing abnormalities. Commonly there is some degree of hyperventilation and/or apnea.27-29 The hyperventilation can be significant enough to cause hypocapnea, and some investigators have proposed treatment with gas mixtures containing increased concentrations of carbon dioxide.30 The apneic events can cause a decrease in blood oxygen and occasionally are prolonged to the point of loss of consciousness.

111,114-117 In addition, exercise increases neurogenesis in the adult hippocampus, an effect that

is dependent on increased expression of IGF-1 and VEGF.111,114 IGF-1 has also been shown to underlie the neuroprotective effects of exercise against different types of brain insults.118 In addition to the regulation of these growth factors, exercise has also been shown to influence other neuroprotective mechanisms.119 These positive, neuroprotective actions make exercise one of the key behavioral factors for protecting, or even reversing the damage that Inhibitors,research,lifescience,medical can be caused by environmental, physical, and psychological stressors, and even the susceptibility resulting from genetic vulnerabilities (see Figure 1). Glutamatergic excitotoxicity: stress, depression, and ADT Excess glutamatergic Inhibitors,research,lifescience,medical excitotoxicity

is one of the major mechanisms underlying neuronal damage and loss in the brain, and has been implicated in the pathophysiology of a variety of disorders, including those resulting from acute insult (eg, stroke induced ischemia or trauma) and neurodegenerative disorders (eg, amyotrophic lateral sclerosis, Huntington’s chorea, epilepsy, and Alzheimer’s disease.120,121 This section discusses evidence for excess glutamate in stress related mood disorders, the cellular mechanisms that contribute to glutamate Inhibitors,research,lifescience,medical excitotoxicity, and pharmacological strategies for intervention and treatment. Excess glutamate in depression and stress Abnormal glutamate levels and function have been implicated in psychiatric illnesses, Inhibitors,research,lifescience,medical including schizophrenia, anxiety, and mood disorders.122-124 Glutamatergic abnormalities have been reported in the plasma, serum, cerebrospinal fluid (CSF), and brain tissue of individuals suffering from mood disorders.123 Functional in vivo measures of glutamate content in the brain using proton magnetic resonance spectroscopy (II-MRS) show elevated glutamate levels in the occipital Vemurafenib in vivo cortex of depressed patients, although decreases have been reported in other regions.123,125 Preclinical studies also demonstrate a role for glutamate in the

Inhibitors,research,lifescience,medical actions of stress. Microdialysis studies have shown that stress increases extracellular levels of glutamate in the PFC and hippocampus,126,127 consistent with the possibility that atrophy of CA3 neurons arises in part through increased glutamate neurotransmission.128,129 This hypothesis is supported by studies demonstrating that TCL N-methyl-D-aspartic acid (NMDA) receptor antagonists attenuate stress-induced atrophy of CA3-pyramidal neurons.29,32,130 Stress or glucocorticoid treatment also increases the susceptibility to other types of neuronal insults, including excitotoxins and ischemia.129,131 There are several possible mechanisms that could contribute to the overactivation of glutamate in response to stress and in depression, including a decrease or loss of mechanisms for inactivation of glutamate.

168 A meta-analysis of numerous antidepressant buy BIIB057 studies similarly found women have a. better response to MAOIs than do men.165 In contrast, however, a. clinical trial comparing the efficacy of imipramine versus phenelzine in the treatment of 100 depressed patients found significantly more men than women responded to phenelzine treatment.153 The literature on the possible effects of sex on the Inhibitors,research,lifescience,medical treatment of bipolar disorder is not as extensive as that seen

for treatment of depression. Sex is not. a. valid predictor of response to lithium treatment of bipolar disorder,169 and a retrospective study of 1548 bipolar patients treated with lithium found no sex difference in treatment response rate.170 Another study of 360 bipolar patients reported a nonsignificant, superior response in women despite lower mean plasma levels of lithium.171 Data, then, while exiguous, do not suggest, a meaningful difference in pharmacodynamic Inhibitors,research,lifescience,medical response to bipolar

pharmacotherapy in men and women. Neuroleptics Underlying sex differences in the age of onset, course, and symptomatology of schizophrenia present difficulties when studying potential sex differences in treatment response to Inhibitors,research,lifescience,medical neuroleptic medications. Nonetheless, many studies have examined sex differences in treatment, response to neuroleptics. After initial observational studies noted that, females responded better to neuroleptic treatment,172 clinical trials of neuroleptic efficacy were conducted, and most confirmed that females respond better to neuroleptic treatment than do males,173-181 despite comparable drug plasma levels.182 However, many of these studies were compromised by their failure to sufficiently control for sex differences in smoking, dose, Inhibitors,research,lifescience,medical weight, and severity and type of symptomatology. Several more recent studies found no sex differences in treatment response to neuroleptic Inhibitors,research,lifescience,medical medication,183-186 and two studies of neuroleptic-refractory patients showed a trend for males to respond better to clozapine treatment than

females187,188 (although results from studies of neuroleptic-refractory patients might, not be generalizable).The inconsistency in results regarding sex differences in treatment response to antipsychotic medication may be due to differences in choice of neuroleptic and dose. For example, in a. study of 50 schizophrenic patients, females isothipendyl responded significantly better to clozapine treatment at 100 mg/day,but there were no sex differences in response among schizophrenic subjects randomly assigned daily doses of 300 or 600 mg/day.189 Some studies claim that female schizophrenic patients require lower doses of neuroleptics (after accounting for weight differences) than male schizophrenic patients,190,191 while other studies find no significant, sex difference in neuroleptic dose requirements.192-194 This contradiction could reflect differences in neuroleptics used.