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By K. Orknarok. Clarkson University.

Genital and colorectal LGV lesions can also develop secondary bacterial Follow-Up infection or can be coinfected with other sexually and Patients should be followed clinically until signs and symp- nonsexually transmitted pathogens buy viagra vigour uk impotence bicycle seat. Diagnosis is based on clinical suspicion buy 800 mg viagra vigour fast delivery erectile dysfunction after zoloft, epidemiologic information, and the exclusion of other etiologies for procto- Management of Sex Partners colitis, inguinal lymphadenopathy, or genital or rectal ulcers. Persons who have had sexual contact with a patient who C. NAATs for (azithromycin 1 gm orally single dose or doxycycline 100 mg C. Azithromycin might prove useful for treatment Chlamydia serology (complement fxation titers >1:64) of LGV in pregnancy, but no published data are available can support the diagnosis of LGV in the appropriate clinical regarding its safety and efcacy. Comparative data between types of serologic tests in pregnant women. Serologic test Persons with both LGV and HIV infection should receive interpretation for LGV is not standardized, tests have not been the same regimens as those who are HIV negative. Prolonged validated for clinical proctitis presentations, and C. In the absence of specifc LGV diagnostic testing, patients with a clinical syndrome consistent with LGV, including proc- Syphilis tocolitis or genital ulcer disease with lymphadenopathy, should be treated for LGV as described in this report. Syphilis is a systemic disease caused by Treponema pallidum. On the basis of clinical fndings, the disease has been divided Treatment into a series of overlapping stages, which are used to help guide Treatment cures infection and prevents ongoing tissue treatment and follow-up. Persons who have syphilis might seek damage, although tissue reaction to the infection can result in treatment for signs or symptoms of primary infection (i. Nontreponemal test titers usually decline after manifestations that include, but are not limited to, skin rash, treatment and might become nonreactive with time; however, mucocutaneous lesions, and lymphadenopathy), neurologic in some persons, nontreponemal antibodies can persist for a infection (i. Latent infections treated during the primary stage revert to being serologically (i. Latent syphilis acquired within the preced- titers should not be used to assess treatment response. Treatment for both late latent syphilis chemiluminescence immunoassays (201,202). Tis strategy and tertiary syphilis might require a longer duration of therapy will identify both persons with previous treatment for syphilis because organisms might be dividing more slowly; however, and persons with untreated or incompletely treated syphilis. Te positive predictive value for syphilis associated with a treponemal screening test result might be lower among popu- Diagnostic Considerations lations with a low prevalence of syphilis. If the nontreponemal test is negative, then the locally developed PCR tests for the detection of T. If a second treponemal Venereal Disease Research Laboratory [VDRL] and RPR) and test is positive, persons with a history of previous treatment 2) treponemal tests (e. Tose without a history agglutination [TP-PA] assay, various EIAs, and chemilumines- of treatment for syphilis should be ofered treatment. Te use of only one type of serologic history or results of a physical examination suggest a recent test is insufcient for diagnosis, because each type of test has infection, previously untreated persons should be treated for limitations, including the possibility of false-positive test results late latent syphilis. If the second treponemal test is negative, in persons without syphilis. False-positive nontreponemal further evaluation or treatment is not indicated. However, atypical syphilis a reactive nontreponemal test should receive a treponemal test serologic test results (i. When Nontreponemal test antibody titers may correlate with serologic tests do not correspond with clinical findings disease activity, and results should be reported quantitatively. Sequential serologic tests in abnormalities) warrant further investigation and treatment for individual patients should be performed using the same test- neurosyphilis. Laboratory testing is helpful in supporting the ing method (e. Te VDRL and RPR are equally valid assays, but to diagnose neurosyphilis in all instances. Cerebrospinal fuid quantitative results from the two tests cannot be compared (CSF) laboratory abnormalities are common in persons with directly because RPR titers frequently are slightly higher than early syphilis. Te VDRL in cerebrospinal fuid (CSF-VDRL), 28 MMWR December 17, 2010 which is highly specifc but insensitive, is the standard serologic desensitized and treated with penicillin (see Management of test for CSF. When reactive in the absence of substantial con- Patients Who Have a History of Penicillin Allergy). Most other tests are both insensi- other symptoms that usually occur within the frst 24 hours tive and nonspecifc and must be interpreted in relation to other after the initiation of any therapy for syphilis. Patients should test results and the clinical assessment. Terefore, the labora- be informed about this possible adverse reaction. Te Jarisch- tory diagnosis of neurosyphilis usually depends on various Herxheimer reaction occurs most frequently among patients combinations of reactive serologic test results, CSF cell count who have early syphilis, presumably because bacterial burdens or protein, and a reactive CSF-VDRL with or without clinical are higher during these stages. Among persons with HIV infection, the CSF manage symptoms, but they have not been proven to prevent leukocyte count usually is elevated (>5 white blood cell count this reaction. Te Jarisch-Herxheimer reaction might induce [WBC]/mm3); using a higher cutof (>20 WBC/ mm3) might early labor or cause fetal distress in pregnant women, but improve the specifcity of neurosyphilis diagnosis (204). Te this should not prevent or delay therapy (see Syphilis During CSF-VDRL might be nonreactive even when neurosyphilis is Pregnancy). Te CSF FTA-ABS test is less specifc for neurosyphilis than the CSF-VDRL but is highly Sexual transmission of T. Selection of the appro- syphilis in a sex partner might be infected even if priate penicillin preparation is important, because T. Reports have indicated results are not available immediately and the opportunity that practitioners have inadvertently prescribed combination for follow-up is uncertain. Practitioners, pharmacists, and pur- of unknown duration who have high nontreponemal chasing agents should be aware of the similar names of these serologic test titers (i. For the purpose of determining a treatment therapy agent for treating syphilis (206). Parenteral penicillin G is the only therapy with documented Sexual partners of infected patients should be considered efcacy for syphilis during pregnancy. Pregnant women with at risk and provided treatment if they have had sexual contact syphilis in any stage who report penicillin allergy should be with the patient within 3 months plus the duration of symp- toms for patients diagnosed with primary syphilis, 6 months Vol. Treatment should be guided by the results of this evaluation. Primary and Secondary Syphilis Invasion of CSF by T. Terefore, in the absence Parenteral penicillin G has been used efectively for more of clinical neurologic fndings, no evidence exists to support than 50 years to achieve clinical resolution (i. Symptomatic neurosyphilis develops in only a limited vent late sequelae. However, no comparative trials have been number of persons after treatment with the penicillin regimens adequately conducted to guide the selection of an optimal recommended for primary and secondary syphilis.

In general buy viagra vigour visa erectile dysfunction treatment in dubai, the variate measure of sleep quantity based on both diary and sedating properties of antidepressants are related to antago- polysomnographic sleep measures (96) discount viagra vigour 800 mg mastercard impotence in young men. For instance, fluvoxamine the treatment of insomnia. Some antidepressant drugs also has a relatively alerting effect relative to desipramine that can cause or exacerbate insomnia problems. Selective seroto- in turn is more alerting than amitriptyline (97,98). In addition, serotonergic specific antide- comparison of fluoxetine with trazodone showed that the pressants can lead to anomalous sleep stages characterized later drug was associated with more improvements in in- Chapter 133: Current and Experimental Therapeutics of Insomnia 1939 somnia symptoms, but also with a greater percentage of specific receptors in the suprachiasmatic nucleus of the hy- sedating events during the daytime (100). In addition, melatonin shifts circadian parisons between fluoxetine and nefazodone has consis- rhythms according to a phase response curve (110,111). Doses greater than 1 mg are likely to induce supraphysiologic concentrations. Clinical trials have Antihistamines employed doses ranging from. Antihistamines such as diphenhydramine and doxylamine During daytime administration, melatonin causes sleepi- are the most widely available over-the-counter preparations ness in fatigue and healthy subjects (112,113). The mechanism of action of these drugs in- ministered at night to healthy subjects, melatonin decreases volves inhibition of histamine H1 receptors. Histaminic sleep latency (114) and the number of awakenings, and neurons in the posterior hypothalamus promote wakeful- improves sleep efficiency in an experimental insomnia para- ness through interactions with ascending cholinergic nuclei digm (115). Inhibition Studies in insomnia patients have also yielded inconsis- of H1 receptors leads to decreased alertness and subjective tent findings. Single-night administration seems to produce sedation. The elimination half-life of diphenhydramine very little effect (116). Subjective sleep ratings showed no ranges from 3 to 5 hours, within increases in elderly persons. Trials of melatonin in elderly people have Despite their widespread use, a large body of well-docu- ranged from 1 to 21 days. The most consistent effect is mented research does not support the efficacy of antihista- reduced sleep latency with some evidence as well for reduced mines. Diphenhydramine 50 mg, improved subjective rat- nighttime wakefulness using sustained-released preparations ings of sleep quality, sleep time, sleep latency, and (119–122). In a carefully designed 14-day crossover trial, wakefulness after sleep onset in middle-aged subjects with immediate- and sustained-release melatonin were associated insomnia (103). Amore recent study comparing the effects with shortened sleep latency, but no change in sleep time, of lorazepam versus a combination of lorazepam plus di- sleep efficiency, wakefulness, or subjective sleep measures phenhydramine showed a slight advantage for the combina- (123). On most sleep measures, the two drug carefully evaluated. Melatonin has effects on reproductive preparations were fairly similar. Studies of antihistamines cycles in several mammalian species, and reports have indi- in elderly people demonstrate subjective sedative properties cated the potential for worsening of sleep apnea and im- comparable in magnitude to those of benzodiazepines and paired cognitive and psychomotor performance during day- confirmed by effects such as increased sleep time, decreased time administration. There are also some concerns regarding awakening, and shorter sleep latency (105,106). Adverse effects of antihistamines include a range of cog- nitive and performance impairments (107). The anticholin- Valerian Extract ergic effects of these medications may be of particular con- cern in elderly subjects. The relative safety and efficacy of Valerian extract is one of the most widely used herbal reme- antihistamines with more sustained use has not been exam- dies for insomnia. They contain a number of potentially active compounds, including sesquiterpenes and valepotriates. Data regarding its efficacy and safety have in these preparations (124,125). The study designs, doses, and outcome mea- cross the blood–brain barrier, so this is an unlikely mecha- sures used in melatonin trials have been quite variable and nism of action. Other potential actions include affinity for may contribute to inconsistent findings (108). In particular, four double-blind pla- on sleep and wakefulness may result from interaction with cebo-controlled studies have examined doses of 400 to 900 1940 Neuropsychopharmacology: The Fifth Generation of Progress mg of valerian extract over periods of time from 1 to 8 days, With regard to behavioral treatments, one of the major and in diverse subject populations ranging from healthy challenges is designing well manualized and 'exportable' young adults to elderly insomniacs (126–129). Subjective treatments that can be applied more readily in a variety of effects include decreased sleep latency and improved sleep treatment settings, including primary care settings. One study also reported decreased studies have begun to examine the optimal combination of subjectively rated awakenings (126). Findings from these studies are hampered by small be developed. These studies do not demonstrate the effi- from basic neuroscience sources. For instance, recent evi- cacy of valerian extract in most groups of individuals with dence has accumulated regarding the role of adenosine as primary insomnia. Relative underacti- Clinical studies have suggested a generally favorable side vity of adenosinergic neurotransmission could potentially effect profile for valerian extract; however, the sedative ef- result in reduced sleep drive. Finally, done regarding its consequences for health and role func- recent findings regarding the role of orexin in sleep/wake tioning. Individuals with insomnia complain not only of regulation could have direct implications for the neurobi- sleep disturbance, but daytime consequences as well. In ad- ology and pharmacologic treatment of insomnia (133,134). This will help to define the underlying path- mal management of insomnia disorders. Finally, genetic studies have been very useful for identifying abnormalities associated 1. Prevalence and persistence of sleep complaints in a rural elderly community sample: the with narcolepsy and circadian rhythm sleep disorders. Arch Gen Psychiatry 1985; Several issues also remain with regard to treatment as- 42:225–232. Sleep complaints among elderly persons: an epidemiologic study of three communities. Epidemiologic study of sleep distur- issues are of considerable importance, given the potential bances and psychiatric disorders. The optimal duration of treatment and the conceptualiza- 6. Incidence and remis- tion of potential 'maintenance' treatments for insomnia is sion of insomnia among elderly adults: an epidemiologic study also an area open for further investigation.

A higher suicide risk was demonstrated for those who were discount viagra vigour 800 mg erectile dysfunction diet pills, 1) the offspring of young parents buy discount viagra vigour erectile dysfunction and diabetic neuropathy, 2) the children of mothers of high parity, 3) the children of non-professional parents, and 4) of low birth weight. This study suggests that less than optimal perinatal circumstances impact on the individual, perhaps through personality development, limiting coping skills in later life. Sociological factors have a profound effect on the rate of suicide. Thus, suicide is not simply a matter for mental health services. In 1970, Stengel identified the important risk factors as being male, older, widowed, single or divorced, childless, high density population, residence in big towns, a high standard of living, economic crisis, alcohol consumption, broken home in childhood, mental disorder, and physical illness. While many of these hold today, residence in the country has replaced “residence in big towns” and low socioeconomic status has replaced “a high standard of living”. Lists of risk factors have been gathered for decades, but, they have high sensitivity and low specificity, while suicide has a low base rate - leading to unmanageably large numbers of both false positives and false negatives. A Sydney based group has extremely robustly stated that risk categorization (using risk factors) plays little or no role in the prevention of suicide (Large and Ryan, 2014 a&b; Large et al, 2011 a&b). These authors recommend that patients with mental disorder and other suffering individuals should be closely examined and all possible treatment/assistance should be provided – it is the treatment/management of issues rather than the classification of risk which is helpful. Some recent studies reported certain factors playing a stronger role than mental disorder. Almeida et al (2012) examined the suicidal thoughts of older people, found social disconnectedness and stress accounted for a larger proportion of cases than the mood disorders. Park et al (2013) have emphasized the importance of strained family relationships and a tolerant attitude to suicide. Schneider et al (2013) have emphasized the importance of obesity, smoking and living alone and conclude, “Suicide prevention measures should not only subjects with mental disorders but also address other adverse conditions”. Some medically orientated groups make observations which encourage the belief that mental health professionals can prevent suicide. For example, a recent study (Beautrais, 2004) of people who had made a suicide attempt found that after 5 years, 6. The paper concludes, “These findings imply the need for enhanced follow-up, treatment, and surveillance of all patients making serious suicide attempts”. This argument is logical, but impractical; most services are already doing their best and there is little evidence that any form of therapy is effective and maintaining intensive follow-up for 5 years would be impossible (from many points of view). In another example (Burgess et al, 2000), “Data on patient and treatment characteristics were examined by three experienced clinicians” and they found that “20% of the suicides were considered preventable. An exemplary admission procedure does not stop the patient out on leave getting drunk or being rejected by a lover; it does not strengthen the last straw for that individual. Beck et al (1999) studied outpatients at high risk of suicide, people 100 times more likely to suicide than members of the general population. They found the suicide rate among this high risk population was only 0. Thus, to save one life, even in this high risk group, it would be necessary to provide infallible care, 24 hours per day to 500 people for one year. Also, the support offered would need to be in a form acceptable to each individual. Powell et al (2000) studied psychiatric inpatient suicide. They compared those who had suicided as inpatients with a control group and identified risk factors. However, they concluded, “Although several factors were identified that were strongly associated with suicide, their clinical utility is limited by sensitivity and specificity, combined with the rarity of suicide, even in this high-risk group”. Appleby et al (1999) conducted comprehensive analysis of 10 040 suicides. They found, “Most… (of the deceased)… were thought to have been at no or low immediate risk at the final contact”. Fahy et al (2004) asked 7 experienced mental health professionals to read the notes of 78 psychiatric patients, and attempt to predict which 39 had suicided. The readers considered all known suicide risk factors. The result was that these skilled clinicians did no better than chance. The authors state, “…these disappointing findings call into question the clinical utility of risk factor findings to date”. There have been a number of well resourced small studies, in which high risk groups have been given sustained attention with special counseling and additional support. In none of these was there a significant difference in outcome when the experimental was compared to a control group. Reviewing these studies, Gunnell and Frankel (1994) found, “No single intervention has been shown in a well conducted randomized controlled trial to reduce suicide”. Similar conclusions have recently been made with respect of suicide among young people (Robinson et al, 2010). To date, 5 men have completed suicide at Guantanamo prison camp. Even with the reputation of the most powerful nation in the world in the balance, in the most secure environment on the planet, and with all possible resources, suicide could not be indefinitely prevented. Hospital admission Not infrequently, following a suicide, there is criticism of mental health professionals and systems for failing to admit people to hospital or, having admitted them, failing to provide some particular service/supervision. Most psychiatrists, however, have known closely supervised patients who have suicided. Powell et al (2000) described their experience, “…two inpatients were under continuous observation. One of these two jumped through a window and deliberately cut his neck with the broken glass, the other ran to a railway line and was hit by a train. In response to budgetary constraints, admissions to psychiatric hospital in Fulton County Georgia, USA, had to be reduced. Over the same time period, the suicide rate of the county did not increase, but fell, from 12 to 10/100 000 (not statistically significant). Thus, ready admission to hospital does not improve the suicide rate of a general population. Another group admitted to hospital for their own safety are people with an episode of a disorder like major depressive disorder, who appear to be in some danger of suicide. The idea here is that hospital is a safe place where the mental disorder can be most efficiently treated. The Sydney based researchers mentioned above have put forward a revolutionary idea, “Nosocomial Suicide” - that psychiatric admission may increase the risk of suicide (Large et al, 2014). For some individuals, adverse aspects of psychiatric ward admission may include stigmatization, a sense of abandonment and heightened vulnerability. This idea needs close examination and may change psychiatric practice. The impact of suicide on others Impact on relatives and friends. There is surprisingly little standardized data on the effect of relatives and friends of those who suicide.

There are also a variety of preclinical data to support likely to be weak 5-HT2C and potent 5-HT2A antagonists the importance of relatively high 5-HT2A compared to D2 compared to typical neuroleptic drugs discount viagra vigour online amex prostate cancer erectile dysfunction statistics. Subsequently viagra vigour 800mg fast delivery impotence zantac, neu- receptor affinity to preserve striatal function. For example, rochemical (120) and behavioral (96,124) data have been Ishikane et al. THEROLEOFTHE5-HT1A RECEPTOR IN THEROLEOFTHE5-HT2C RECEPTOR IN ANTIPSYCHOTIC DRUG ACTION ANTIPSYCHOTIC DRUG ACTION: 5-HT2A AND 5-HT2C INTERACTIONS The 5-HT1A receptor is located pre- and postsynaptically. The presynaptic 5-HT1A receptor is an autoreceptor located There has been some consideration given to the role of on cell bodies of raphe neurons; stimulation leads to inhibi- 5-HT2C receptors in the action of atypical antipsychotic tion of firing of 5-HT neurons. The 5-HT2Creceptor is found throughout the central 5-HT receptors generally leads to hyperpolarization of 1A nervous system (CNS), including the ventral tegmentum neurons, which is opposite of the effect of stimulation of and the nucleus accumbens (121). There is extensive evidence that cannot specific 5-HT2C agonists and antagonists, evidence for a be reviewed in detail here that indicates that 5-HT1A recep- tonic inhibitory action of 5-HT2C receptors on the burst tor agonists and 5-HT2A receptor antagonists produce simi- firing of mesolimbic and mesocortical dopaminergic neu- lar neurochemical and behavioral effects on a variety of mea- rons has been obtained. For example, DOI injected bilaterally into neurons is inhibited or increased by 5-HT2C agonists or the rat medial prefrontal cortex elicits a dose-dependent antagonists, respectively. This is consistent with microdia- head twitch response. This effect is inhibited by M100907 lysis studies that show that 5-HT2C antagonists increase and ketanserin, relatively selective for 5-HT2A receptors at extracellular concentrations of DA in the nucleus accum- appropriate doses, but not the selective 5-HT2C antagonist bens, striatum, and medial prefrontal cortex (91,122). Pretreatment with the 5-HT1A agonist studies found no significant differences between groups of 8-OH-DPAT also inhibited the head twitch response to novel antipsychotic drugs and typical neuroleptics with re- DOI (127). Ahlenius (128) first suggested that stimulation 826 Neuropsychopharmacology: The Fifth Generation of Progress of 5-HT1A receptors might produce an antipsychotic like models and suggest this may be due to blocking the inhibi- action on the basis of behavioral studies in animals using the tory effects of 5-HT1A receptor stimulation on the firing of direct 5-HT1A agonist 8-OH-DPAT. This suggests that a partial agonist, demonstrated that 8-OH-DPAT enhanced the antipsy- acting as an antagonist, may sometimes be of benefit with chotic-like effect of the D2/D3 antagonist raclopride (129) regard to effects relevant to schizophrenia. The THE ROLE OF SEROTONIN RELEASE IN ability of clozapine to reverse olanzapine-induced catalepsy ANTIPSYCHOTIC DRUG ACTION is blocked by the selective 5-HT1Aantagonist WAY 100635, suggesting the effect of clozapine was mediated by stimula- tion of 5-HT1A receptors. The beneficial effect of 5-HT1A The antagonism of multiple 5-HT receptors by clozapine agonists appears to be mediated by inhibition of median would be expected to enhance the release of 5-HT by feed- raphe serotoninergic neurons (132). Thus, it is surprising that Ferre and Arti-´ 5-HT1A agonists have different regional effects on DA gas (136) reported that clozapine decreased 5-HT release release in the rat brain. Thus, Ichikawa reported that clozapine (20 mg/kg) and risperidone (1 mg/ et al. The effect of 5-HT1A receptor stimu- tracellular 5-HT levels in both regions. If so, this is not the explanation for the effects including clozapine, ziprasidone, quetiapine, and tiospi- of clozapine or olanzapine on negative symptoms because rone, are partial agonist at the 5-HT1A receptor. Their affin- olanzapine, sulpiride, haloperidol, and M100907 had no ities for the 5-HT1A receptor are similar to their affinities effect on extracellular 5-HT levels in either region. The enhance- agonist properties, as it could be blocked by WAY-100635, ment of 5-HT efflux in the prefrontal cortex may contribute a 5-HT1A antagonist. These findings suggest that the 2-AND 1-ADRENERGIC MECHANISMS combination of D2 antagonism and 5-HT1A agonism pro- AND ATYPICAL ANTIPSYCHOTIC DRUGS vides some of the key features of atypical antipsychotic agents. S16924, a 5-HT1A partial agonist D2 antagonist, is an example of a putative atypical antipsychotic drug based Most of the atypical antipsychotic drugs are potent antago- on this model. It has atypical antipsychotic properties very nists of the 1 or 2 adrenoceptors, or both. Thus, risperi- similar to those of clozapine in a variety of relevant animal done 9-hydroxyrisperidone, clozapine, olanzapine, zotep- models (64). Whether this or similar compounds will have ine, quetiapine, ORG-5222, sertindole and ziprasidone are the same spectrum of efficacy and side effect advantages as potent 1 antagonists (22). Prazosin, an 1 adrenoceptor the multireceptor antagonists that are relatively more potent antagonist, has, like clozapine and other atypical antipsy- 5-HT2A than D2 antagonists remains to be determined. It is noteworthy but not the core of the nucleus accumben, signifying a lim- that clozapine has both relatively more potent 5-HT2A an- bic rather than a striatal effect of 1 antagonism (91). These tagonism than D2 antagonism as well as 5-HT1A partial authors also suggested that 1 antagonism may explain the agonism. This may be part of the mixture that accounts for atypical properties of sertindole, which has been reported its particular advantages over other atypical antipsychotic to achieve as high an occupancy of D2 receptors as typical drugs. All of the atypical agents men- 5-HT1A antagonist, attenuated the effect of MK-801, an tioned above are also potent 2 antagonists, with the excep- NMDA antagonist on locomotor activity, prepulse inhibi- tion of zotepine and sertindole (22). They cite other evidence that 5-HT1A an- of clozapine and iloperidone. However, McAllister and Rey tagonists may improve learning and memory in animal (139) were unable to reverse the effects of loxapine or halo- Chapter 58: Mechanism of Action of Atypical Antipsychotic Drugs 827 peridol on catalepsy with 2 antagonists and showed that the role of 5-HT2A receptors and suggestive evidence of the the effect of clozapine to reverse loxapine-induced increase roles of the 5-HT1A, 5-HT2C, and 1 receptors in various in catalepsy was due to its anticholinergic rather than its actions of clozapine, risperidone, olanzapine, quetiapine, zi- adrenoceptor blocking properties. Clozapine produces mas- prasidone, iloperidone, sertindole, and related atypical anti- sive increases in plasma norepinephrine, which may indicate psychotic drugs. Atypical antipsychotic drugs that are po- that it can cause effective stimulation of -adrenoceptors tent 5-HT2A antagonists relative to their D2 receptor receptors in brain (140). The addition of idazozan, an 2 blocking property appear to potentiate 5-HT1A-mediated antagonist, to fluphenazine, a typical neuroleptic, was re- effects on dopaminergic neurons in the mesocortical, meso- ported by Littman et al. The effects in the mesocor- to clozapine in a small group of neuroleptic-resistant pa- tical regions appear to be mediated by modulation of gluta- tients with schizophrenia. These results need to be repli- mate release from pyramidal neurons. Idazoxan has also been shown to improve attentional been found to preferentially increase DA efflux in the mPFC and executive dysfunction in patients with dementia of the compared to limbic and striatal regions. They also increase frontal type (142), suggesting that some of the cognitive acetylcholine release in the PFC. Effects on 5-HT2C, enhancing effects of the atypical antipsychotic drugs might 5-HT3, 5-HT4, 5-HT6, and 5-HT7 receptors may also be be related to their blocking properties. Another antag- relevant to some of their actions, e. Other models of atypicality appear performance in aged rats (143). Polymorphisms of the to be effective, including partial DA agonists such as aripi- 1 and receptors have been reported not to predict response prazole. Selective D2/D3 antagonists such as amisulpride 2 to clozapine (144). At this time, multirecep- In this regard, it is of interest that idazoxan has been tor agents appear to be more promising as antipsychotic shown to preferentially increase DA efflux in the rat mPFC agents for the majority of psychiatric patients because of by an action at the terminal area (145). This effect appears important interactions between neural circuits that employ multiple neurotransmitters. This effect was closely coupled to the increase in DA efflux.

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