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Elliott and co- tomatology in HIV-1-infected patients is not clear (147) order nolvadex overnight, workers (151) blindly and randomly assigned 75 HIV-sero- it is prudent that the medical evaluation of depressive symp- positive patients to treatment with imipramine buy genuine nolvadex online, paroxetine buy nolvadex pills in toronto, toms in HIV-1-infected patients include an assessment of or placebo. Of the 75 enrolled subjects, 75% completed 6 serum B12 levels. The two antidepressants were found to be equally effi- from HIV-1 involvement of the CNS. Earlier case studies cacious at 6, 8, and 12 weeks, and both were significantly of symptomatic HIV-1-infected persons have reported psy- more efficacious than placebo. Side effects of the tricyclic chotic symptoms, including delusions, bizarre behavior, and antidepressants markedly influenced attrition. Mood disturbances, including euphoria, ir- rate in the imipramine group was 48%, 20% in the paroxe- ritability, and labile or flat affect, have often accompanied tine group, and 24% in the placebo group. Similarly, anxiety and colleagues (152) reported that fluoxetine was more effective agitation were reported in almost half of the reported cases. Rabkin and colleagues (153) recently described had a progressively worsening course, with de- completed a double-blinded, placebo-controlled, 8-week mentia or death occurring within a few months after the trial with fluoxetine in 120 HIV-seropositive subjects. Psychosis may be more fre- Among the subjects who completed the 8-week trial, 74% of Chapter 90: Neuropsychiatric Manifestations of HIV-1 Infection and AIDS 1291 the fluoxetine group responded to treatment, in comparison of the potential for drug interactions between antidepres- with 47% of the placebo group. When intention-to-treat sants that potentially inhibit the CPY450 3A4 isoenzyme analysis was used, the differences between the treatment system and protease inhibitors and for adverse effects of groups were less remarkable (57% of the fluoxetine-treated herbal therapy. Although the outcomes of the open-label subjects responded compared with 41% of the placebo studies have generally been consistent with those of the group). Drug treatment did not alter levels of CD4 cell available double-blinded, randomized, placebo-controlled counts. Thus, the available data suggest that the selective trials, these findings must nonetheless be interpreted cau- serotonin re-uptake inhibitors (SSRIs) are effective and well tiously. Effects of Psychostimulants and Novel Agents Fernandez et al. With either In a study related to the one described above, Rabkin and agent, subjects showed a response rate of approximately colleagues (154) enrolled HIV-infected subjects with 50%; however, subjects treated with desipramine experi- depression who had failed imipramine treatment (i. Although depression at baseline as measured on the and a DSM-III-R diagnosis of depressive disorder, the re- Hamilton Depression Scale (HAM-D) was more severe in sponse rate to dextroamphetamine treatment was 75%. Although systematic follow- tions in their HAM-Dscores. Fluoxetine treatment did not up evaluations were not conducted, anecdotal evidence sug- alter CD4 counts. Fluoxetine was tolerated better than gested that the treatment effect (improved mood and en- imipramine. In an open-label trial of 28 depressed HIV- ergy) was maintained for up to 2 years in some subjects. Side effects resulted in a loss of 18% of the total troamphetamine (5 to 25 mg/d) responded during the 12- sample. Sertraline did not alter the counts of either CD4 week course of treatment, another preliminary observation cells or natural killer cells. Placebo-controlled trials are Ferrando and colleagues (156) conducted a 6-week open- necessary to confirm these promising observations. Seventy-three percent of subjects energy and with sexual dysfunction. In a double-blinded, completed the trial, and of these, 83% responded to their placebo-controlled trial (6-week trial followed by 12-week assigned treatment. Most of the subjects who dropped out open-label maintenance), testosterone injections were effec- did so because of complaints of agitation, anxiety, and in- tive in improving both mood and libido, energy, and body somnia during weeks 1 through 3. Both depression and muscle mass in 70 HIV-seropositive men with hypogonadal somatic symptoms perceived to be related to HIV infection symptoms who completed the trial (162). Differences in efficacy be- found that exercise may augment improvement in psycho- tween the three SSRIs could not be ascertained reliably be- logical and nutritional status in HIV-seropositive patients cause of the study design and small sample size. In an 8-week open- cently, these authors performed a small open trial label pilot study of 45 HIV-positive subjects, the adrenal comparing fluoxetine (n 21) and sertraline (n 9) in steroid dihydroepiandrosterone (DHEA) appeared promis- HIV-infected women (157). Sixty percent of the women ing for improving mood in addition to anabolic and andro- completed the trial, and of these, 78% were responders (e. Sig- and Other Psychiatric Conditions nificant improvement in HAM-Dscores was noted between weeks 2 through 6 of the study. Recently, a 73% response Antidepressant therapy is effective and can improve the rate was demonstrated with nefazodone in a small open trial quality of life of HIV-infected persons. An open-label study recently re- fection (165), although it is well established that antidepres- vealed that the efficacy of the protease inhibitor indinavir sants are effective agents for the treatment of chronic pain, (which is a metabolized by the 3A4 isoenzyme system) is particularly antidepressants with noradrenergic properties markedly reduced by the concomitant administration of St. The fects more frequently with tricyclic antidepressants than do reduction in indinavir levels was estimated to be sufficient to patients with AIDS-related complex and asymptomatic cause drug resistance and treatment failure. Better-tolerated antide- that psychotropic drugs such as antidepressants can improve pressants with effects on serotoninergic and noradrenergic the quality of life of HIV-positive persons, further research neurotransmitter systems include venlafaxine, mirtazepine, is needed to determine whether effective treatment can im- and paroxetine; these may prove useful and are awaiting prove medical outcomes in selected subsets of HIV-infected controlled studies. The multifactorial nature of HIV infection has led research- ers to examine the influence of stress, depression, and other Treatment of Psychotic Symptoms psychosocial factors on the course of this disease. A growing literature points to the potentially harmful effects of stress The treatment of psychotic disorders in HIV-infected pa- and depression on cellular immunity (173–176), and to the tients has been less well studied than the treatment of mood potentially negative impact of these psychosocial factors on disorders. Several reports have noted that HIV-seropositive the course of several types of cancer (177–180). Among patients may be more sensitive to the extrapyramidal side patients with breast cancer, severe life stress has been associ- effects associated with dopamine-receptor antagonists (149, ated with a greater probability of relapse (179), and psycho- 168). This is thought to be related to the subcortical motor social interventions to improve coping skills have resulted slowing associated with HIV infection. In a case series of in increased numbers and function of natural killer cells 21 patients with psychotic symptoms (12 had mania with and longer survival in patients with breast cancer or mela- psychotic features), risperidone was found to be efficacious noma (177,178,181). Investigators found no relationship be- antipsychotic agents may be increased (170). Controlled tween psychosocial and psychiatric factors such as depressive studies are needed in this area. However, a relationship infected patients with psychotic symptoms or mood disor- was noted between the number and severity of HIV-related ders. Pharmacologic knowledge can be used to therapeutic symptoms and levels of depressive disorders, distress, and advantage and to avoid potential untoward effects. Potential interactions commonly accepted markers of HIV disease progression. Psychotropic drugs, non-nucleoside reverse tran- Prospective studies conducted for longer time intervals scriptase inhibitors, and protease inhibitors may serve as have found that depression may significantly predict HIV substrates for various cytochrome P-450 enzymes in the disease progression. Each of these classes of compounds may possess en- Study, a 9-year longitudinal study of 395 seropositive gay zyme-inducing or enzyme-inhibiting properties, and drugs men, researchers found that subjects classified as depressed Chapter 90: Neuropsychiatric Manifestations of HIV-1 Infection and AIDS 1293 at study entry on the CES-D(186) progressed more rapidly symptoms. The small number of subjects with elevated to AIDS (187). The median time to first AIDS diagnosis scores may partially account for this outcome.

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The results from the GAIN American study common adverse event that led to treatment withdrawal in are not yet available discount 10 mg nolvadex with amex. Fewer binding sites have been character- tive functional independence (97) buy nolvadex 20 mg cheap. The difference was not ized on the AMPA receptor compared to the NMDA recep- significantly different but in a subgroup analysis of 545 tor cheap nolvadex amex. Competitive quinoxalinedione antagonists bind to the patients who had total anterior circulation syndrome AMPA binding site and there are also noncompetitive GYKI (TACS), the percentage of those reaching relative functional [GYKI 52466,1-(4-aminophenyl)-4-methyl-7,8-methylen- independence was 40. This subgroup efficacy has nists, benzodiazepine binding-site antagonists, and pore- prompted the testing of clomethiazole in large ischemic ce- blocking antagonists (86). The pore-blocking antagonists rebral infarctions (CLASS-I), ischemic infarctions in those are mostly from spider toxins and are not appropriate for who receive tPA (CLASS-T), and intracerebral hemorrhage clinical development. Previous failed clinical trials for stroke may KA receptor antagonist, EGIS-9637, which demonstrates have shown efficacy had there been subgroup targeting like neuroprotective efficacy in both focal and global animal that being carried out in the CLASS-I study. However, it ischemia models, but the clinical development has not is difficult to categorize subgroups of strokes while operating begun and little is known of the tolerability (87). One of the under the extreme time constraints stroke treatment re- more common CNS effects of AMPA receptor antagonists is quires. A recent protocol for grading strokes has been devel- sedation. All of the AMPA receptor antagonists in clinical oped (ASPECTS, which addresses the need for rapid diag- trials for the treatment of acute stroke are competitive antag- nosis and assessment of infarct (99). NBQX and other quinoxalinediones are neuroprotective in animal models of ischemia, even when administered up to 12 hours following reperfusion (88). The main problem OTHER THERAPEUTIC TARGETS with quinoxalinediones has been nephrotoxicity owing to Voltage-Gated Channels the poor solubility of these compounds (89). One AMPA receptor antagonist, ZK-200775, progressed to phase IIa Potassium channel openers may rescue injured penumbral but these trials were discontinued in 1998 owing to excessive neurons, thus reducing the size of the infarct and improving sedation (90). Yamanouchi Pharmaceuticals have developed neurologic outcome. The novel potassium channel opener, a series of competitive AMPA receptor antagonists that are BMS-204352, is being assessed in the Potassium-channel neuroprotective in animal models and exhibit improved sol- Opening Stroke Trials (POST) in which medication is ad- ubility (91–93). In phase I trials YM90K was well tolerated ministered within 6 hours of onset of symptoms. The pri- and in spite of a high rate of urinary excretion there were mary endpoint is change in lesion volume at 12 weeks deter- only mild changes in kidney function markers with a single mined by diffusion/perfusion MRI. These phase I trials were followed by phase II trials using the AMPA receptor antagonist, YM872, Opioid Receptor Antagonists which has a solubility 800-fold greater than NBQX or YM90K at pH 7 (95). The The competitive -selective opioid receptor antagonist Cer- only adverse effect reported in the YM872 phase I study vene (Nalmefene) is neuroprotective in animal models of 1334 Neuropsychopharmacology: The Fifth Generation of Progress ischemia and clinically safe (100). In a phase II trial in differences in outcome or mortality. The results from the patients with acute ischemic stroke treated with 6, 20, or 899 patient phase III trial comparing 2,000 mg citicoline 60 mg Cervene there was no significant functional improve- to placebo (105) failed to meet the primary endpoint, an ment compared to placebo after 3 months (100). However, citicoline ary analysis showed an improved 3-month outcome in pa- was shown to be safe and there was a higher percentage tients less than 70 years of age. Treatment with a monoclonal anti-ICAM-1 antibody Free Radicals, Nitric Oxide, and inhibits leukocyte adhesion by blocking leukocyte attach- Inflammation ment and migration through cerebral endothelial cells and During reperfusion, oxygen-free radicals contribute to dam- reduces neurologic deficits in rodent ischemia models (34). Superoxide, hydrogen peroxide, and hydroxyl radi- 1996 showed that the anti–ICAM-1 antibody treated pa- cals are responsible for damaging membranes and degrading tients had a worse outcome than placebo-treated patients DNA. In experimental models, agents such as vitamin E, (35). LeukArrest (Hu23F2G) is another human antibody glutathione, superoxide dismutase, iron chelators, lazaroids, that inhibits neutrophil movement from the blood into the NPY-059, and catalase have been tested as free radical scav- brain by specifically targeting CD11/CD18 molecules on engers. One of the most tested agents, Triliazad mesylate the surface of neutrophils. A recently completed phase II (Freedox), an inhibitor of lipid peroxidation, is neuropro- trial showed LeukArrest to be safe and suggested an im- tective in stroke models (37). In a phase II study of over proved neurologic outcome. The Hu23F2G Phase III 400 patients treated with 6 mg/kg per day tirilazad for 3 Stroke Trial (HALT) with 310 patients was begun in early days within 6 hours of onset, no significant outcome relative 1999. The Randomized Trial of High Dose Tirilazad in Acute Stroke (RANTTAS II) phase III trials of a higher dose was stopped because of CONCLUSION AND FUTURE DIRECTIONS: a lack of efficacy (102). Similarly, the antioxidant Ebselen, THE ARSENAL OF A UTOPIAN STROKE which has glutathione peroxidase-like activity, showed no CARE CENTER efficacy (103). NPY-059 is currently in early phase II trials by Centaur. Given the worldwide efforts focusing on cloning the human Lubeluzole (Prosynap) is a benzothiazole that blocks glu- genome and the parallel efforts to identify disease specific tamate-induced nitric oxide-mediated neurotoxicity in rats. Because there a continuous infusion of 10 or 20 mg per day for 5 days, are currently only 450 clinical targets of therapeutic inter- respectively. This trial was terminated early owing to high vention worldwide, there are at least 9,000 new genes for mortality in the high-dose group (36). Clinical development which we have no idea of function and no pharmacologic was subsequently stopped after a large phase III trial (Lub- tools with which to study them. One thing is certain; we Int-13) failed to show efficacy. During ischemia phosphatidylcholine is efforts to increase blood flow may include angiogenesis broken down into free fatty acids, which in turn generate using a recombinant adenovirus expressing vascular endo- free radicals. Citicoline has been studied as a neuropro- thelial growth factor (VEGF) or perhaps other gene therapy tectant as well as a promoter of neural plasticity and repair delivered vascularly. Still more effort is being focused on after stroke through its actions to promote membrane syn- NMDA receptors, but in developing safer compounds such thesis, to decrease the levels of free fatty acids and to pro- as ARL 15896 and GV150526 with a better therapeutic mote the regrowth of axons and nerve terminals. In a phase ratio than agents that previously failed in trials. Trials are II study, oral citicoline (CerAxon; 500, 1,000, and 2,000 well underway for some AMPA receptor antagonists like mg per day) was administered within 24 hours for a 6- YM872 and the results of these will reveal whether this week period (104). A dramatic improvement in functional strategy is a viable one worthy of further attention. A phase III trial of fibroblast growth factor (Biblast, citicoline versus placebo failed to demonstrate significant bFGF, Trafermin) was discontinued because of no efficacy Chapter 93: Current and Experimental Treatment of Stroke 1335 relative to the placebo group. The glial derived growth fac- ulation of stroke patients: simulation model. Br Med J 1999; tor, GFG2, is being developed by Cambridge NeuroScience 319:288–289. Temporal profile of neu- (CNSI) for treating neurodegenerative disorders and may ronal damage in a model of transient forebrain ischemia. Another avenue of therapy is to Neurol 1982;5:491–498.

Among women with osteoporosis (N=3214) order nolvadex with paypal, alendronate produced a greater increase in BMD at the hip and femoral neck in the group with eGFR <45 ml/min than women with eGFR ≥45 ml/min buy 20mg nolvadex fast delivery. However at the spine the increase in BMD was greater in women with eGFR ≥45 ml/min buy discount nolvadex 20mg on-line. There was no significant interaction between renal function and increase in BMD. The risk reduction was significant in women with eGFR ≥45 ml/min for both clinical and spine fractures, but NS in women with eGFR <45 ml/min. R+A alfacalcidol Risedronate + alfacalcidol: +2% from baseline (p<0. Bisphosphonates appeared to have benefits on bone mineral density in people with CKD. The studies did not include prevention of osteoporosis in people with a GFR <30 ml/min/1. Guidelines on the management of osteoporosis do not make recommendations that relate to people with CKD. It is then hydroxylated in the liver to form 25-hydroxyvitamin D (calcidiol) and then hydroxylated 160 13 Specific complications of CKD – renal bone disease in the kidney to 1,25-dihydroxyvitamin D (calcitriol), which is the most active form. Vitamin D deficiency can therefore occur as a result of decreased intake or absorption, reduced sun exposure, increased hepatic catabolism, or decreased endogenous synthesis (via 25-hydroxylation in the liver and subsequent 1-hydroxylation in the kidney). Active vitamin D has a variety of actions on calcium, phosphate, and bone metabolism. By increasing intestinal calcium and phosphate reabsorption and increasing the effect of parathyroid hormone (PTH) on bone, in health vitamin D has the net effect of increasing the serum calcium and phosphate concentrations. Vitamin D deficiency or resistance interferes with these processes, sometimes causing hypocalcaemia and hypophosphataemia. Since hypocalcaemia stimulates the release of PTH, however, the development of hypocalcaemia is often masked. The secondary hyperparathyroidism, via its actions on bone and the kidney, partially corrects the hypocalcaemia but enhances urinary phosphate excretion, thereby contributing to the development of hypophosphataemia. In people with CKD the kidney component of this loop is increasingly compromised as CKD advances. As renal function declines, the hydroxylating activity of renal 1α-hydroxylase on 25-hydroxy- vitamin D3 also decreases, resulting in decreased production of active vitamin D (1,25-dihydroxy- vitamin D3) and decreased intestinal absorption of calcium. The decrease in calcium and active vitamin D3 alleviates the repression of parathyroid hormone (PTH) production, resulting in hyperproliferation of parathyroid cells. High PTH levels cause an increase in bone remodelling, leading to high bone-turnover (osteitis fibrosa), loss of bone density and structure. This excess bone remodelling liberates calcium and phosphorus from bone, resulting in hypercalcaemia and hyperphosphataemia and increasing the risk for vascular calcification. Vitamin D supplementation in people with CKD should therefore be driven by the underlying metabolic abnormality. This in turn will depend on the stage of CKD but is complicated by the fact that in the population with the highest prevalence of CKD, the older population, vitamin D deficiency is common. Cutaneous vitamin D production and vitamin D stores decline with age coupled with the fact that intake is often low in older subjects. Furthermore, even in those with adequate vitamin D intake, achlorhydria, which is common in older people, limits vitamin D absorption. Nutritional forms of vitamin D include ergocalciferol and cholecalciferol; active forms of vitamin D include alfacalcidol, calcitriol and paricalcitol. Elderly patients are likely to be vitamin D deficient from diet, lack of sunlight and poor absorption for which they will need nutritional vitamin D. However as CKD progresses (particularly in stages 4 and 5), renal function is impaired to such a degree that active vitamin D may also be required. Outcomes of interest included adverse events, fractures, changes in serum calcium, phosphorus, PTH, osteocalcin, alkaline phosphatase, GFR, and bone mineral density. All of these studies are limited by small sample sizes (N=25–220), and very few presented intention to treat analyses. There were no studies of acceptable methodological quality that compared different vitamin D metabolites head-to-head. Two of these RCTs titrated the dose of calcitriol from 0. One RCT compared 6 months of treatment with calcitrol (N=8, 1 µg/day) or calcidiol (N=9, 4000 IU/day) in people with chronic renal failure. Two RCTs investigated the effects of treatment with alfacalcidol (1-α-hydroxycholecalciferol) compared to placebo in people with mild to moderate CKD (creatinine clearance 10–60 ml/min). RCT (N=89 alfacalcidol and N=87 placebo, 24 months follow-up) titrated the dose of alfacalcidol from 0. Most of the participants had abnormal bone histology at baseline (NS difference between the trial arms). A pooled analysis of 3 RCTs with identical inclusion/exclusion criteria and different dosing regimens (3 times weekly or once daily) compared paricalcitol (N=107, 6 months follow-up, mean dose was 1. Although this study was not a systematic review, it was included as an RCT (albeit pooled) due to lack of studies of non-dialysis CKD populations. Serum calcium One RCT showed that serum calcium significantly increased with calcitrol (0. By contrast BMD of the lumbar spine (L2–L4), femoral neck, and trochanter significantly decreased in the placebo group (p<0. Serum calcium Two RCTs showed that mean serum calcium increased significantly in people taking alfacalcidol, while there were NS changes in calcium in people taking placebo, p<0. At 24 months, iPTH returned to baseline levels in those with alfacalcidol treatment. At the end of the study only 1 person in the alfacalcidol group had osteocalcin levels above the reference range (4. After 24 months treatment, 54% of people taking alfacalcidol and 82% on placebo had bone abnormalities (no p given). The eroded bone surface significantly decreased in the alfacalcidol group while it increased in the placebo group, p=0. Also, alfacalcidol was associated with a significant decrease of active eroded surface compared with placebo, p=0. NS changes in total body BMD in the placebo or the alfacalcidol NS changes in forearm BMD in the placebo or the alfacalcidol groups continued 169 Chronic kidney disease Table 13. Serum calcium Mean serum calcium increased slightly in people taking paricalcitol, while there were small decreases in serum calcium in the placebo group, NS between groups. Significantly more people taking paricalcitol achieved iPTH <110 ng/l compared with those on placebo. In the stage 4 CKD group (N=22) there was NS change in iPTH. Tablets of ergocalciferol combined with calcium are the cheapest form of vitamin D, but preparations of cholecalciferol combined with calcium are also cheaper than alfacalcidol and calcitriol. The GDG observed that cholecalciferol is the most commonly prescribed form used to treat simple vitamin D deficiency in primary care.

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Balti- macogenomics order 20 mg nolvadex with mastercard, or other potential developments buy cheap nolvadex 20 mg. Compliance in the long-term treatment tion order nolvadex amex, it is hoped that increasing emphasis on studying a of schizophrenia. Fluphenazine and in the context of better informed benefit-to-riskassessment social therapy in the after care of schizophrenic patients: relapse and documentation of cost-effectiveness will lead to clinical analysis of a two-year controlled study of fluphenazine decanoate 546 Neuropsychopharmacology: The Fifth Generation of Progress and fluphenazine hydrochloride. The assessment of psychosis: a practical 1283– 1294. Handbook of psychiatric mea- and olanzapine on cognitive function in schizophrenia. Washington, DC: American Psychiatric Association, 2000. The randomized concentration-controlled clinical trial: versus systematic inquiry about emergent clinical events with an information rich alternative to the randomized placebo-con- SAFTEE: implication for clinical research. MELTZER It is fitting to include in Neuropsychopharmacology: The Fifth future. A great advance was the development of combinato- Generation of Progress a group of chapters concerned with rial chemistry and rapid, robotic characterization of the many of the important issues related to: (a) the development pharmacologic profile of the vast libraries of compounds of new drugs (e. Together with greatly improved relation to drug metabolism, discovery, and development; methods for analysis of structure–activity relationships, it (f) the ethical issues concerning clinical trials and neuropsy- has been possible to develop putative pharmaceuticals with chiatric research in general; (g) governmental (at least the desired pharmacologic profile. The old cliche,´ beware United States) regulation of the process of developing and what you desire because you may get it, is relevant here, utilizing new drugs; and (h) the evaluation of the impact because it much easier now to come up with the desired of drug treatment on outcome of neuropsychiatric disorders pharmacologic profile than it is to be certain that what is from the perspectives of economics, clinical endpoints, and sought is what should be sought. There is not yet sufficient humanistic considerations. Although the majority of these understanding of what is needed in the way of an optimal issues are the same in many parts of the world where this antidepressant, anxiolytic, antipsychotic, mood stabilizer, book will be read, there are clear differences in ethical atti- antidementia, or other type of drug, especially when a truly tudes toward clinical research and governmental regulation novel compound is sought. It is beyond the scope ical models in the development of psychotropic drugs of this volume to consider the worldwide variations in these mainly focuses on animal models for the major psychiatric issues. All the chapters that have preceded this section bear disorders. These authors point out that this approach may on the subject matter addressed here because new drug de- seem somewhat old-fashioned compared to approaches such velopment depends so heavily on our understanding of the as high throughput screening and utilization of molecular function of the brain in general, neurotransmitter and mod- biological techniques to develop targets based on gene ulator receptors and elimination mechanisms, theories of expression and identification methods; however, they cor- the etiology of the major neuropsychiatric disorders, efficacy rectly state that preclinical models are required (emphasis and side effects of existing treatments, and an understanding added) to provide initial assessment of the functional effects of the mechanism of action of existing drugs. We are The process of new drug development has changed not yet to the point where new chemical entities go directly greatly in the few years since the last volume in this series into patients or even normal volunteers without some evi- and is likely to change even more rapidly in the immediate dence that clinically relevant effects might be present. We 442 Neuropsychopharmacology: The Fifth Generation of Progress can expect major advances in the development of preclinical quent utilization have never been better summarized than models as our knowledge of disease processes and our ability they are in the chapter by Greenblatt and colleagues. Ad- to alter the genome in laboratory animals increase. Knock- vances in this area yield the information needed to use drugs out and knockin mouse models will increasingly guide drug wisely. This area of research has matured to the point where discovery and testing. The importance of research designed the fundamental principles are well understood and can be to identify new drug targets based on the Human Genome readily incorporated into the processes of drug development Project and the ensuing effort to characterize the genes in- and utilization. Information about drug interactions that volved in neuropsychiatric disorders and the action of drugs affect efficacy, elimination, and toxicity are ever more essen- used to treat neuropsychiatric illness is discussed in various tial in the current area of polypharmacy. Ozdemir¨ and colleagues discuss pharmacogenetics, the chapters throughout this volume rather than in a single chapter in this section. A key part of this refers to genetic variations oughly explored by Wong and colleagues, who note that in the liver enzymes that metabolize drugs. Greenblatt and the importance of biomarkers as a means to reduce the cost colleagues consider this as well as the genetic factors that of drug development, improve the ability to predict out- determine pharmacodynamics, and thus directly impact on come, and expedite the identification of desired endpoints efficacy and side effects. The extraordinary They also consider how genomic research will play an in- development of a variety of brain imaging methods, includ- creasingly important role in drug discovery and develop- ment, including the design of safer and more efficient clini- ing magnetic resonance imaging, functional magnetic reso- cal trials. Their term 'personalized therapeutics' is nance imaging, single photon emission computed tomogra- provocative. Have doctors not tried to do this since time phy, and positron emission tomography, appears to be immemorial? Genetic information will aid the process to particularly suited for this purpose. Given the cost associ- be more science than art (rather than the reverse). This would seem to be the view of the authors of drug dosage and choice. However, more classical methods the United States-based National Bioethics Advisory Com- such as neuroendocrine testing or examining the effect of mission (NBAC) or the newest version of the Declaration treatments on peripheral processes such as changes in saliva, of Helsinki. NBAC, in particular, has singled out research serum, and blood cells still can be valuable at various stages on the mentally ill for more stringent regulation and unique of drug development. The chapter on ethical aspects of neuropsychia- Clinical trials abound in psychiatry. Good clinical trials tric research by Pinals and Appelbaum thoughtfully analyzes are much more rare. Problems in trial design, identification these recommendations as well as the fundamental princi- of appropriate patients, recruitment, retention, and ethical ples that should guide policy in this area. Professional socie- issues surrounding the use of placebos are very much with ties such as the ACNP have developed guidelines for investi- us and show signs of becoming more rather than less intract- gators in an effort to show that there is an awareness of the able in the near future. The cost of clinical trials in Western obligation to protect subjects who agree to research to countries has grown enormously, leading to fewer and the greatest possible extent with minimal diminution of the smaller trials that are often market-driven rather than de- information to be gained from the study. A 'safe' study signed to answer the most important research questions. It is a sign of progress that broader outcome tutional review boards (IRB) are becoming increasingly re- measures other than global psychopathology are increasingly strictive around clinical research with the mentally ill, based the focus of clinical trials. For example, the recognition that in part on a poor understanding of the intactness of their cognition may be a more important endpoint than the re- decisional capacities. It is imperative that methods to assure duction of positive or negative symptoms in the evaluation competence to give consent that meets the legitimate con- of a new drug for schizophrenia is an enormous advance cerns of IRBs are employed in all trials. This chap- Section 4: Drug Discovery and Evaluation 443 ter explains what was (and probably still is) guiding the best outcomes now possible has risen greatly as a percentage policies of the regulators of the FDA, which has worldwide of gross national product in both developing and developed influence directly and indirectly. Advances in medical research will surely suffer if a primer on getting a new drug application approved by there is insufficient attention to demonstrating that new that agency. The critical issue of distinguishing the process of evaluating treatment outcomes utilizing the between efficacy and effectiveness research and the need for Economic, Clinical, Humanistic outcomes (ECHO) model. These three perspectives on outcome are intimately inter- In conclusion, this section on new drug development twined.