Cultured hippocam- little effect on enzyme activity) caused a progressive motor pal neurons from PS1M146V knock in mice display in- neuron disease resulting in death by 6 months in transgenic creased vulnerability to glutamate generic 20mg prednisolone amex, which is correlated with mice (191) buy cheap prednisolone 20mg online. Because the mouse gene for SOD1 is unaffected perturbed calcium homeostasis order 5mg prednisolone amex, increased oxidative stress, in the transgenic mice, the results indicate that these muta- and mitochondrial dysfunction. Glutamate toxicity is po- tions in SOD1 cause a gain-of-function that results in motor tentiated by ROS mediated inhibition of EAATs; two stud- neuron death. Chapter 6: L-Glutamic Acid in Brain Signal Transduction 81 The reason for the selective vulnerability of motor neu- inotropic non–NMDA receptors may be of value in the rons in ALS is unknown. Various molecular and neuro- treatment of motor neuron disease (198). Further research chemical features of human motor neurons may render this may allow the development of therapies that target specific cell group differentially vulnerable to such insults. Motor neurons have a very high expression of the cytosolic free radical scavenging enzyme Cu/ZnSOD1, which may render SCHIZOPHRENIA this cell group more vulnerable to genetic or posttransla- tional alterations interfering with the function of this pro- Kim and associates reported diminished concentrations of tein. The low expression of calcium binding proteins and glutamate in CSF of patients with schizophrenia and first GluR2 AMPA receptor subunit by vulnerable motor neuron proposed that hypofunction of glutamatergic systems might groups may render them unduly susceptible to calcium- cause the disorder (199). This finding has been replicated mediated toxic events following GluR activation (192). In a High levels of mRNA for GluR1, GluR3, and GluR4 are postmortem study, Tsai and associates (140) studied eight expressed in normal human spinal motor neurons; however, brain regions and found decreased concentrations of gluta- GluR2 subunit mRNA was not detectable in this cell group, mate and aspartate in the frontal cortex and decreased con- predicting that normal human spinal motor neurons express centration of glutamate in the hippocampus of patients with calcium-permeable AMPA receptors unlike most neuronal schizophrenia as compared to controls. Furthermore, the groups in the human CNS (193); however, this has not been concentration of NAAG was increased in the hippocampus borne out in studies of mouse spinal cord in the context of and the activity of GCPII was selectively reduced in the the mouse models of ALS, where GluR2 is well represented frontal cortex, temporal cortex, and hippocampus of people in spinal cord motor neurons (194). Subsequent studies with magnetic reso- sure triggers substantial mitochondrial calcium loading in nance spectroscopy have revealed significant reductions in motor neurons, but causes little mitochondrial accumula- the level of N-acetylaspartate (NAA), the product of NAAG tion in forebrain GABAergic interneurons, neurons that ex- by GCPII, in the very same regions—frontal cortex, tem- press large numbers of calcium-permeable AMPA/kainate poral cortex, and hippocampus (204). Brief exposure to Initial ligand binding studies in postmortem schizo- either AMPA or kainate caused mitochondrial depolariza- phrenic brain have revealed increases in the non–NMDA tion in motor neurons, whereas these effects were only ob- iGLURs in the prefrontal cortex (205,206) and decreases served in the GABAergic neurons after exposure to the non- in the hippocampus (207,208). Strychnine-insensitive desensitizing AMPA receptor agonist kainate. Finally, binding, which labels the glycine modulatory site on the blocking mitochondrial calcium uptake attenuated AMPA/ NMDA receptor, is increased throughout the primary sen- kainate receptor-mediated motor neuron injury. Thus, mi- sory cortex and related associational fields in schizophrenia tochondrial calcium uptake and consequent ROS genera- (209). Molecular approaches have shown a reduction in tion may be central to the injury process (195). Quantifica- mRNA encoding luR2 in the hippocampus and parahippo- tion of mRNA expression in spinal cord showed a significant campus of people with schizophrenia, and reduced editing widespread loss of NR2A from both dorsal and ventral of GluR2 in the prefrontal cortex (210,211). Although the horns with losses of 55% and 78%, respectively, in ALS as density of NMDA receptors in the prefrontal cortex of peo- compared to control. These results were substantiated by ple with schizophrenia was normal, the relative subunit analysis of spinal cord homogenates, which showed a signifi- composition differed significantly from controls with a large cant total decrease of 50% in NR2A message for ALS as increase observed for NR2D (212). A convincing link between glutamatergic dysfunction Riluzole, which attenuates the glutamate neurotransmit- and schizophrenia came from anecdotal and subsequent ter system, has been shown to prolong survival in patients controlled studies of the neuropsychologic effects of disso- with ALS (197). Riluzole affects neurons using three mecha- ciative anesthetics, which are noncompetitive antagonists of nisms: by inhibiting excitatory amino acid release, inhibit- the NMDA receptor (213). When chronically abused, PCP ing events following stimulation of iGluRs, and stabilizing produces a syndrome in normal individuals that closely re- the inactivated state of voltage-dependent sodium channels. Subanesthetic doses of keta- tor subtypes and the effect of chronic treatment with NBQX mine administered to normal subjects produces positive in the spinal cord of motor neuron disease (mnd) mice. These findings suggest that selective antagonism of characteristic of schizophrenia (214). When administered 82 Neuropsychopharmacology: The Fifth Generation of Progress to schizophrenic subjects, subanesthetic doses of ketamine nist at the glycine modulatory site with 60% efficacy and exacerbate delusion, hallucinations, and thought disorders readily crosses the blood–brain barrier (230). These effects are attenuated by ics and exhibiting prominent negative symptoms revealed the atypical antipsychotic clozapine but not haloperidol. Chronic PCP serine dose of 100 mg per day in a small open trial with treatment produced more perseveration and fewer nonspe- medication-free schizophrenics (232). D-cycloserine at 50 cific cognitive deficits in monkeys that persisted after dis- mg per day significantly improved negative symptoms when continuation. Notably, these memory deficits were pre- added to conventional antipsychotics in an 8-week fixed vented by clozapine treatment (220). Notably, full response for negative symptoms was 222), which was associated with impaired performance on a not achieved until after 4 to 6 weeks of treatment. Furthermore, administra- zapine responders because clozapine has substantial effects tion of a group I mGluR agonist blocked PCP-induced glutamate release without affecting dopamine release (223). To the contrary, two separate trials the rodent have been shown to be comparable to humans of D-cycloserine at 50 mg per day added to clozapine re- in a positron emission tomographic study in which [11C]- sulted in worsening of negative symptoms (234,235). In raclopride binding in striatum was used to measure dopa- contrast, trials in which the full agonists, glycine or D-ser- mine release; subanesthetic doses of ketamine cause in- ine, were added to clozapine yielded no additional change creased dopamine release in human subjects (224). A If the symptoms of schizophrenia result from hypofunc- plausible explanation for these findings is that clozapine tion of NMDA receptors, then agents that enhance NMDA may exert its effects on negative symptoms and cognitive receptor function would be predicted to reduce symptoms. Electrophysiologic studies in the hippocam- Support for this inference comes from electrophysiologic pal slice indicate that the glycine modulatory site is not fully studies in the hippocampal slice where clozapine enhances occupied because of efficient transport of glycine by the NMDA receptor currents (238). GLYT-1 transporter on astroglia so that the modulatory site As hippocampal interneurons appear more sensitive to is subject to pharmacologic manipulation (133).

Mainte- conducted for regulatory purposes and representative prac- nance aims at preventing a new depressive episode—a recur- tices generic 10 mg prednisolone amex. When continuation ends and maintenance begins for Patients with minimally treatment-resistant buy 10mg prednisolone otc, or non- an individual is unclear order prednisolone 20mg overnight delivery, although classically recovery from chronic forms of depressions enter trials. These patients are: the episode is estimated by when the episode would have (a) rarely severely ill; (b) rarely inpatients; (c) never psy- spontaneously ended based on the duration of prior epi- chotic; (d) rarely encumbered by common concurrent Axis sodes, if such information is available. The need for more III (general medical) or other Axis I (psychiatric) disorders; prolonged (i. Perhaps as a consequence, placebo response rates exactly how long to provide antidepressant treatment re- are often substantial (e. Consensus strongly recommends providing a 50% to 60% response rate (34). These recommenda- proval and the procedures characteristic of current practice. Whether patients with two episodes of major fore, also to adjust dosages); (c) use more frequent treatment depression plus a risk factor for recurrence should also be visits; (d) limit acute phase trial durations (e. Furthermore, recent regulatory and mar- toms with normalization of function) to define a clinical ket forces have encouraged studies in depressed children, 'success,' contrary to clinical practice recommendations adolescents, and geriatric patients. The National Institute of Mental Health (NIMH) has Routine clinical diagnoses often sharply disagree with recently begun to address some of the knowledge gaps noted those established by structured interviews (51) (Kashner et in the preceding by emphasizing effectiveness trials of anti- al. In addition, global judg- depressant treatments in children/adolescents, adults, and ments of the severity of illness, even if codified by the Clini- geriatric patients. The emphasis (50) was based on the reali- cal Global Impression-Improvement Scale (CGI-I) (52), zation that efficacy trials for regulatory approval are only may relate only modestly to symptom severity ascertained by the first step in defining a treatment. That is, they establish itemized clinician ratings, such as the Montgomery-Asberg˚ the safety and efficacy of an agent in carefully conducted, Depression Rating Scale (MADRS) (53) or the Hamilton highly internally valid designs. Generalizability of tolerabil- Rating Scale for Depression (HRS-D) (54,55) or the Inven- ity and efficacy findings requires different study designs. These When to use one as opposed to another agent (alone or in differences in clinical procedures used in efficacy RCTs and combination) requires still different study designs. For example, there is a reasonably strong basis DEPRESSION to believe that medications differ in their spectrum of ac- tions (1). That is, some patients/depressions respond to one Clinicians routinely confront a host of practical questions agent, whereas others respond to a different agent (58,59), that are not addressed in efficacy RCTs designed for regula- especially if the medications differ regarding presumed tory approval. These questions include the following: mechanisms of action. What is the 'next best' treatment following either an 'fit' into a multistep treatment plan is often left to tenuous unsatisfactory clinical response or intolerance to the inferences based on presumed mechanisms of action, to 'ex- first agent? What is a sufficient trial duration beyond which re- How to treat depressions that respond minimally or partially sponse is not likely (minimal duration)? What is a sufficient trial duration for those benefiting Perhaps pharmaceutical companies are reluctant to from the treatment beyond which further treatment search for specific indicators of when an agent is preferred (unchanged) is unlikely to produce any more sympto- or to study agents used as second or third steps in treatment- matic or functional improvement (maximal duration)? When is it best to augment the first agent with a second tors. Without specific indications of when to use an agent, treatment? When is it best to switch from the first agent a 'broad' spectrum of action can be claimed. Do antidepressants differ in their ability to produce largely avoided by the pharmaceutical industry, perhaps in response or remission, and if so, for which depression fear of finding that their agent will not fare as well as a is each better? Do different medications differ in the time to onset of economic forces within the industry provide a strong impe- clinical benefit or time to remission? What treatments are recommended if there is a return vital—information (e. Selecting the Initial Treatment In spite of these knowledge gaps, the industry has devel- oped a large number of newer antidepressants that are sim- All antidepressant medications have established efficacy in pler to take, better tolerated, and safer in overdose. Some even have placebo-con- 1084 Neuropsychopharmacology: The Fifth Generation of Progress trolled evidence supporting efficacy in dysthymic disorder drug–drug interactions, or likelihood of remission play a (sertraline) (15) or other 'nonmajor' disorders, such as pre- major role in selecting the first agent. However, when to How to Select the 'Next Best' Treatment select one over another agent is not well defined. Clinicians following an Unsatisfactory Response (or use 'rules of thumb' to make these judgments, but such Intolerance) to the First Agent reasonable guesses are rarely supported by prospective RCT evidence. A major clinical problem is selecting the 'next' agent if For example, more recently, efficacy for some antidepres- the first is ineffective, only partially effective, or not well sants has been established for other psychiatric conditions tolerated. When TCAs fail, the MAOIs have roughly a 50% commonly found in the presence of major depressive disor- response rate based on both open and randomized trials der, including: (a) venlafaxine for generalized anxiety disor- (58,59). Based on open trials (70), paroxetine (71,72), and sertraline (73) for panic disor- (80–83), a second SSRI is associated with a 40% to 60% der. It is logical to argue that if a clinical depression is response rate following failure with the first SSRI, although accompanied by a concurrent additional psychiatric disor- not all studies agree (84,85).

Investigators have sug- from long-term storage could be demonstrated for the gested that the defining characteristics of nootropics should treated group on the rapid automatized naming test buy prednisolone 20 mg mastercard. Al- include lack of peripheral effect prednisolone 5mg discount, absence of action on blood though there was no significant difference between the flow order 20 mg prednisolone overnight delivery, and an increase in brain metabolism (83). The by epileptogenic kindling procedures are prevented by pre- treated group also improved their single word reading on treatment with piracetam (84). Piracetam (100 mg/kg, IP) the Wide Range Achievement Test (WRAT). Hypobaric hypoxia of pregnant rats is followed by sphere, a 12-week, double-blind, placebo-controlled study the reduction of weight gain of the newborn pups, delayed of developmental dyslexics was conducted. Six study sites impairment of memory (passive and active tasks), and treated 257 dyslexic boys between the ages of 8 and 13 changes of extrapolative water escape. Piracetam (200 mg/ years who were significantly below their potential in reading kg/d) administered at early postnatal period (from the performance. The children were of at least normal intelli- eighth to the twentieth day of life) corrected behavioral gence, had normal findings on audiologic, ophthalmologic, disturbances and physical development in rats (86). Pirace- neurologic, and physical examination, and were neither edu- tam (800 mg/kg) administered orally once daily for 5 days cationally deprived nor emotionally disturbed. Piracetam before training completely antagonized the scopolamine- was found to be well tolerated in this study population. Early studies by Dimond and Brouwers suggested that Piracetam was given in a 3,300-mg daily dose to half of piracetam could facilitate transfer of information across the a group of 55 dyslexic boys aged 8 to 13 years, in a 12-week, callosal pathways and hence is a 'superconnector' drug double-blind, placebo-controlled study. Numerous studies with neurologically normal and the subjects received placebo. Compared with the placebo dyslexic adults indicated that the drug could enhance verbal control group, the boys treated with piracetam did not show learning. An statistically significant improvements above their baseline early report on reading involved 16 dyslexic men matched scores on measures of perception, memory, language, read- with 14 student volunteers for a 21-day trial of piracetam. How- It was found, using a double-blind crossover technique, that ever, reading speed and numbers of words written in a timed 608 Neuropsychopharmacology: The Fifth Generation of Progress period were significantly enhanced in subjects treated with analysis and increasing attentional resources among dyslexic piracetam as compared with placebo. Effective reading and children when the stimuli are recognized as having linguistic writing ability, taking both rate and accuracy into considera- significance (96). These effects were shown to be dose re- tion, were also significantly improved in the piracetam lated in a subsequent study (97). One negative study examined the interaction of pirace- Two hundred twenty-five dyslexic children between the tam and tutoring (98). Sixty children with dyslexia (41 boys, ages of 7 years 6 months and 12 years 11 months whose 19 girls; ages 9 to 13 years) were enrolled in a 10-week reading skills were significantly below their intellectual ca- summer tutoring program that emphasized word-building pacity were enrolled in a multicenter, 36-week, double- skills. They were randomly and blindly assigned to receive blind, placebo-controlled study. Piracetam-treated children either placebo or piracetam. The children were subtyped as showed significant improvements in reading ability (Gray 'dysphonetic' or 'phonetic' on the basis of scores from Oral Reading Test) and reading comprehension (Gilmore tests of phonologic sensitivity and phoneme-grapheme cor- Oral Reading Test). Treatment effects were evident after respondence skills. Of the 53 children who completed the 12 weeks and were sustained for the total period (36 weeks) program, 37 were classified as dysphonetic and 16 as pho- (94). The phonetic group improved significantly more in The neurophysiologic mechanisms involved in the effects word-recognition ability than the dysphonetic group. Over- of piracetam were examined in studies using event-related all, the children taking medication did not improve more potentials. Eight- to 12-year-old dyslexic boys were ran- than the nonmedicated children in any aspect of reading. Chil- netic subgroup gained most in word recognition. Event-related potentials to letters and shapes, for active and SUMMARY AND CONCLUSIONS passive responses, were recorded at the vertex and left and right parietal areas of the scalp. Performance measures in- Significant difficulties continue to bedevil the definition of cluded letter and form hits, misses, commission errors, and LD, including problems surrounding various criteria such reaction times. Piracetam increased the amplitude of a late as an IQ/learning discrepancy or low absolute achievement positive component (believed to correspond to P300) at the level. Approaches that define the disorder by resistance to vertex for letter hits. Piracetam also increased the latency high-quality instruction may be the most valid for purposes of this component in both hemispheres, but only for active of identifying persons with LDs in genetic, neuroimaging, responses (letter hits) in the left hemisphere and passive and pharmacologic studies. The high degree of comorbidity responses (correct rejections and misses) in the right hemi- with many psychiatric disorders raises further issues for sphere. Reaction time to letter hits was significantly corre- studies requiring a homogeneous symptom pattern, and it lated with the latency of the P300 component, a finding seems likely that further advances will require replacing suggesting that letters created increased effort or attentional broad clinical patterns with more specific processing deficits demand on the subjects compared with forms.

One compound has very anxiety scores using both clinician and patient ratings generic prednisolone 40mg overnight delivery,sug- recently been described as a water-soluble nonpeptide CRF1 gesting that this mechanism may provide an exciting novel receptor antagonist (NBI 30775 purchase 20 mg prednisolone,also referred to as therapy in patients suffering with major depressive disorder buy cheap prednisolone 5mg online. R121919) that demonstrates high affinity,and has a supe- Although it is of great importance at this stage to develop rior in vitro and in vivo profile compared to other nonpep- these compounds as tools in the ultimate understanding of tide CRF receptor antagonists (91). This compound does not nism,will prove beneficial in neuropsychiatric disorders interact at all with the CRF binding protein and was shown such as depression or anxiety. Should compounds such as to be as potent as the peptide antagonist D-Phe CRF(12- this continue to demonstrate efficacy in these disorders 41) at inhibiting the CRF-stimulated cAMP accumulation without severely compromising the stress axis as a whole, from cells that express the human CRF1 receptor and CRF- they would validate the CRF hypothesis for depression and stimulated ACTH release from cultured rat anterior pitui- anxiety and provide an entirely novel treatment for these tary cells in vitro. In vivo, this molecule potently attenuated devastating diseases. Chapter 7: Corticotropin-Releasing Factor 105 CONCLUSION 5. Corticotropin-releasing factor: basic and clinical studies of a neuropeptide. Corticotropin-releasing factor is the key regulator of the 6. Solution structure of human corticotropin releasing factor by 1H NMR and distance that,in turn coordinates the synthesis and secretion of glu- cocorticoids from the adrenal cortex. CRF also functions geometry with restrained molecular dynamics. Synthetic competitive antagonist of and receptors are widely distributed in the CNS and play corticotropin-releasing factor: effect on ACTH secretion in the a critical role in coordinating the autonomic,electrophysio- rat. Cloning and Clinical data have implicated CRF in the etiology and distribution of expression of the rat corticotropin-releasing factor (CRF) gene. In: Corticotropin releasing factor: basic and clinical pathophysiology of various endocrine,psychiatric,and neu- studies of a neuropeptide. Second messenger regula- contribute to the symptomatology seen in neuropsychiatric tion of mRNA for corticotropin-releasing factor. In: Corticotropin disorders such as depression,anxiety-related disorders,and releasing factor. Chichester,England: John Wiley and Sons,1993: anorexia nervosa. The organization parent in neurodegenerative disorders such as AD,PD,and of ovine corticotropin-releasing factor immunoreactive cells and HD as they relate to dysfunction of CRF neurons in brain fibers in the rat brain: an immunohistochemical study. Sawchenko PE,Swanson LW Organization of CRF immunoreac- native ligands for these subtypes serve not only to increase tive cells and fibers in the rat brain: immunohistochemical stud- ies. In: Corticotropin-releasing factor: basic and clinical studies of our understanding of the system but provide a basis for a neuropeptide. The corticotropin-releasing factor ders that are associated with aberrant levels of CRF. Boca Raton,FL: CRC Press, gies directed at developing specific and selective CRF agents 1992:129–184. Neurotransmitter regulation of the have yielded many nonpeptide small molecule CRF1 recep- CRF secretion in vitro. In: Corticotropin-releasing factor: basic and tor antagonists and a preliminary proof-of-concept has en- clinical studies of a neuropeptide. Boca Raton,FL: CRC Press, couraged the further development of such agents. Complete amino acid promise for novel therapies for the treatment of these var- sequence of urotensin I,a hypotensive and corticotropin releasing ious neuropsychiatric disorders without severely compro- neuropeptide from Catoftomus. Amino acid composition and mising this highly complex hormonal system. Clearly with sequence analysis of sauvagine,a new active peptide from the the recent advances made within a very short period of time, skin of Phyllomedusa sauvagei. Cloning and sequence increasingly complex neurohormone system. Characteriza- ACKNOWLEDGMENT tion of the genomic corticotropin-releasing factor (CRF) gene from Xenopus laevis: two members of the CRF family exist in Dr. De Souza is a stockholder in Neurocrine Biosciences, amphibians. Urocortin,a mam- malian neuropeptide related to fish urotensin I and to corticotro- 1. Characterization of a 41-residue pin-releasing factor. Physiological and behavioral responses trophin releasing factor receptors. Identification of a tor of anxiety of stress responses?