By S. Charles. Fordham University.

Neuronal depolarization of pre- facilitate an influx of sodium discount 200mcg cytotec with mastercard. However order cytotec without a prescription, some of the kainate synaptic neurons in turn depends on activation of non- and AMPA receptors are comprised of subunits that allow NMDA receptor-gated channels and other depolarizing calcium permeability (38) buy cytotec no prescription. This may be relevant to ischemic neurotransmitter receptors discount cytotec 100mcg fast delivery. The excitatory action of depo- injury because in neurons after cerebral ischemia, glutamate larizing neurotransmitter receptors is countered by hyperpo- receptor 2 (GR2), a subunit necessary for non-NMDA re- larizing receptor-gated ion channels, such as the GABA ( - FIGURE 92. A simplified neuronal circuit diagram illustrating the ion channels that determine the syn- aptic release of glutamate and intraneuronal Ca2 concentrations in response to ischemia. Chapter 92: Molecular Pathophysiology of Stroke 1321 aminobutyric acid) receptor. Propagation of the action po- progressively less effective; however, such agents are effective tential induced by depolarization of the neuronal cell body up to 2 hours after the onset of middle cerebral artery occlu- requires voltage-dependent sodium channels. In the clinical trials, most patients were release of glutamate itself depends on P- and Q-type voltage- enrolled 6 to 12 hours after the onset of ischemia, long after dependent calcium channels. Glutamate release into the the time that these drugs were effectively administered in synaptic cleft can bind to the NMDA receptor and open animal studies. As a result, calcium enters the cell Whatever the reason for the failure of these anti-excito- driven by its concentration gradient. However, intraneu- toxic drugs in human trials, it has become clear that it may ronal calcium may increase by other mechanisms. Post- be more practical to select treatment approaches that target synaptic voltage-dependent calcium channels may allow cal- mechanisms that are active at longer intervals after ischemia. Also, Na may enter the cell via the NMDA recep- tor-gated channel and depolarize the neuron. Thus, excito- toxicity may be ameliorated at a number of sites in vivo. MECHANISMS OF PROGRAMMED CELL Many drugs that can inhibit excitotoxicity at each of DEATH these steps have been developed. GABA agonists such as clomethazole have been shown to be neuroprotective in vivo Many of the key molecular events in programmed cell death and are currently undergoing clinical trials (47,48). Just as calcium entry dent models of stroke, BW1003,619 and phosphenytoin into the neuron is a key step in excitotoxicity, the release prevent prolonged opening of the voltage-dependent so- of cytochrome c from the mitochondria is a key event in dium channel, ameliorate increases in extracellular gluta- initiating apoptosis in many cell types. Cytosolic cyto- mate, and decrease infarction volume (49–51). Drugs that prevent prolonged opening of P- and Q-type calcium chan- nel antagonists are also neuroprotective in animal models of stroke (52). In contrast to their very limited effects in primary neuronal tissue culture models, non-NMDA antag- onists are very effective in both global and focal ischemia models in rodents. Indeed, such agents have a longer time window of efficacy than do NMDA antagonists when ad- ministered after the onset of ischemia (53,54). Likewise, voltage-dependent calcium channel antagonists are not ef- fective in vitro; however, the voltage-dependent calcium channel antagonist nimodipine is effective in reducing in- farction volume in temporary focal ischemia in rats (55). Blockade of excitotoxicity via all these pharmacologic strategies has proved effective in temporary focal ischemia models in rodents, the model that most closely resembles human stroke. Unfortunately, results with these agents in human trials have to date been very disappointing, for sev- eral possible reasons. First, drugs that affect neurotransmis- sion in the brain have many undesirable side effects, which in turn have led to reductions to doses that may have been ineffective. Side effects include effects on respiration and cardiac rhythm. In addition, agents that directly antagonize the NMDA receptor may injure a circumspect population of neurons in the cingulate and retrosplenial cortex in ro- dents (56), and may induce hallucinations and psychosis in humans (57). Another obvious reason for the lack of efficacy in these drugs in clinical trials is the time interval between the onset of ischemia and the administration of drug. When given before the onset of ischemia, these treatments can spare 50% or more of ischemic rat brain tissue from eventual FIGURE 92. A schematic diagram illustrating the molecular infarction. When given after the onset of ischemia, they are mechanisms that control programmed cell death. Caspase 9 then cleaves and activates other cas- (69,70). Activation of these receptors triggers activation of pases, including caspase 3. The cleaved bid then translocates from the cyto- executing programmed cell death. They were first identified plasm to the mitochondria, where it initiates cytochrome c by their homology with CED3, the key gene that irreversibly egress (72). Other mechanisms by which the initiation of commits neurons in C. Finally, DNA base oxidation and other DNA damage other cellular functions. Among the caspases, caspase 3 has may initiate programmed cell death via expression of the the closest homology with CED3 and appears to play a key p53 transcription factor. These and other mechanisms may role as the final committed step in programmed cell death. These proteolytic targets of caspase 3 include cytoskeletal protein(s), DNA repair proteins such as PARP, and other proteins (59). Caspase 3 also cleaves PROGRAMMED CELL DEATH AFTER ICAD, an inhibitor of CAD, an endonuclease that cleaves CEREBRAL ISCHEMIA DNA between histosomes. The result is cleavage of DNA between histosomes, a hallmark of programmed cell death Evidence indicates that many of the mechanisms that initi- (60). The mRNA of the Fas ligand is the cytosol is controlled by several mechanisms. Expression of the Fas the bcl-2 family play an important role in controlling cyto- ligand and associated proteins and infarction volumes was chrome c egress. Anti-apoptotic bcl-2 family members, such smaller in LPR mice that expressed a dysfunctional Fas li- as bcl-2 itself and bcl-x-long, inhibit the egress of cyto- gand than in wild-type controls (75). Pro-apoptotic members of the bcl-2 fam- also up-regulated after cerebral ischemia in rat brain (76). Expression of the TNF receptor balance between the pro-apoptotic and anti-apoptotic bcl-2 is also increased after cerebral ischemia (78). TNF-binding family proteins in the mitochondrial membrane determines protein, a protein that binds and inhibits TNF- , reduced whether permeability of the membrane will increase to allow infarction volume after middle cerebral artery occlusion in egress of cytochrome c into the cytoplasm. However, ischemic injury was exacerbated in circumstances, cytochrome c exits the mitochondria via the TNF- -receptor null mice, which suggests that TNF signal- mitochondrial permeability transition pore. This pore can ing pathways may instead have beneficial effects in ischemic open in response to prolonged depolarization, produced by injury under some circumstances (80). Caspase 8, which is such stimuli as an increase in intracellular calcium (63). Changes in bax may also interact with this pore (64). However, bcl-2 expression and activity of both the ERK and JNK kinase family members themselves may form pores in membranes pathways occur following cerebral ischemia. The M-termi- (65), and some evidence indicates that bax induces egress nal kinases of c-Jun are activated after ischemia and phos- of cytochrome c from the mitochondria independently of phorylate c-Jun (82). The increased expression of ERK after the mitochondrial permeability transition pore (66). Initia- focal ischemia and inhibitor of NEK-1, another kinase in tion of the mitochondrial apoptosis is also controlled by the ERK pathway, protect the brain against focal cerebral expression and translocation of other numerous bcl-2 family ischemia (83,84). For example, translocation of bax from the cyto- event in cerebral ischemia reperfusion injury and may trig- sol to the mitochondria initiates programmed cell death ger expression of p53 (85,86). Bad is phosphorylated before being translocated to the after cerebral ischemia (87). More than 20 additional proteins are A number of studies in cerebral ischemia support a role found in the bcl-2 family, including many that are also for bcl-2 family genes in controlling ischemic neuronal involved in mitochondrial homeostasis. In rodent models of ischemia, anti-apoptotic mem- in apoptosis, egress of cytochrome c from the mitochondria, bers of the bcl-2 family, including bcl-2 and bcl-x long, are is controlled by bcl-2 family proteins.

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For some individuals order discount cytotec online, adverse aspects of psychiatric ward admission may include stigmatization purchase cytotec 100mcg mastercard, a sense of abandonment and heightened vulnerability purchase cytotec 200 mcg overnight delivery. This idea needs close examination and may change psychiatric practice buy cheap cytotec on line. 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. Anecdotally, suicide causes much suffering in at least some relatives and friends. This may be greater when the relationship has been difficult between the person who suicides and those who are left. Some authors believe suicide can represent an aggressive act, an angry rejection and punishment of friends and relatives. The Executive Director of the Alliance of Hope for Suicide Survivors (Walker, 2014) states that the unfounded popular media catch-cry “Suicide is Preventable” increases the “survivor guilt” of friends and relatives. For mental health professionals, suicide of patients is inevitable and has been designated an “occupational hazard” (Ruskin et al, 2004). Ting et al (2006) described the impact of client suicide on mental health social workers, which in extreme cases included refusing to see further clients who appear to be at some risk, leaving the place of work and even the state. Alexander et al (2000) studied psychiatrists and reported that following the suicide of a patient, a large proportion develop symptoms suggestive of depression, which last for at least a month, and 15% consider taking early retirement. Following a suicide the trainees became “over cautious” in their management of patients, which was to the disadvantage of patients. Eagles et al (2001) state, “it seems probable that onerous expectations of prediction and prevention…contribute to the distress which suicides cause psychiatrists”. Such expectations of prediction are based on an incomplete understanding of the field and are unfair. There is a world wide shortage of trained mental health professionals, and any process which further depletes this pool exposes rather than protects patients. Scrutiny of systems is supposed to ensure the maintenance of high standards. Critics of systems frequently suggest that additional steps need to be taken to protect patients. This results in the introduction of additional paper work, so that every aspect of patient care is fully documented and staff are more, but not completely, legally protected. A problem which arises is that staff need to spend so much time on defensive documentation that there is little left to spend with patients. An additional consequence of post suicide criticism has been the locking of open wards. With the closing of the old psychiatric hospitals, new psychiatric wards were established in general hospitals. Overtime many general hospital psychiatric wards have been converted into secure (locked) facilities. This is, at least in part, a response to criticisms made during the scrutiny of the suicide of unrestricted patients who have been able to leave wards and complete suicide. On balance, the closure of open wards to prevent the unpredictable is a retrograde step. His view is that “The person who suicides in an inpatient setting is frightened, sad, lonely, disaffected, tired from sleepless night and feels that life is hopeless and futile”. He believes that in the psychiatric ward there is a need to provide “warmth, human connection, reality and hope”. Finally, he stated that some strategies designed to “protect” patients serve to further isolate them and “paradoxically make suicide more likely”. Rates of suicide As Durkheim observed, the rates of suicide differ from one country to another, and they are relatively stable. While this difference may to some extent reflect different methods of “diagnosis” and data management, cultural factors are of overwhelming importance. Japan, suicide, 1970-2002 40 35 30 25 Male 20 Female 15 10 5 0 Suicide in Japan over a 32 year period. A sharp rise in the suicide rate of men in the late 1990s reflects an economic downturn. Australia, suicide, 1921-2006 30 Male 25 Female Persons 20 15 10 5 0 supplied by the Australian Bureau of Statistics Pridmore S. During the 1990s there was an increase in suicide rate which largely remains unexplained. From 1997, there has been a general reduction in suicide rate, again, largely unexplained. Of interest is a fall in suicide rates from 1935 to 1945. This is the usual response during wartime, and is believed to be because the community draws together against a common enemy. Also of interest is the increase in suicide rate from the early 1960s, lasting till the late 1960s. However, the Vietnam War divided the people of Australia, with public protests and great public unease, which may explain this apparent anachronism. Suicide by patients: questionnaire study of its effect on consultant psychiatrists. Suicide within 12 months of contact with mental health services: national clinical survey. Spatial clusters of suicide in the municipality of Sao Paulo, 1996-2005. Suicide ideation at its worst point: a predictor of eventual suicide in psychiatric outpatients. Suicide and Life-Threatening Behavior 1999; 29: 1-9. Suicide and psychiatric diagnosis: a worldwide perspective. Major depression: does a gender-based down-rating of suicide risk challenge its diagnostic validity? Australian and New Zealand Journal of Psychiatry 2001; 35:322-328. Lessons from a comprehensive clinical audit of users of psychiatric services who committed suicide. Burgess P, Pirkis J, Jolly D, Whiteford H, Saxena S. Australian and New Zealand Journal of Psychiatry 2004: 38:933-939. Elderly suicide and the 2003 SARS epidemic in Hong Kong. International Journal of Geriatric Psychiatry 2006; 21: 113-118. Dumais, A, Lesage A, Alda M, Rouleau G, Dumont M, Chawky N, Roy M, Mann J, Benkelfat C, Turecki G. Risk factors for suicide completion in major depression: a case- control study of impulsive and aggressive behaviors in men. American Journal of Psychiatry 2005; 162: 2116-2124. Role of psychiatrists in the prediction and prevention of suicide: a perspective from north-east Scotland. Ernst C, Lalovic A, Lesage A, Seguin M, Tousignant M, Turecki G. Societal integration and age-standardized suicide rates in 21 developed countries, 1955-1989. Suicidality in panic disorder: a comparison with schizophrenic, depressed and other anxiety disorder outpatients.

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No significant difference was found in adverse with autistic disorder and other PDDs indicated that the effects between secretin and placebo buy generic cytotec 100mcg. Two additional con- drug was poorly tolerated and of limited efficacy cytotec 200 mcg cheap. The results trolled studies have reported similar findings (63 cytotec 100 mcg sale,64) buy 100mcg cytotec with mastercard. Based from that study are consistent with those from a number on the results of these systematic investigations, secretin of open-label reports suggesting that SRIs may be less well cannot be recommended as a treatment for the target symp- tolerated and less effective in younger (prepubertal) autistic toms associated with autistic disorder. Although this developmental difference in Glutamatergic Agents tolerability and response to SRIs may be a dose-related phe- nomena, other factors need to be considered. Recent data The N-methyl-D-aspartate (NMDA) subtype of glutamate indicate that significant changes in measures of 5-HT func- receptor is central to developmental processes including tion occur during puberty in autistic individuals. For exam- neuronal migration, differentiation, and plasticity (65). Dis- ple, McBride and co-workers (58) found that mean platelet turbances in glutamatergic function, via reduced neu- 5-HT levels were significantly higher in prepubertal autistic rotropic actions of glutamate or excessive neurotoxic effects, children than prepubertal normal controls, but no signifi- could alter neurodevelopment substantially (66). During cant difference was found between postpubertal male autis- the past 5 to 10 years, significant advances have been made tic subjects and postpubertal normal controls (58). Further- in the identification of potential pharmacotherapies affect- more, Chugani and associates (59) reported results from a ing glutamatergic function for a number of neuropsychiatric positron emission tomography brain imaging study showing disorders (67). Thus, pre- and postpubertal autistic subjects may inary results from studies of drugs that modulate glutamate have significant differences in brain 5-HT function that neurotransmission in autistic disorder have been published. Phar- Lamotrigine is a drug that attenuates some forms of cortical macogenetic differences among autistic individuals, which glutamate release via inhibition of sodium channels, P- and may affect SRI tolerability and responsivity, will also require N-type calcium channels, and potassium channels. Another report de- Novel Therapeutic Strategies scribed improvement in self-injurious behavior, irritability, and disturbed sleep in an 18-year-old woman with profound Secretin mental retardation and a generalized seizure disorder who Secretin is a polypeptide hormone secreted primarily by the was given open-label lamotrigine (70). Interestingly, the endocrine cells in the upper gastrointestinal (GI) tract that subject showed improvement in measures of 'fixed facial is involved in regulating pancreatic exocrine secretion. A expression, lacks emotional responsivity,' 'resists any form synthetic form of secretin is Food and Drug Administration of physical contact,' and 'inactive, never moves sponta- (FDA) approved for use in the diagnosis of particular GI neously. In 1998, Horvath and co-workers (61) published represent a 'prosocial' effect of the drug. In a double-blind, a report that described marked improvement in language placebo-controlled study, 39 subjects with autistic disorder, and social behavior in three children with autistic disorder ages 5 to 19 years old, were given placebo or the NMDA who received secretin as part of a routine diagnostic workup receptor antagonist amantadine (71). No significant difference was found between drug 574 Neuropsychopharmacology: The Fifth Generation of Progress and placebo on parent ratings, although clinician-rated mea- viduals with autistic disorder, as well as studies designed to sures of hyperactivity and inappropriate speech showed sta- determine the effects of these drugs on the target symptoms tistically significant improvement. In 'negative' symptoms of schizophrenia can be improved addition, genetic predictors of treatment response, such as with drugs active at the NMDA receptor (72), additional 5-HT transporter protein genotype, should be sought (60). The group II/III meta- reports of putative 'cures' for autistic disorder, such as botropic-glutamate receptor (mGluR II/III) agonists (73) those that surrounded secretin, by conducting controlled and the positive allosteric modulator of -amino-3-hy- studies of such agents. Accepting this responsibility will con- droxy-5-methyl-4-isoxazole propionic acid (AMPA) recep- tribute to ensuring the continued safety of autistic subjects tors, CX516 (Ampakine) (74) may hold promise in this and provide family members with data on which to base regard. Fi- the relative efficacy of atypical antipsychotics, such as risper- nally, exploration of promising novel therapeutic strategies, idone, for autistic disorder (30) may be the suppression of such as those affecting glutamatergic and neuroimmune glutamate release via 5-HT2A antagonism (75). Neuroimmune Modulation Neuroimmunologic dysfunction has been implicated in the pathophysiology of autistic disorder (76) and other neuro- ACKNOWLEDGMENTS psychiatric conditions (77). To date, no consistent immu- nologic abnormalities have been found in autistic disorder, This work was supported by an independent investigator although viral and autoimmune hypotheses, among others, award (Seaver Foundation Investigator) from the National have been posited (76). Neurovirologic disease and other Alliance for Research in Schizophrenia and Depression, the insults to the immune system can lead to increased produc- Theodore and Vada Stanley Research Foundation, a re- tion of catabolites of tryptophan, including quinolinate and search unit on Pediatric Psychopharmacology Contract, no. Thus, neuro- Health, and the State of Indiana Division of Mental Health. McDougle has received research support from Pfizer, inconsistent with altered glutamatergic function, as de- Eli Lilly, and Janssen Pharmaceutica, and has served on scribed above. Controlled studies of agents that have direct effects on immune function, however, have not been conducted in autistic disorder. Such research on neuroim- REFERENCES mune interactions may yield important data on pathophysi- 1. Diagnostic and statistical man- ology, if not etiology, in a subset of autistic subjects. Washington, DC: American Psychiatric Association, 1994. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CONCLUSION CpG-binding protein 2. Oxytocin-a neuropeptide for affiliation: evidence from Significant progress in the neuropsychopharmacology of au- behavioral, receptor autoradiographic, and comparative studies. Increased affiliative fourth edition of this text (80). 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Biol Psychiatry date in the treatment of children with autistic disorder. Arch Gen Psychiatry 1989;46: Checklist: a behavior rating scale for the assessment of treatment 1088–1092. Clonidine treatment response of seven subjects with autistic disorder to clomipramine of hyperactive and impulsive children with autistic disorder. A double- son of clomipramine, desipramine, and placebo in the treatment blind, placebo-controlled study of the efficacy of transdermal of autistic disorder. ECDEU assessment manual for psychopharmacology autism: preliminary evidence of efficacy. The alpha-2 adrener- treatment of stereotypic behaviors and self-injury in patients with gic agonist guanfacine improves memory in aged monkeys with- developmental disabilities. J Am Acad Child Adolesc Psychiatry out sedative or hypotensive side effects: evidence for alpha-2 re- 1992;31:1157–1160. 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