Sito in Italia dove è possibile acquistare la consegna acquisto Viagra a buon mercato e di alta qualità in ogni parte del mondo.

Legal Fallacies of Antipsychotic Drugs
Steven K. Erickson, JD, LLM, PhD, J. Richard Ciccone, MD,Steven B. Schwarzkopf, MD, J. Steven Lamberti, MD, and Michael J. Vitacco, PhD Advances in the biological sciences have dramatically improved the understanding of schizophrenia and relatedpsychotic illnesses. One of the most compelling findings is the substantial degree to which cognition is impaired inthese illnesses and the remedial effects that antipsychotic drugs have in treating these cognitive impairments.
Despite these promising discoveries, legal cases and scholarship remain replete with pejorative associations withantipsychotic drug action. References to antipsychotic medications as mind-altering drugs and their effects as“synthetic sanity” misconstrue the beneficial effects these medicines have on cognition. We review the prevailinglegal attitude of antipsychotic medications and contrast these views with prevailing scientific knowledge. Weconclude that legal opinion is misinformed about the effects of antipsychotic medications on cognition.
J Am Acad Psychiatry Law 35:235– 46, 2007
One of the persisting quagmires in modern psychia- sis,14,15 while consistent treatment with anti- try and law has been the disparity between current psychotic medications is associated with improved scientific knowledge regarding mental illnesses and long-term outcomes.16–18 Consequences of treat- legal scholarship, court decisions, and public policy ment nonadherence include a fourfold increase in the regarding these illnesses. Within the past two decades risk of suicide,19 a near fourfold increase in relapse,20 in particular, the surge of scientific information re- and an increased risk of violent behavior.20 In addi- garding the pathogenesis of schizophrenia and re- tion, nonadherence is associated with increased rates lated illnesses—aided by multiple neuroimaging of hospitalization, use of emergency psychiatric ser- techniques1; genetic studies2,3; and neurodevelop- vices, arrests, violence, victimizations, poorer mental mental,4 amino-acid, and oxidative-stress models5 of functioning, poorer life satisfaction, greater sub- psychiatric illness— has greatly expanded the knowl- stance use, and more alcohol-related problems.21,22 edge base and confidence within psychiatry as to the The rate of treatment nonadherence among patients nature of these illnesses.6 Among the most promi- with psychotic disorders varies widely, but a recent nent of these advances has been an appreciation of meta-analysis places the rate at about one-quarter of the importance of negative symptoms,7,8 impaired cognition,9–11 and the therapeutic qualities of anti- Schizophrenia is unquestionably a disease of the psychotic medications beyond treating the overt, brain. A plethora of neuropathological studies have demonstrated that it is associated with substantial These developments build on the growing under- anatomical and functional abnormalities in the standing that untreated psychosis engenders exten- brain.24–28 These include volumetric loss of gray sive detrimental consequences related to progno- matter in the frontal lobes,29,30 enlarged lateral ven-tricles,31,32 and atrophic temporal and prefrontal Dr. Erickson is a MIRECC Fellow, Yale University/VA Healthcare lobes.33 While the absence of gliosis in these illnesses Network, West Haven, CT; Dr. Ciccone is Director, Psychiatry and places them outside the domain of traditional neuro- Law Program, and Professor, Department of Psychiatry, University ofRochester Medical Center, Rochester, NY; Dr. Schwarzkopf is Clini- degenerative disorders, evidence of neuronal atrophy cal Associate Professor, Department of Psychiatry, University of Roch- and apoptosis,34,35 decreased neuropil,36 abnormal ester Medical Center, Rochester, NY; Dr. Lamberti is Director, Long-Term Care Program, University of Rochester Medical Center, and neuronal density,37,38 and progressive structural brain Associate Professor of Psychiatry, Department of Psychiatry, Univer- changes39,40 suggests a progressive neurodevelopmen- sity of Rochester Medical Center, Rochester, NY; and Dr. Vitacco is tal disorder with plausible atypical neurodegenerative Associate Director of Research, Mendota Mental Health Institute,Madison, WI. Address correspondence to: Steven K. Erickson, JD, LLM, PhD, Yale University/VA Healthcare Center, 950 Campbell Despite these compelling findings, the law re- Avenue, Bldg. 36, West Haven, CT 06516. E-mail: mains replete with negative associations between Volume 35, Number 2, 2007
Legal Fallacies of Antipsychotic Drugs
psychotic illnesses and effective treatments, espe- incorporated into American criminal law as a consti- cially antipsychotic medications. The case of Sell v. tutional right. As such, it is unsurprising that com- United States42 neglected any meaningful discussion petency evaluations remain one of the most common regarding the propensity of antipsychotic medica- areas of forensic psychiatry practice.45 Its corner- tions to improve cognitive abilities in persons with stone in both forensic practice and criminal law re- schizophrenia and related psychotic disorders and flects the strong penchant in American jurisprudence the detriment that patients incur when allowed to toward individual culpability and moral blame- forgo proper psychiatric treatment. The Sell decision continues an enduring skepticism by the courts and Criminal defendants can be found incompetent to legal scholars toward psychiatric treatment, which is stand trial for a variety of reasons, including stable evident by its continued reference to antipsychotic characteristics such as low intelligence levels. How- medications as “mind-altering drugs”43 that produce ever, most competency deficits result from severe “synthetic sanity,”44 denoting a misconstrued appreci- mental disorders, usually psychotic illnesses, that are ation for the pathogenesis of psychotic illnesses, the fluid in nature and amenable to treatment.47 The meaning of recovery from a biomedical perspective, and long-recognized principal method for treating psy- the benefits of pharmacological agents used in the treat- chotic illnesses is pharmacotherapy with antipsy- chotic medications.48,49 Unfortunately, as many cli- In this review, the legal approach toward antipsy- nicians, researchers, and family members of those chotic medications will be explored by focusing on afflicted with these devastating illnesses have known case law and legal scholarship surrounding involun- for decades, psychosis frequently entails a loss of in- tary administration of antipsychotic medications to sight and deluded thinking that leaves the afflicted incompetent defendants, prison inmates, and civilly person unable to understand the benefits of treat- committed patients. Current scientific understand- ment.50 Although antipsychotic medications are ef- ing regarding psychotic illnesses, particularly cogni- fective in restoring rationality in persons with psy- tion, and the capacity of antipsychotic medications chosis, denial of illness and paranoia often necessitate to improve cognitive abilities will be examined. Fur- involuntary treatment. Such treatment, unsurpris- thermore, the hazards of untreated psychosis will be ingly, is often necessary for competency restoration, discussed, particularly in light of the emerging neu- and pharmacotherapy is the chief method of ropsychiatric literature on the phenomenon of dura- tion of untreated psychosis (DUP) and neurotoxicity Perhaps the quintessential case that provides in- through glutamate dysregulation in psychotic ill- sight into the court’s concerns regarding involuntary nesses. Finally, a call for a more informed public administration of antipsychotic medications for res- policy and legal perspective on severe mental illnesses toration of competency is Riggins v. Nevada, decided will be discussed, focusing on diminishing the con- in 1992.52 Riggins was convicted of murder and sen- tinued stigma associated with these illnesses that cur- tenced to death. Upon appeal, he claimed that the rent legal authority, represented by cases such as Sell, denial of his motion during trial to suspend admin- inadvertently perpetuate by their continued depre- istration of thioridazine infringed on his constitu- ciatory position toward effective treatments.
tional right to privacy and presentation of his pre-sumably psychotic demeanor during his insanity Seminal Legal Cases
defense. Justice O’Connor, writing for the majority,held that the forcible administration of antipsychotic Competency to Stand Trial
medication violated Riggins’ Sixth and Fourteenth A fundamental concept of American criminal law Amendment rights. The Court held that testimony is that defendants cannot be tried for any crime un- by defense experts regarding the alleged disabling ef- less they have a factual and rational understanding of fects of thioridazine on Riggins’ ability to interact the charges against them, a rudimentary knowledge with counsel, produce testimony, or comprehend the of the criminal proceedings, and the ability to assist trial proceedings was pervasive and that Riggins their attorneys in their defense. Known as compe- should have enjoyed the right to forgo treatment, tence to stand trial, this doctrine evolved from 17th- allowing the jurors “to assess Riggins’ demeanor century English jurisprudence and has been firmly fairly” (Ref. 52, pp 137– 8). The strong presumption The Journal of the American Academy of Psychiatry and the Law
Erickson, Ciccone, Schwarzkopf, et al.
that antipsychotic medications interfere with the de- tency; and (6) the medication must be medically fendants’ ability to communicate with their attor- neys and present their “true” demeanor is a themepassionately endorsed by many legal scholars.53–55 Prison Inmates With Psychotic Disorders
Eleven years later, in Singleton v. Norris,44 the In 1990, the United States Supreme Court held in Eighth Circuit considered whether a death row in- Washington v. Harper,43 that inmates with severe mate could be restored to competency involuntarily mental illnesses, who are deemed to be dangerous to after adjudication, to face the death sentence. A themselves or others, can be forcibly medicated with- sharply divided court held that such practice was out the need for a full judicial hearing. The inmate, constitutionally permissible. Judge Heaney, writing Walter Harper, was convicted of robbery and incar- for the dissent in a revealing opinion regarding the cerated in state prison from 1976 to 1980, housed legal perception of antipsychotic medications, called mainly in the prison’s mental health unit. He was Singleton’s restored competency “artificial” and that subsequently released on parole on the condition “drug-induced sanity is not the same as true sanity.” that he receive mental health treatment in the com-munity. After assaulting two nurses, Harper’s parole The dissent also cited as authoritative several legal was revoked, and he was returned to prison, where he scholars who claimed that “despite their beneficial initially voluntarily received antipsychotic medica- effects, antipsychotic drugs merely mask the debili- tions, but later refused treatment. The state, relying tating symptoms of major mental disorders” and pro- on the Supreme Court’s prior holding in Vitek v. vide only “synthetic sanity” (Ref. 44, p 1034; empha- Jones,56 held an administrative hearing, finding Harper in need of treatment and ordered that he be Again in 2003, the courts ruled on involuntary involuntarily medicated. Harper filed a civil suit, al- administration of antipsychotic medications and leging that the state’s practice violated his federal competency in the decisive case, mentioned earlier, constitutional rights of due process, equal protec- of Sell v. United States.42 In Sell, the United States Supreme Court considerably limited the practice of Justice Stevens, writing the dissenting opinion, involuntary restoration by citing its concerns that held that the administration of antipsychotic drugs antipsychotic medications can infringe on a defen- was akin to electroconvulsive therapy or psychosur- dant’s constitutional rights under the Sixth and gery and unfortunately introduced into the Court’s Fourteenth Amendments. Justice Breyer, writing for lexicon the term “mind-altering drugs” as synony- the majority and citing the American Psychological mous with antipsychotic medications (Ref. 43, pp Association’s amicus curie brief claiming that psycho- 240 –1). In citing the Supreme Court of Massachu- sis can resolve without pharmacologic interventions, setts case In re Guardianship of Roe,57 Justice Stevens held that the sedation accompanying administration noted as pervasive that court’s conclusion that anti- of antipsychotic medications can “interfere” with de- psychotic drugs have a “well-established likelihood of fendants’ communication with their attorneys, pre- severe and irreversible adverse effects” (Ref. 43, p vent them from “rapidly reacting” to trial develop- 241; internal quotations omitted). Justice Stevens ments, and diminish the expression of emotions (Ref. 42, pp 185– 6). Consequently, the Court held, The State might seek to compel Harper to submit to a mind- involuntary administration of antipsychotic medica- altering drug treatment program as punishment for the crime he tions for purposes of restoration may only occur in committed in 1976, as a “cure” for his mental illness, or as a limited circumstances. The requirements being that: mechanism to maintain order in the prison. The Court [major-ity opinion] today recognizes Harper’s liberty interest only as (1) the administration of psychotropics must be for against the first justification [Ref. 43, p 241; emphasis added].
an important governmental interest; (2) they mustdirectly further that interest; (3) it must be “substan- Cases of Treatment Over Objection
tially likely” that administration of psychotropics Similar to cases of competency to stand trial and will restore competency; (4) the psychotropics must penological interest, involuntary administration of be “unlikely” to interfere with the ability of a defen- antipsychotic medications have been addressed by dant to communicate with his/her attorney; (5) less the courts in a variety of other contexts, most prom- intrusive measures are unlikely to restore compe- inently in cases of civil treatment over objection. The Volume 35, Number 2, 2007
Legal Fallacies of Antipsychotic Drugs
courts have acknowledged in these circumstances as limited areas of functioning, leaving other areas un- well the compelling state interests of involuntary impaired” (Ref. 58, p 210; citing Ref. 59, p 342), the pharmacotherapy and the individual liberty interests court showed a deep misunderstanding of the perva- of the afflicted patient. Analogous to the court’s per- siveness of psychotic symptoms and impaired judg- ception of antipsychotic drugs in competency cases ment that often accompany acute exacerbations of and prison inmate cases, however, cases of civil treat- ment over objection provide further illumination as The safeguarding of individual liberties is an im- to the mindset of the judiciary and legal community portant function of the courts. Indeed, antipsychotic that these treatments invariably exert harmful effects medications are associated with numerous side ef- on cognition, and hence, infringe on constitutional fects, including tardive dyskinesia, neuroleptic ma- lignant syndrome, dyslipidemia, and metabolic The decisive case of Riese v. Mary’s Hosp. & Med. syndrome.60,61 Tolerability is a major factor in pa- Ctr.,58 is emblematic of most cases of civil treatment tient dissatisfaction with these agents,62 and the over objection. Ms. Riese had a history of chronic global blockade of dopamine inherent in these drugs schizophrenia since her early 20s, but was success- reduces hedonic pleasure and motivation.63,64 In- fully treated with thioridazine, allowing her to avoid deed, there is much room for improvement in the hospitalization for over 10 years. After she began to pharmacological armamentarium of treatments for have bladder problems, her doctors switched her to psychotic illnesses. But the implication that such molindone, which was ineffective. In 1985, Ms.
medicines are mind controlling and have the propen- Riese was voluntarily admitted for exacerbation of sity to sabotage intentionality of free thinking shows her psychotic symptoms and was eventually treated a fundamental misunderstanding of the effects that again with thioridazine. After Ms. Riese became ag- these life-saving medications have in millions of peo- itated and refused further medication, she was con- ple. More crucially, the notion that antipsychotic verted to involuntary status, given intramuscular in- drugs impair cognition in persons with psychosis is in jections, and required further hospitalization for her direct opposition to the wealth of scientific studies active psychotic symptoms. Ms. Riese sued, contend- that have demonstrated just the opposite—that these ing that California law provided her with a right to refuse antipsychotic medication on the grounds ofprivacy and free speech.
Neurocognition in Schizophrenia
Justice Kline, writing for the majority, held that Perhaps the greatest scientific achievement in the absent a judicial determination of incompetency, in- realm of schizophrenia and related illnesses within formed consent was required before treatment with the past 15 years has been the appreciation and in- antipsychotic medications was permissible. Citing tensive study of comorbid cognitive impairments that these medications were “by intention mind al- that usually accompany these chronic illnesses. Con- tering” and “possess a remarkable potential for un- clusive evidence has demonstrated that the severity of dermining individual will and self-direction” and cognitive deficits is strongly linked with long-term may result in “sudden death” (Ref. 58, p 203), the prognosis and overall functioning.65 Consequently, court held that psychiatric hospitalization for psy- vigorous research has focused on identifying aspects chosis alone did not presume incompetency, and of these impairments and exploring effective treat- thus, the hospital had violated Ms. Riese’s constitu- ments.66 A variety of impairments have been identi- tional rights. In a footnote, the court also held that: fied, with the most salient aspects being visual pro- The cited cases protect against intrusions into the mind by cessing, sustained attention, memory, executive means of lie detector tests or therapists’ disclosures. While the functioning, and general intelligence.
present case does not involve such forced revelations of thecontent of the mind, the changing of thoughts contested here is Visual Processing
no less intrusive [Ref. 58, p 208, fn 11; internal citations omitted, One of the first cognitive deficits to be identified in schizophrenia was the inability of those afflicted to The court also found New York’s similar determina- discriminate between multiple visual cues.67 Visual tion persuasive. Referencing to the watershed case, processing is a cognitive process that allows interpre- Rivers v. Katz,59 that mental illness “often strikes only tation of a vast array of visual stimuli. This vital cog- The Journal of the American Academy of Psychiatry and the Law
Erickson, Ciccone, Schwarzkopf, et al.
nitive ability was first observed by the 17th century 185– 6) in the courtroom necessarily implies intact philosopher Sir William Hamilton. Recent research attention on the part of the defendant, and thus, its has shown that persons with schizophrenia have par- impairment is significant for mentally ill defendants.
ticular deficits with backward masking, which pre-vents them from interpreting the first stimulus (icon) Memory
Impairment in the ability to learn and recall infor- Although the exact mechanism behind impair- mation from past events is a hallmark feature ment of backward masking remains unknown, it is of schizophrenia.74,75 While an exhaustive review of believed to involve a disruption of the magnocellular the memory deficits involved in schizophrenia is be- and parvocellular pathways that leads to either dis- yond the scope of this article, the putative impair- ruption of the icon or overemphasis of the mask.69 ments observed generally include deficits in explicit The importance of visual processing deficits in and working memory. Explicit memory includes schizophrenia is that they impair a person’s ability to tasks that rely on conscious recollection of specific, scan the environment quickly, create an internal rep- previous events that can be articulated. Numerous resentation of the environment, and extract relevant studies have shown that persons with schizophrenia information. Thus, inherent in this deficit is the dif- have impairments in domains of explicit memory, ficulty in making transitory perceptual judgments including verbal recall76,77 and, to a lesser extent, when presented with multiple visual cues in the In addition, working memory deficits have been observed in medicated and medication-naı¨ve persons Sustained Attention
with schizophrenia.79 Working memory is the pro- Attention is an invaluable process of cognitive cess of actively holding information in consciousness functioning. In schizophrenia, impaired attention and manipulating it in service of guiding behavior.
has been observed for many decades by researchers Working memory deficits usually persist throughout and has been a focal point of many neuropsycholog- the course of schizophrenia80; however, findings in ical studies.69 From a neurocognitive perspective, at- several studies suggest that some atypical antipsy- tention contains several subcomponents, many of chotic medications may be associated with improve- which are impaired in schizophrenia.70 Sustained at- tention is a process that allows a person to identify The importance of memory cannot be overstated.
and select a target (signal) among extraneous targets Memory is believed to be crucial in learning84 and its (noise). When the task is completed over time, this value in everyday functioning is intuitive. The ability facet of attention is referred to as vigilance.
to form new memories and recall past events is While vigilance decrement (i.e., the loss of vigi- strongly related to a person’s overall ability to form a lance during execution of a task) does not appear coherent, functional understanding of the environ- severely impaired in schizophrenia,71 deficits in vig- ment. Memory impairment has also been associated ilance levels (i.e., the overall vigilance given to the with those at high risk of psychotic illnesses.85 In task at hand), latent inhibition, and selective atten- addition, results of several studies suggest that schizo- tion are prevalent.72 Selective attention is the ability phrenia is associated with other impairments of to pay attention to one source of sensory input while memory, including semantic86 and visual memory,87 disregarding others. Latent inhibition is the ability to as well as prominent encoding deficits88 that further adapt to changing rules that give emphasis to a stim- disrupt the capacity of persons with schizophrenia to ulus. In schizophrenia, deficits in selective attention adduce logically the stimuli in their environment.
and latent inhibition have been well documented.73 Both impairments have obvious relevance to per- Executive Functioning
sons with schizophrenia involved in legal proceed- Executive functioning is a fundamental attribute ings, since attention can be defined as a cognitive of higher cognitive functioning in primates.89 This process necessary for complex situations that require concept refers to a host of neurocognitive activities a person to discriminate among multiple sensory in- that are involved in planning, problem solving, and puts. As discussed in Sell, the ability of defendants to alternating between tasks. It appears to be more dis- “rapidly react” to changing situations (Ref. 42, pp turbed than other neurocognitive deficits in schizo- Volume 35, Number 2, 2007
Legal Fallacies of Antipsychotic Drugs
phrenia and most likely involves decreased activity in challenged this theory and suggest that psychotic ill- the prefrontal cortex.90 Executive functioning may nesses such as schizophrenia involve progressive be related to working memory,91 and the failure of changes in brain structure and function that signal an additional studies to find an association between these two aspects of cognition probably is represen-tative of the heterogeneity of schizophrenia.
Role of Glutamate
Impairment in executive functioning has been asso- Glutamate is an excitatory amino acid implicated ciated with negative symptoms, including avolition and in the pathology of psychotic illnesses. Its role has alogia,92 and may be associated with poor insight,93 been discerned from animal models of exposure occupational competence,94 and independent living,95 to phencyclidine (PCP) and involves activity of N- although methodical problems limit these last two find- methyl-D-aspartate (NMDA) receptors.105 NMDA ings.69 Surely, impairments in executive functioning receptors play a crucial role in memory, learning, have direct relevance to persons with mental illness who synaptic development and neuroplasticity, sensory are involved in legal proceedings. The ability to assist information, and coordinated movements.106 It is counsel competently, weigh the risks and benefits of theorized that glutamatergic dysregulation occurs via plea-bargaining conditions, and appreciate the poten- secondary pathways, in which inhibition of NMDA tial long-term repercussions of court orders necessarily receptors leads to disinhibition of cortical excitatory involves abilities related to planning and abstract cholinergic neurons by way of decreased stimulation of inhibitory ␥-aminobutyric acid (GABA) neurons,which leads to autoexcitotoxicity of glutamate.107 General Intelligence
Within this context, glutamate neurotoxicity leads to Schizophrenia is associated with low intelligence dopamine hyperactivity, which produces pathogenic quotients (IQ), even when family and environmental factors are controlled for,96 and low IQ appears dur- While histopathological studies have consistently ing childhood before the development of symptoms failed to demonstrate large-scale neuronal loss in of schizophrenia.97 Whether intelligence in schizo- schizophrenia similar to that in other neurodegenera- phrenia is a mediating factor that is independent of tive disorders,108 some have postulated that the re- the illness or a marker of the genetic predisposition duced cancer rates in people with schizophrenia109 remains unclear, yet poor performance on neuropsy- are related to the accelerated apoptosis observed chological measures of intellectual abilities appears through abnormal expression of cortical Bcl-2 pro- independent of general intelligence.98 Nonetheless, teins in both treated and drug-naı¨ve patients with there is evidence of an association between low intel- schizophrenia.110,111 Significant neuronal reduc- ligence and risk of schizophrenia.99 Low intelligence tions have been noted in the thalamus, nucleus ac- and schizophrenia are associated with earlier onset of cumbens,112,113 and GABAergic interneurons in lay- illness and worse prognosis.100,101 The prevalence of ers II, III, V, and VI of the anterior cingulate of low intelligence in schizophrenia is estimated at postmortem brains,114 and neuronal atrophy appears likely in schizophrenia.115 Agents that indirectly en-hance NMDA receptor function via the glycine Duration of Untreated Psychosis
modulatory site have shown promise in treating neg- and Neurotoxicity
ative symptoms and the impaired cognition observed The idea that active psychosis is fundamentally in schizophrenia.116,117 These findings suggest some related to a neurotoxic process dates back to the early neurodegenerative process occurs in schizophrenia.
days of psychiatry. Emil Kraepelin is well-known forconceptualizing psychosis as an illness of invariable Duration of Untreated Psychosis
deterioration, presumably resulting from neuronal Within the past two decades, increased attention death.103 The neurodevelopmental hypothesis, how- has been given to the duration of untreated psychosis ever, has been the dominant paradigm for the past (DUP) and its association with treatment response several decades. It posits that schizophrenia is borne and functional outcome. Studies have examined the through early developmental insults that manifest in onset and duration of symptoms until the point of later life as the disease.104 Recent discoveries have first treatment. Notably, this period appears quite The Journal of the American Academy of Psychiatry and the Law
Erickson, Ciccone, Schwarzkopf, et al.
long118,119 and has spurred intense interest in early psychotic agents because of the erroneous belief that detection and treatment programs.120 Although it these medications exert some form of mind control remains unsettled whether DUP is pathogenic or is or altered state of consciousness. On the contrary, simply a marker of more malignant forms of psycho- antipsychotic medications have the propensity to im- sis,119 when viewed within the emerging theory of prove cognition in many areas directly relevant to glutamate dysregulation and possible toxicity of un- competence, whether it is competence to stand trial treated psychosis to the brain, DUP represents a pos- or competence to make informed decisions regarding sible reemergence of the neurodegenerative theory of medical treatment. Indeed, antipsychotic medica- schizophrenia39,121,122—although some disagree tions restore cognitive capacities that are often se- with this assessment in favor of a disconnectivity hy- verely impaired by psychosis—a disease of the brain.
pothesis.123 Nonetheless, a recent meta-analysisconfirmed that DUP is associated with a host of neg- Older Agents
ative outcomes,14 while another recent study demon- For many years, it was presumed that the older, strated long-term DUP associations with poorer global first-generation antipsychotic drugs had no effect or functioning and increased positive symptoms.124 even a deleterious effect on cognition. Recent studies Duration of untreated psychosis has been associated have disproven this conclusion. Many of the early with a lack of acute treatment response,125,126 studies examining these agents had methodological poor premorbid functioning,127,128 increased posi- problems ranging from being underpowered to ad- tive129,130 and negative symptoms,129,131poorer out- ministration of excessively high dosages of the come,132 and increased cognitive deficits.133,134 Others drugs.141,142 Indeed, the permissive use of haloperi- have found no relationship between DUP and some of dol as a comparator agent, with its high extrapyrami- these variables.135,136 Nonetheless, there is a growing dal side effects was a primary reason for the use of consensus that DUP is an important prognostic factor perphenazine in the recent NIH Clinical Antipsy- in psychotic illnesses. Whether the deficits associated chotic Trials of Intervention Effectiveness (CATIE).143 with DUP can be fully restored with proper treatment Studies have shown that first-generation antipsy- remains unknown; however, the long-term course and chotic medications are associated with improvement prognosis for those with long DUP appears poor.137 across a wide-range of cognitive domains, includingexecutive functioning, sustained attention, memory, Improvement of Cognition by
language function, time perception, and ocular mo- Antipsychotic Medications
tor function.142 Low-dose haloperidol has shown a An abundance of studies have clearly demon- more rapid onset and equal overall efficacy of cogni- strated that consistent treatment with antipsychotic tive improvement than the newer agent, risperidone, medications improves cognition in patients with across measures of executive functioning, memory, schizophrenia and related psychotic disorders. How- sustained attention, and visual processing.144 These ever, the notion of psychotropic drugs as mind-alter- results remain consistent, even accounting for con- ing by legal scholars and the courts is in no way a comitant use of anticholinergic medications.
reference to their beneficial effects. They are viewedas “chemical straightjackets” impinging on free Newer Agents
thought and the exercise of individual judgment.138 The 1990s saw a rapid transition of treatments for The expansion of privacy rights rooted in the funda- psychotic disorders, most notably the wide-spread mental autonomy recognized by the courts since the use of newer, second-generation antipsychotic drugs.
1960s is the touchstone of the right to refuse un- While older agents exerted their effects primarily on wanted medical treatments.139 Yet, it is well recog- the D receptor, newer agents exponentially ex- nized that significant governmental interests, includ- panded the number and type of receptors engaged in ing personal safety, competence to stand trial, and treatment. A wealth of data has been generated ex- the established right of the state to care for incompe- amining the effects of these second-generation drugs tent citizens under its parens patria powers can over- and their effects on cognition. The abundance of data strongly suggests that second-generation anti- Nonetheless, as demonstrated in this article, the psychotic medications significantly improve a host of courts are wary of involuntary treatment with anti- cognitive functions. These improvements include Volume 35, Number 2, 2007
Legal Fallacies of Antipsychotic Drugs
performance on measures of verbal fluency,145–148 Conclusions
executive functioning,145,149,150 vigilance,148,151,152 Antipsychotic medications are not mind-altering sustained attention,145,153,154 memory,83,155,156 drugs as construed by legal scholars and the courts.
and numerous other cognitive processes.157–159 Rather, they are beneficial treatments that uncontro- Moreover, the effects are sustained over time and vertibly improve cognition among patients with psy- are independent of positive symptom severity.
chotic disorders, including schizophrenia. Whether Investigational drugs that directly target NMDA are the task involves making competent and informed in development160 with the NMDA receptor coago- treatment decisions, assisting defense counsel during nists glycine, D-serine, and D-cycloserine already trial, or enduring the hardships of prolonged incar- showing promise for adjunctive remediation of the ceration, these medicines enhance a person’s ability cognitive deficits seen in schizophrenia.116,161 In ad- to make rational decisions. There is evidence that dition, reversible inhibitors of the enzyme acetyl cho- antipsychotic medications may prevent further clin- linesterase have also been shown to improve these ical deterioration due to potentially permanent oxi- dative-stress processes occurring in the brains ofthose affected with psychotic disorders.163,164 Thetime is ripe and the evidence overwhelming that the Antipsychotic Medications and Persons
deprecatory attitudes toward these life-saving medi- Involved in Legal Proceedings
cines are unwarranted and contradictory to the aims As demonstrated, patients with schizophrenia and of beneficence, autonomy, dignity, and justice that related psychotic illnesses often have substantial def- medical ethics and the law passionately seek. The icits in a host of cognitive abilities. Antipsychotic onus is on the courts to make informed decisions medications, both typical and atypical, improve cog- regarding such important matters as civil commit- nitive functioning in these patients. Cognitive abili- ment and competency and this necessarily entails an ties such as executive functioning, memory, and at- accurate and current understanding of questions tention are surely important for any person involved brought before them. In terms of antipsychotic in legal proceedings in which important issues in- drugs, the first step is the declaration that antipsy- cluding liberty interests are at stake. While antipsy- chotic medications are “mind-saving drugs.” chotic medications are associated with several nega-tive side effects, including many serious and References
debilitating diseases, forgoing treatment is associated 1. Sharma T: Brain Imaging in Schizophrenia: Insights and Appli- with numerous negative outcomes, including severe cations. London: Remedica Publishing, 2001 2. Hall D, Gogos JA, Karayiorgou M: The contribution of three strong candidate schizophrenia susceptibility genes in demo- In referring to antipsychotic medications as graphically distinct populations. Genes Brain Behav 3:240 – 8, “mind altering” or their effects as “synthetic san- ity,” the legal community misconstrues their cog- 3. Norton N, Williams HJ, Owen MJ: An update on the genetics of schizophrenia. Curr Opin Psychiatry 19:158 – 64, 2006 nitive restorative properties in favor of a view akin 4. Weinberger DR: Implications of normal brain development for to psychedelic drugs of abuse. Antipsychotic drugs the pathogenesis of schizophrenia. Arch Gen Psychiatry 44: do not override personal choice or intentionality 5. Konradi C, Heckers S: Molecular aspects of glutamate dysregu- or “control” the persons who receive them. On the lation: implications for schizophrenia and its treatment. Phar- contrary, abundant evidence suggests otherwise.
That is, antipsychotic drugs improve cognitive ca- 6. Miyamoto S, LaMantia AS, Duncan GE, et al: Recent advances in the neurobiology of schizophrenia. Mol Interv 3:27–39, 2003 pacities that are vitally important to persons in- 7. Harvey PD, Koren D, Reichenberg A, et al: Negative symptoms volved in legal proceedings who have psychotic and cognitive deficits: what is the nature of their relationship? disorders. Consequently, in any legal system that 8. Kirkpatrick B, Fenton WS, Carpenter WT Jr, et al: The NIMH- values competent defendants who can appreciate MATRICS consensus statement on negative symptoms. Schizo- the legal proceedings against them and assist in their defense, antipsychotic medications should be 9. Breier A, Schreiber JL, Dyer J, et al: National Institute of Mental Health longitudinal study of chronic schizophrenia: prognosis embraced for those defendants afflicted with se- and predictors of outcome. Arch Gen Psychiatry 48:239 – 46, The Journal of the American Academy of Psychiatry and the Law
Erickson, Ciccone, Schwarzkopf, et al.
10. Green MF: What are the functional consequences of neurocog- 29. Neckelmann G, Specht K, Lund A, et al: MR morphometry nitive deficits in schizophrenia? Am J Psychiatry 153:321–30, analysis of grey matter volume reduction in schizophrenia: asso- ciation with hallucinations. Int J Neurosci 116:9 –23, 2006 11. Milev P, Ho B-C, Arndt S, et al: Predictive values of neurocog- 30. McDonald C, Bullmore E, Sham P, et al: Regional volume de- nition and negative symptoms on functional outcome in schizo- viations of brain structure in schizophrenia and psychotic bipolar phrenia: a longitudinal first-episode study with 7-year follow-up.
disorder: computational morphometry study. Br J Psychiatry 12. Stip E, Chouinard S, Boulay LJ: On the trail of a cognitive 31. Pantelis C, Yucel M, Wood SJ, et al: Structural brain imaging enhancer for the treatment of schizophrenia. Prog Neuropsycho- evidence for multiple pathological processes at different stages of pharmacol Biol Psychiatry 29:219 –32, 2005 brain development in schizophrenia. Schizophr Bull 31:672–96, 13. Weiss EM, Bilder RM, Fleischhacker WW: The effects of sec- ond-generation antipsychotics on cognitive functioning and psy- 32. Styner M, Lieberman JA, McClure RK, et al: Morphometric chosocial outcome in schizophrenia. Psychopharmacology 162: analysis of lateral ventricles in schizophrenia and healthy controls regarding genetic and disease-specific factors. Proc Natl Acad Sci 14. Perkins DO, Gu H, Boteva K, et al: Relationship between dura- tion of untreated psychosis and outcome in first-episode schizo- 33. Wright IC, Rabe-Hesketh S, Woodruff PWR, et al: Meta-anal- phrenia: a critical review and meta-analysis. Am J Psychiatry ysis of regional brain volumes in schizophrenia. Am J Psychiatry 15. Malla A, Norman R, Manchanda R, et al: Symptoms, cognition, 34. Glantz LA, Gilmore JH, Lieberman JA, et al: Apoptotic mecha- treatment adherence and functional outcome in first-episode nisms and the synaptic pathology of schizophrenia. Schizophr psychosis. Psychol Med 32:1109 –19, 2002 16. Robinson D, Woerner MG, Alvir JMJ, et al: Predictors of relapse 35. Jarskog LF, Glantz LA, Gilmore JH, et al: Apoptotic mecha- following response from a first episode of schizophrenia or nisms in the pathophysiology of schizophrenia. Prog Neuropsy- schizoaffective disorder. Arch Gen Psychiatry 56:241–7, 1999 chopharmacol Biol Psychiatry 29:846 –58, 2005 17. Gitlin M, Nuechterlein K, Subotnik KL, et al: Clinical outcome 36. Roberts RC, Roche JK, Conley RR: Synaptic differences in the following neuroleptic discontinuation in patients with remitted patch matrix compartments of subjects with schizophrenia: a recent-onset schizophrenia. Focus 2:122–30, 2004 postmortem ultrastructural study of the striatum. Neurobiol Dis 18. Wyatt RJ, Green MF, Tuma AH: Long-term morbidity associ- ated with delayed treatment of first admission schizophrenic 37. Cotter D, Mackay D, Chana G, et al: Reduced neuronal size and patients: a re-analysis of the Camarillo State Hospital data. Psy- glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex 12:386 – 19. Herings RM, Erkens JA: Increased suicide attempt rate among patients interrupting use of atypical antipsychotics. Pharmaco- 38. Pantelis C, Yucel M, Wood SJ, et al: Structural brain imaging evidence for multiple pathological processes at different stages of 20. Fenton WS, Blyler CR, Heinssen RK: Determinants of medica- brain development in schizophrenia. Schizophr Bull 31:672–96, tion compliance in schizophrenia: empirical and clinical find- 39. DeLisi LE, Sakuma M, Tew W, et al: Schizophrenia as a chronic 21. Ascher-Svanum H, Faries DE, Zhu B, et al: Medication adher- active brain process: a study of progressive brain structural ence and long-term functional outcomes in the treatment of change subsequent to the onset of schizophrenia. Psychiatry Res schizophrenia in usual care. J Clin Psychiatry 67:453– 60, 2006 22. Swartz MS, Swanson JW, Hiday VA, et al: Violence and severe 40. Mathalon DH, Sullivan EV, Lim KO, et al: Progressive brain mental illness: the effects of substance abuse and nonadherence volume changes and the clinical course of schizophrenia in men: to medication. Am J Psychiatry 155:226 –31, 1998 a longitudinal magnetic resonance imaging study. Arch Gen Psy- 23. Nose M, Barbui C, Tansella M: How often do patients with psychosis fail to adhere to treatment programmes? —a system- 41. Woods BT: Is schizophrenia a progressive neurodevelopmental atic review. Psychol Med 33:1149 – 60, 2003 disorder? Toward a unitary pathogenetic mechanism. Am J Psy- 24. Ananth H, Popescu I, Critchley HD, et al: Cortical and subcor- tical gray matter abnormalities in schizophrenia determined 42. Sell v. United States, 539 U.S. 166 (2003) through structural magnetic resonance imaging with optimized 43. Washington v. Harper, 494 U.S. 210 (1990) volumetric voxel-based morphometry. Am J Psychiatry 159: 44. Singleton v. Norris, 108 F.3d 872 (8th Cir. 1997) 45. Robbins E, Waters J, Herbert P: Competency to stand trial 25. Bagary MS, Symms MR, Barker GJ, et al: Gray and white matter evaluations: a study of actual practice in two states. J Am Acad brain abnormalities in first-episode schizophrenia inferred from magnetization transfer imaging. Arch Gen Psychiatry 60:779 – 46. Morse SJ: Inevitable mens rea. Harv J Law & Pub Pol’y 27:51– 26. Burns J, Job D, Bastin M, et al: Structural disconnectivity in 47. Viljoen JL, Zapf PA, Roesch R: Diagnosis, current symptom- schizophrenia: a diffusion tensor magnetic resonance imaging atology, and the ability to stand trial. J Forensic Psychol Pract study. Br J Psychiatry 182:439 – 43, 2003 27. Cahn W, Pol H, Bongers M, et al: Brain morphology in anti- 48. Freedman R: Schizophrenia. N Engl J Med 349:1738 – 49, 2003 psychotic-naive schizophrenia: a study of multiple brain struc- 49. Sawa A, Snyder SH: Schizophrenia: diverse approaches to a com- tures. Br J Psychiatry 181:66 –72, 2002 28. Narr KL, Bilder RM, Toga AW, et al: Mapping cortical thickness 50. Amador XF, Flaum M, Andreasen NC, et al: Awareness of illness and gray matter concentration in first episode schizophrenia.
in schizophrenia and schizoaffective and mood disorders. Arch Volume 35, Number 2, 2007
Legal Fallacies of Antipsychotic Drugs
51. Morse SJ: Involuntary competence. Behav Sci Law 21:311–28, 76. Daban C, Martinez-Aran A, Torrent C, et al: Specificity of cog- nitive deficits in bipolar disorder versus schizophrenia: a system- 52. Riggins v. Nevada, 504 U.S. 127 (1992) atic review. Psychother Psychosom 75:72– 84, 2006 53. Tomashefsy S: Antipsychotic drugs and fitness to stand trial: the 77. Toulopoulouand T, Murray RM: Verbal memory deficit in pa- right of unfit accused to refuse treatment. U Chi Law Rev 52: tients with schizophrenia: an important future target for treat- ment. Expert Rev Neurother 4:43–52, 2004 54. Fentiman LC: Whose right is it anyway?—rethinking compe- 78. Calev A: Recall and recognition in chronic nondemented schizo- tency to stand trial in light of the synthetically sane insanity phrenics: use of matched tasks. J Abnorm Psychol 93:172–7, defendant. U Miami Law Rev 40:1109 – 69, 1986 55. Breneman DA: Forcible antipsychotic medication and the un- 79. Honey GD, Fletcher PC: Investigating principles of human fortunate side effects of Sell v. United States. Harv J Law & Pub brain function underlying working memory: what insights from schizophrenia? Neuroscience 139:59 –71, 2006 80. Park S, Holzman PS: Schizophrenics show spatial working mem- 57. In re Guardianship of Roe, 421 N.E.2d 40 (Mass. 1981) ory deficits. Arch Gen Psychiatry 49:975– 82, 1992 58. Riese v. St. Mary’s Hosp. & Med. Ctr., 271 Cal. Rptr. 199 (Cal.
81. Green MF, Marshall BD Jr, Wirshing WC, et al: Does risperi- done improve verbal working memory in treatment-resistant 59. Rivers v. Katz, 495 N.E.2d 337 (N.Y. 1986) schizophrenia? Am J Psychiatry 154:799 – 804, 1997 60. Lamberti JS, Olson D, Crilly JF, et al: Prevalence of the meta- 82. Harvey PD, Bowie CR, Loebel A: Neuropsychological normal- bolic syndrome among patients receiving clozapine. Am J Psy- ization with long-term atypical antipsychotic treatment: results of a six-month randomized, double-blind comparison of ziprasi- 61. American Psychiatric Association: Practice Guidelines for the done vs. olanzapine. J Neuropsychiatry Clin Neurosci 18:54 – Treatment of Patients With Schizophrenia. Washington, DC: 83. McGurk SR, Carter C, Goldman R, et al: The effects of cloza- 62. Marder SR: Subjective experiences on antipsychotic medica- pine and risperidone on spatial working memory in schizophre- tions: synthesis and conclusions. Acta Psychiatr Scand 111: 84. Chen C, Tonegawa S: Molecular genetic analysis of synaptic 63. Kapur S, Mizrahi R, Li M: From dopamine to salience to psy- plasticity, activity-dependent neural development, learning, and chosis: linking biology, pharmacology and phenomenology of memory in the mammalian brain. Ann Rev Neurosci 20:157– psychosis. Schizophr Res 79:59 – 68, 2005 64. Berridge KC, Robinson TE: What is the role of dopamine in 85. Brewer WJ, Francey SM, Wood SJ, et al: Memory impairments reward: hedonic impact, reward learning, or incentive salience? identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. Am J Psychiatry 162:71– 8, 65. Sevy S, Davidson M: The cost of cognitive impairment in schizo- 86. McKay AP, McKenna PJ, Bentham P, et al: Semantic memory is 66. Fenton WS, Stover EL, Insel TR: Breaking the log-jam in treat- impaired in schizophrenia. Biol Psychiatry 39:929 –37, 1996 ment development for cognition in schizophrenia: NIMH per- 87. Saykin AJ, Shtasel DL, Gur RE, et al: Neuropsychological defi- spective. Psychopharmacology 169:365– 6, 2003 67. Asarnow RF, Granholm E, Sherman T: Span of Apprehension in cits in neuroleptic naive patients with first-episode schizophre- nia. Arch Gen Psychiatry 51:124 –31, 1994 68. McClure RK: The visual backward masking deficit in schizo- 88. Brerion G, Amador X, Smith MJ, et al: Mechanisms underlying phrenia. Prog Neuropsychopharmacol Biol Psychiatry 25:301– memory impairment in schizophrenia. Psychol Med 27:383–93, 69. Green MF: Schizophrenia From a Neurocognitive Perspective: 89. Stuss DT, Alexander MP: Executive functions and the frontal Probing the Impenetrable Darkness. Needham Heights, MA: lobes: a conceptual view. Psychol Res 63:289 –98, 2000 90. Sharma T, Antonova L: Cognitive function in schizophrenia: 70. Bowie CR, Harvey PD, Bowie CR: Cognition in schizophrenia: deficits, functional consequences, and future treatment. Psychi- impairments, determinants, and functional importance. Psychi- 91. Goldman-Rakic PS: Prefrontal Cortical Dysfunction in Schizo- 71. Cornblatt BA, Lenzenweger MF, Erlenmeyer-Kimling L: The phrenia: The Relevance of Working Memory. New York: Raven continuous performance test, identical pairs version: II. Con- trasting attentional profiles in schizophrenic and depressed pa- 92. Berman I, Viegner B, Merson A, et al: Differential relationships between positive and negative symptoms and neuropsychologi- 72. Nuechterlein KH, Barch DM, Gold JM, et al: Identification of cal deficits in schizophrenia. Schizophr Res 25:1–10, 1997 separable cognitive factors in schizophrenia. Schizophr Res 72: 93. Mohamed S, Fleming S, Penn DL, et al: Insight in schizophre- nia: its relationship to measures of executive functions. J Nerv 73. Keshavan MS, Berger G, Zipursky RB, et al: Neurobiology of early psychosis. Br J Psychiatry 187:8 –18, 2005 94. Lysaker P, Bell M: Insight and cognitive impairment in schizo- 74. Green MF, Nuechterlein KH, Gold JM, et al: Approaching a phrenia. Performance on repeated administrations of the Wis- consensus cognitive battery for clinical trials in schizophrenia: consin Card Sorting Test. J Nerv Ment Dis 182:656 – 60, 1994 the NIMH-MATRICS conference to select cognitive domains 95. Brekke JS, Raine A, Ansel M, et al: Neuropsychological and and test criteria. Biol Psychiatry 56:301–7, 2004 psychophysiological correlates of psychosocial functioning in 75. Lencz T, Smith CW, McLaughlin D, et al: Generalized and schizophrenia. Schizophr Bull 23:19 –28, 1997 specific neurocognitive deficits in prodromal schizophrenia. Biol 96. Aylward E, Walker E, Bettes B: Intelligence in schizophrenia: meta-analysis of the research. Schizophr Bull 10:430 –59, 1984 The Journal of the American Academy of Psychiatry and the Law
Erickson, Ciccone, Schwarzkopf, et al.
97. Goldberg TE, Hyde TM, Kleinman JE, et al: Course of schizo- 117. Lane H-Y, Chang Y-C, Liu Y-C, et al: Sarcosine or d-serine phrenia: neuropsychological evidence for a static encephalopa- add-on treatment for acute exacerbation of schizophrenia: a ran- domized, double-blind, placebo-controlled study. Arch Gen 98. Kremen WS, Seidman LJ, Faraone SV, et al: Intelligence quo- tient and neuropsychological profiles in patients with schizo- 118. Larsen TK, Friis S, Haahr U, et al: Early detection and interven- phrenia and in normal volunteers. Biol Psychiatry 50:453– 62, tion in first-episode schizophrenia: a critical review. Acta Psychi- 99. David AS, Malmberg A, Brandt L, et al: IQ and risk for schizo- 119. McGlashan TH: Duration of untreated psychosis in first- phrenia: a population-based cohort study. Psychol Med 27: episode schizophrenia: marker or determinant of course? Biol 100. Hassiotis A, Ukoumunne OC, Byford S, et al: Intellectual func- 120. McGlashan TH, Zipursky RB, Perkins D, et al: The PRIME tioning and outcome of patients with severe psychotic illness North America randomized double-blind clinical trial of olanza- randomised to intensive case management. Report from the pine versus placebo in patients at risk of being prodromally UK700 trial. Br J Psychiatry 178:166 –71, 2001 symptomatic for psychosis. I. Study rationale and design. Schizo- 101. Chaplin R, Barley M, Cooper SJ, et al: The impact of intellectual functioning on symptoms and service use in schizophrenia. J In- 121. Lieberman JA: Is schizophrenia a neurodegenerative disor- der?—a clinical and neurobiological perspective. Biol Psychiatry 102. Hassiotis A: Prevalence and characteristics of patients with severe mental illness and borderline intellectual functioning: report 122. Weinberger DR, McClure RK: Neurotoxicity, neuroplasticity, from the UK700 randomised controlled trial of case manage- and magnetic resonance imaging morphometry: what is happen- ment. Br J Psychiatry 175:135– 40, 1999 ing in the schizophrenic brain? Arch Gen Psychiatry 49:553– 8, 103. Kraepelin E: Dementia Praecox and Paraphrenia. New York: 123. McGlashan TH: Is active psychosis neurotoxic? Schizophr Bull 104. Marenco S, Weinberger DR: The neurodevelopmental hypoth- esis of schizophrenia: following a trail of evidence from cradle to 124. Clarke M, Whitty P, Browne S, et al: Untreated illness and grave. Dev Psychopathol 12:501–27, 2000 outcome of psychosis. Br J Psychiatry 189:235– 40, 2006 105. Byrd JC, Bykov V, Rothman R: Chronic haloperidol treatment 125. Ucok A, Polat A, Genc A, et al: Duration of untreated psychosis up-regulates rat brain PCP receptors. Eur J Pharmacol 140: may predict acute treatment response in first-episode schizo- phrenia. J Psychiatr Res 38:163– 8, 2004 106. Stephan KE, Baldeweg T, Friston KJ: Synaptic plasticity and 126. Marshall M, Lewis S, Lockwood A, et al: Association between dysconnection in schizophrenia. Biol Psychiatry 59:929 –39, duration of untreated psychosis and outcome in cohorts of first- episode patients: a systematic review. Arch Gen Psychiatry 62: 107. Heresco-Levy U: Glutamatergic neurotransmission modulation and the mechanisms of antipsychotic atypicality. Prog Neuro- 127. Keshavan MS, Haas G, Miewald J, et al: Prolonged untreated psychopharmacol Biol Psychiatry 23:1113–23, 2003 illness duration from prodromal onset predicts outcome in first 108. Jarskog FL, Miyamoto S, Lieberman JA: Schizophrenia: new pathological insights and therapies. Ann Rev Med 58:59 –71, episode psychoses. Schizophr Bull 29:757– 69, 2003 128. Harrigan SM, McGorry PD, Krstev H: Does treatment delay in 109. Catts VS, Catts SV: Apoptosis and schizophrenia: is the tumour first-episode psychosis really matter? Psychol Med 33:97–110, suppressor gene, p53, a candidate susceptibility gene? Schizophr 129. Larsen TK, Moe LC, Vibe-Hansen L, et al: Premorbid function- 110. Jarskog LF, Gilmore JH, Selinger ES, et al: Cortical Bcl-2 pro- ing versus duration of untreated psychosis in 1 year outcome in tein expression and apoptotic regulation in schizophrenia. Biol first-episode psychosis. Schizophr Res 45:1–9, 2000 130. Harris MG, Henry LP, Harrigan SM, et al: The relationship 111. Jarskog LF, Selinger ES, Lieberman JA, et al: Apoptotic proteins between duration of untreated psychosis and outcome: an eight- in the temporal cortex in schizophrenia: high bax/bcl-2 ratio year prospective study. Schizophr Res 79:85–93, 2005 without caspase-3 activation. Am J Psychiatry 161:109 –15, 131. de Haan L, Linszen DH, Lenior ME, et al: Duration of untreated psychosis and outcome of schizophrenia: delay in intensive psy- 112. Pakkenberg B: Pronounced reduction of total neuron number in chosocial treatment versus delay in treatment with antipsychotic mediodorsal thalamic nucleus and nucleus accumbens in schizo- medication. Schizophr Bull 29:341– 8, 2003 phrenics. Arch Gen Psychiatry 47:1023– 8, 1990 132. Loebel AD, Lieberman JA, Alvir JM, et al: Duration of psychosis 113. Young KA, Manaye KF, Liang CL, et al: Reduced number of and outcome in first-episode schizophrenia. Am J Psychiatry mediodorsal and anterior thalamic neurons in schizophrenia.
133. Scully PJ, Coakley G, Kinsella A, et al: Psychopathology, execu- 114. Jentsch JD, Roth RH: The neuropsychopharmacology of phen- tive (frontal) and general cognitive impairment in relation to cyclidine: from NMDA receptor hypofunction to the dopamine duration of initially untreated versus subsequently treated psy- hypothesis of schizophrenia. Neuropsychopharmacology 20: chosis in chronic schizophrenia. Psychol Med 27:1303–10, 115. Rajkowska G, Selemon LD, Goldman-Rakic PS: Neuronal and 134. Amminger GP, Edwards J, Brewer WJ, et al: Duration of un- glial somal size in the prefrontal cortex: a postmortem morpho- treated psychosis and cognitive deterioration in first-episode metric study of schizophrenia and Huntington disease. Arch schizophrenia. Schizophr Res 54:223–30, 2002 135. Rund BR, Melle I, Friis S, et al: Neurocognitive dysfunction in 116. Javitt DC: Is the glycine site half saturated or half unsaturated?— first-episode psychosis: correlates with symptoms, premorbid ad- effects of glutamatergic drugs in schizophrenia patients. Curr justment, and duration of untreated psychosis. Am J Psychiatry Volume 35, Number 2, 2007
Legal Fallacies of Antipsychotic Drugs
136. Craig TJ, Bromet EJ, Fennig S, et al: Is there an association zapine vs. clozapine. Int J Neuropsychopharmacol 9:135– 45, between duration of untreated psychosis and 24-month clinical outcome in a first-admission series? Am J Psychiatry 157:60 – 6, 151. Joober R, Rouleau GA, Lal S, et al: Neuropsychological impair- ments in neuroleptic-responder vs. -nonresponder schizophrenic 137. Bottlender R, Sato T, Ja¨ger M, et al: The impact of the duration patients and healthy volunteers. Schizophr Res 53:229 –38, of untreated psychosis prior to first psychiatric admission on the 15-year outcome in schizophrenia. Schizophr Res 62:37– 44, 152. Serper MR, Harvey PD, Davidson M: Attentional and clinical neuroleptic response in schizophrenia: a study with the contin- 138. Mossman D: Unbuckling the ‘chemical straitjacket’: The legal uous performance test. Cogn Neuropsychiatry 2:241–9, 1997 significance of recent advances in the pharmacological treatment 153. Liu SK, Chen WJ, Chang C-J, et al: Effects of atypical neuro- of psychosis. San Diego Law Rev 39:1033–164, 2002 leptics on sustained attention deficits in schizophrenia: a trial of 139. Winick B: The Right to Refuse Mental Health Treatment.
risperidone versus haloperidol. Neuropsychopharmacology 22: Washington, DC: American Psychological Association, 1997 140. Erickson SK, Vitacco MJ, Van Rybroek G: Beyond overt vio- 154. Keefe RS, Young CA, Rock SL, et al: One-year double-blind lence: Wisconsin’s progressive civil commitment statute as a study of the neurocognitive efficacy of olanzapine, risperidone, marker of a new era in mental health law. Marq Law Rev 89: and haloperidol in schizophrenia. Schizophr Res 81:1–15, 2006 155. Thornton AE, Van Snellenberg JX, Sepehry AA, et al: The im- 141. Weickert TW, Goldberg TE: First- and second-generation anti- pact of atypical antipsychotic medications on long-term memory psychotic medication and cognitive processing in schizophrenia.
dysfunction in schizophrenia spectrum disorder: a quantitative review. J Psychopharmacol 20:335– 46, 2006 142. Mishara AL, Goldberg TE: A meta-analysis and critical review of 156. Bilder RM, Goldman RS, Volavka J, et al: Neurocognitive effects the effects of conventional neuroleptic treatment on cognition in of clozapine, olanzapine, risperidone, and haloperidol in patients schizophrenia: opening a closed book. Biol Psychiatry 55:1013– with chronic schizophrenia or schizoaffective disorder. Am J Psy- 143. Lieberman JA, Stroup TS, McEvoy JP, et al: The clinical anti- 157. Stip E, Chouinard S, Boulay LJ: On the trail of a cognitive psychotic trials of intervention effectiveness I: effectiveness of enhancer for the treatment of schizophrenia. Prog Neuropsycho- antipsychotic drugs in patients with chronic schizophrenia.
pharmacol Biol Psychiatry 29:219 –32, 2005 158. Jann MW: Implications for atypical antipsychotics in the treat- 144. Green MF, Marder SR, Glynn SM, et al: The neurocognitive ment of schizophrenia: neurocognition effects and a neuropro- effects of low-dose haloperidol: a two-year comparison with ris- tective hypothesis. Pharmacotherapy 24:1759 – 83, 2004 peridone. Biol Psychiatry 51:972– 8, 2002 159. Weiss EM, Bilder RM, Fleischhacker WW: The effects of 145. Harvey PD, Meltzer H, Simpson GM, et al: Improvement in second-generation antipsychotics on cognitive functioning and cognitive function following a switch to ziprasidone from con- psychosocial outcome in schizophrenia. Psychopharmacology ventional antipsychotics, olanzapine, or risperidone in outpa- tients with schizophrenia. Schizophr Res 66:101–13, 2004 160. Krystal JH, D’Souza DC, Mathalon D, et al: NMDA receptor 146. Keefe RS, Bollini AM, Silva SG: Do novel antipsychotics im- antagonist effects, cortical glutamatergic function, and schizo- prove cognition?—a report of a meta-analysis. Psychiatric Ann phrenia: toward a paradigm shift in medication development.
147. Meltzer HY, McGurk SR: The effects of clozapine, risperidone, 161. Tuominen HJ, Tiihonen J, Wahlbeck K: Glutamatergic drugs and olanzapine on cognitive function in schizophrenia. Schizo- for schizophrenia: a systematic review and meta-analysis. Schizo- 148. Harvey PD, Rabinowitz J, Eerdekens M, et al: Treatment of 162. Erickson SK, Schwarzkopf SB, Palumbo D, et al: Efficacy and cognitive impairment in early psychosis: a comparison of risperi- tolerability of low-dose donepezil in schizophrenia. Clin Neuro- done and haloperidol in a large long-term trial. Am J Psychiatry 163. Dakhale G, Khanzode S, Khanzode S, et al: Oxidative damage 149. Hori H, Noguchi H, Hashimoto R, et al: Antipsychotic medi- and schizophrenia: the potential benefit by atypical antipsychot- cation and cognitive function in schizophrenia. Schizophr Res 164. Zhang XY, Tan YL, Cao LY, et al: Antioxidant enzymes and lipid 150. Bender S, Dittmann-Balcar A, Schall U, et al: Influence of atyp- peroxidation in different forms of schizophrenia treated with ical neuroleptics on executive functioning in patients with typical and atypical antipsychotics. Schizophr Res 81:291–300, schizophrenia: a randomized, double-blind comparison of olan- The Journal of the American Academy of Psychiatry and the Law


Microsoft word - restricted category.doc

Catalog of Restricted Foreign Investment Industries I. Agriculture, Forestry, Animal Husbandry and Fishery Industry 1. Seed selection of new varieties of crops, and development and production of seeds (the Chinese party shall have a controlling interest) 2. Processing and export of the logs of precious varieties of trees (limited to equity joint ventures and cooperative joint ventures) 3. Proc

Launch of - stirling pharma

STIRLING PRODUCTS TO LAUNCH GENERIC PHARMACY RANGE FOR IMMEDIATE RELEASE 23 December 2009 • “Stirling Pharma” to launch in Australia in March 2010 • National Australian Sales Representation in Place • Establishment of Relationship with Major International Pharma Australian healthcare company Stirling Products Limited (ASX:STI) advises that the Company has agreed to and establ

Copyright © 2010-2014 Medicament Inoculation Pdf