Prog Neuropsychopharmacol Biol Psychiatry. 2006 Nov 6;

Aripiprazole augmentation in the management of residual symptoms in clozapine-treated outpatients with chronic schizophrenia: An open-label pilot study.

Mitsonis CI, Dimopoulos NP, Mitropoulos PA, Kararizou EG, Katsa AN, Tsakiris FE, Katsanou MN.

Psychiatric Hospital of Athens, Athens University Medical School, 7, Metamorfoseos str., GR-15234 Halandri-Athens, Greece.

OBJECTIVE: The aim of this study was to investigate whether augmentation of clozapine with aripiprazole improves clinically significant residual symptoms in stabilized outpatients with chronic schizophrenia. METHODS: Twenty seven stabilized outpatients meeting criteria for chronic schizophrenia, who had residual symptoms despite clozapine treatment, were assigned to receive oral aripiprazole (15 mg/day) for a period of 16 weeks. Patients remained on clozapine (100-900 mg/day) for at least 12 months, prior to study initiation. Symptoms assessments were made with the Positive and Negative Symptom Scale (PANSS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Mini-Mental State Examination (MMSE), at baseline and at weeks 4, 8, 12, and 16. The Quality of Life Scale (QLS) was administered at baseline and at week 16. RESULTS: There was a statistically significant improvement in the mean scores for PANSS (p<0.05), PANSS negative (p<0.001), MADRS (p<0.05), MMSE (p<0.01), and QLS (p<0.05), but not for PANSS positive (p>0.05). Extrapyramidal side effects (as assessed by the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale) did not vary significantly at any point of the study. No statistically significant change was observed in prolactin levels and body weight. Results were similar for the intention-to-treat (n=27) and completer (n=23) groups. CONCLUSIONS: Aripiprazole augmentation in a group of chronic schizophrenic outpatients treated with clozapine led to a substantial improvement in clinically significant residual symptoms, such as negative-depressive symptoms, cognitive impairment and quality of life, without worsening the side effect burden.

Am J Psychiatry 163:571-573, April 2006
doi: 10.1176/appi.ajp.163.4.571
© 2006 American Psychiatric Association

EDITORIAL
Conflict of Interest
David A. Lewis, Robert Michels, Daniel S. Pine, Susan K. Schultz, Carol A. Tamminga and Robert Freedman
The accompanying editorial from Dr. Kevin Hill, written as he finished his residency, is an articulate statement of an ever-growing conflict of interest that every physician must address in recommending treatment to a patient. His problem with a drug company pen is replicated and enhanced many fold in publishing The American Journal of Psychiatry.
Surveys of physicians find that over 90% of us look to original articles in medical journals as our most preferred source of new information for help in treating patients. That responsibility requires that journals seek 1) authors whose studies yield the most useful new information, 2) reviewers who can probe the veracity of these new findings, 3) editors who can select the best articles for readers, and 4) editorial commentators who can highlight the implications for clinical practice. The object of our conflict of interest policy is to assure our readers that each author, editor, reviewer, and commentator acts only to provide the best information for clinical practice. The task is a daunting one and, for The American Journal of Psychiatry, one that involves over 2,500 submitted articles per year (of which about 250 will be selected for publication), 20 deputy and associate editors, and over 5,000 reviewers. The editors of the Journal are entrusted with the responsibility of formulating and enforcing this policy.
The management of conflict of interest begins with disclosure. Authors are required to inform the Journal about who supported their work and whether they have other financial interests that could potentially affect their article. The Journal publishes work supported by a variety of sources, usually government grants, nonprofit foundations, and pharmaceutical companies. Attention is currently focused on pharmaceutical companies because of well-publicized problems in the complete reporting of data, including the risk of suicide with antidepressant drugs. However, there are also examples of misreporting that do not involve pharmaceutical companies. In cooperation with other international medical journals, we are continually increasing our reporting of the financial interests of our authors. We have adopted the policy of requiring public reporting of the scope of clinical trials at the initiation of study, using vehicles such as www.clinicaltrials.gov, to prevent incomplete and therefore misleading reporting of a study’s results. We require that all authors have complete access to data and that all authors, including industry employees, be identified.
A second safeguard against inaccurate reporting due to conflict of interest is the review process. Editors and reviewers are experts responsible for determining whether articles are accurate reports of the studies. Their role inevitably brings up the issue of their own conflicts of interest. As Editor and Deputy Editors we have this primary responsibility, and report all our financial conflicts in the first issue of each year. We do not work with manuscripts with which we have a conflict. Similarly, reviewers and Associate Editors are asked to disclose any conflict with a manuscript they have been asked to review. The Editor is responsible for determining when such conflicts preclude participation in the editorial and review process. Manuscripts submitted by the Editor and Deputy Editors of The American Journal of Psychiatry represent a special conflict of interest. These manuscripts are handled independently by a special Associate Editor of this journal: Howard Goldman, who is Editor of Psychiatric Services.
Many journals believe that commentaries—review articles, clinical practice articles, and editorials—require special disclosure. For these articles, we ask authors to advise readers about treatment and other clinical issues. We have not set a policy that prohibits authors of commentaries from having such conflicts. Work with the pharmaceutical industry is a useful part of the activity of many clinical investigators. It enables them to interact with scientists in industry, who themselves have considerable expertise in treatment and treatment evaluation, and it enlists our best minds in the development of new therapeutics for our patients. As commentators, these individuals then bring broad experience to their role of advisers to readers. However, our readers need to know of authors’ conflicts, and we need to assure readers that articles are not influenced by conflicting interests. Therefore, we will include with commentary articles a disclosure of the authors’ relevant interests with a notation that an editor has reviewed the article to discern and exclude bias in its conclusions or its clinical recommendations.
There are two interactions in which one needs to be as free from conflicts of interest as possible: in the treatment of a patient, which is why Dr. Hill’s editorial is relevant, and in representing our field to the public. The Journal speaks directly to the public as well as to physicians about the practice of psychiatry. Therefore, the Editorial Board of the Journal and the APA Editor Search Committee required that the new Editor-in-Chief of The American Journal of Psychiatry, as its lead spokesperson, have no commercial conflicts of interest. Dr. Freedman has agreed to this requirement.
The Journal is supported primarily by our readers’ subscriptions. Our readers can be proud of having an independent journal that they support themselves as a primary source of information about their field. However, the Journal also accepts advertising as a secondary source of income. Obviously, most of the advertising is from pharmaceutical companies, which introduces another potential conflict of interest. Some of the pages of our journal are not dissimilar to Dr. Hill’s pen. How do we address this conflict of interest? First, should we accept industry advertising at all? There is no facile solution. The pharmaceutical industry is the ultimate source of most neurobiologically based psychiatric treatments, and it is the most financially successful element in the process. Therefore, it would seem self-defeating to try to ignore its presence and to eschew its support. However, the advertisements are quintessential marketing efforts, incongruously juxtaposed to our more somber articles. The cost of these advertisements is borne not by us, but by our patients.
At the present time we have a policy that restricts but does not preclude such advertising. We do not allow advertising to be facing or interleaved with articles, to prevent an advertisement for a product from appearing with an article about its use. We do not allow advertising that purports to contain educational content, such as industry-sponsored CME articles, to be part of the Journal or to be comailed to our readership. We receive repeated requests for both these features, which are highly desired by advertisers. (It should be noted, however, that article reprints—frequently purchased by industry and distributed in combination with promotional material—are a significant source of income for the Journal.)
A conflict of interest should not be mislabeled as a lack of personal integrity. There are many roles in the development and delivery of treatment to our patients. We cannot treat many of our patients without the help of the medicinal products of the pharmaceutical industry, but the industry itself cannot advocate the value of its products without the voice of independent physicians and medical journals. All of these roles involve an interaction of personal and financial interests. Conflict of interest policies do not eliminate these interactions; they simply make each person’s role apparent to everyone else. Standards are constantly changing and public perception of our independence is critical. Many industry leaders have similar beliefs. Our tolerance of overzealous marketing diminishes everyone’s credibility. Our ability to maintain our integrity as physicians and the independence of our publications is therefore critical to assure our patients of the best possible treatment now and in the future.
 

AMA. 2006;296:220-221.
Update on JAMA's Conflict of Interest Policy
Annette Flanagin, RN, MA; Phil B. Fontanarosa, MD, MBA; Catherine D. DeAngelis, MD, MPH


Since the mid-1980s, JAMA and other medical journals have encouraged authors to disclose conflicts of interest that they may have in the subject matter of their manuscripts.1 In 1989, JAMA began requiring authors to sign a statement declaring all potential financial conflicts of interest and began including all such disclosures in published articles.2 Since that time, the journal's conflict of interest policy has continued to evolve with the goal of improving disclosures and transparency for all involved.3-4 For example, the policy applies to all types of manuscripts, including letters and book reviews, and to all individuals involved in the review, editorial evaluation, and publication process, including peer reviewers, editorial board members, and editors. Most recently, JAMA began requiring authors to specifically indicate if they have no conflicts of interest in the subject matter of their manuscript.4 The International Committee of Medical Journal Editors (ICMJE),5 the Council of Science Editors (CSE),6 and the World Association of Medical Editors (WAME)7 have similar policies.
However, biomedical journals have a wide range of conflict of interest policies (eg, some request disclosures, some require disclosures, and some publish disclosures and some do not).8-9 Journals also define relevant conflicts of interest in different terms to include financial and nonfinancial conflicts or only financial interests, and for financial interests, may define relevance in different monetary amounts or lengths of time. Perhaps because of these different policies, some authors may not fully understand JAMA's requirements for reporting potential conflicts of interest and might not fully disclose their conflicts of interest to JAMA at the time they submit their manuscripts. For example, some authors completely disclose all relevant conflicts of interest in the submitted manuscript, whereas other authors disclose relevant interests in a cover letter or only in the authorship form. The result is an inconsistent approach whereby for some authors, the disclosure is completely transparent to all involved in the manuscript evaluation process, including peer reviewers; but for other authors, the disclosure is made public only at the time of publication. In addition, some authors continue to misunderstand what is expected and provide inaccurate or incomplete disclosures that are discovered after publication and result in a published correction or letter of explanation.10-14
To further improve the transparency of reporting of potential conflicts of interest and to encourage more accurate and complete disclosures, an important new policy is that JAMA will begin requiring all authors to disclose all potential conflicts of interest in the Acknowledgment section of the manuscript at the time of submission. This includes specific financial interests and relationships and affiliations relevant to the subject of the manuscript. Between now and the end of 2006, JAMA will permit submissions of manuscripts in which authors' conflict of interest information is not yet included in the manuscript, but with the understanding that this information will be obtained and submitted promptly—and definitely before any revisions are considered. Beginning January 2007, JAMA will require that complete disclosures of conflicts of interest from all authors, including declaration of no conflicts of interest, are included in the Acknowledgment section of the manuscript. JAMA's Web-based manuscript submission system will require the corresponding author to indicate that this information is included in the manuscript at the time of submission. Authors will continue to complete and sign an authorship responsibility form that includes statements on conflict of interest as well as funding and support.
Conflicts of interest in biomedical science continue to be under intense and increasing scrutiny. To help ensure transparency and complete reporting of this information, JAMA's policies on conflicts of interest have been updated (as noted below).15 All authors are encouraged to read these policies carefully and to follow them completely. By doing so, peer reviewers and editors can expect full disclosure of potential conflicts of interest in manuscripts submitted to JAMA, and physicians, other health care professionals, and the public can expect complete reporting of conflict of interest information in articles published in JAMA.
JAMA Conflict of Interest Policy



"A conflict of interest may exist when an author (or the author's institution or employer) has financial or personal relationships or affiliations that could influence (or bias) the author's decisions, work, or manuscript. All authors are required to disclose all potential conflicts of interest, including specific financial interests and relationships and affiliations (other than those affiliations listed in the title page of the manuscript) relevant to the subject of their manuscript. Authors should err on the side of full disclosure and should contact the editorial office if they have questions or concerns.
All such disclosures should be listed in the Acknowledgment section at the end of the manuscript. Authors without conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject of their manuscript, should include a statement of no such interests in the Acknowledgment section of the manuscript. Failure to include this information in the manuscript may delay evaluation and review of the manuscript.
Authors are expected to provide detailed information about all relevant financial interests and relationships or financial conflicts within the past 5 years and for the foreseeable future (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), particularly those present at the time the research was conducted and through publication, as well as other financial interests (such as patent applications in preparation) that represent potential future financial gain. Although many universities and other institutions have established policies and thresholds for reporting financial interests and other conflicts of interest, JAMA requires complete disclosure of all relevant financial relationships and potential financial conflicts of interest, regardless of amount or value. For example, authors of a manuscript about hypertension should report all financial relationships they have with all manufacturers of products used in the management of hypertension, not only those relationships with companies whose specific products are mentioned in the manuscript. If authors are uncertain about what constitutes a relevant financial interest or relationship, they should contact the editorial office.
For all accepted manuscripts, each author's disclosures of conflicts of interest and relevant financial interests and affiliations and declarations of no such interests will be published. Decisions about whether such information provided by authors should be published, and thereby disclosed to readers, are usually straightforward. Although editors are willing to discuss disclosure of specific conflicts of interest with authors, JAMA's policy is one of complete disclosure of all potential conflicts of interest, including specific financial interests and relationships and affiliations (other than those affiliations listed in the title page of the manuscript) relevant to the subject of their manuscript. The policy requesting disclosure of conflicts of interest applies for all manuscript submissions, including letters to the editor and book reviews. If an author's disclosure of potential conflict of interest is determined to be inaccurate or incomplete after publication, a correction will be published to rectify the original published disclosure statement.
Authors also are required to report detailed information regarding all financial and material support for the research and work, including but not limited to grant support, funding sources, and provision of equipment and supplies in the Acknowledgment section of the manuscript.
All authors must also complete and sign a statement on financial disclosures, funding, and support that is part of the Authorship Form."

AUTHOR INFORMATION

Did earlier schizophrenia treatment studies misinform us, or was CATIE’s comparison of FGAs and SGAs “flawed”?^6,7 This article attempts to reconcile the divergent findings about antipsychotics and EPS and reveals a clinical pearl that suggests how to provide optimum antipsychotic therapy to schizophrenia patients.

What did catie find?

CATIE was a three-phase, 18-month, randomized controlled clinical trial designed to evaluate the effectiveness of five SGAs (risperidone, olanzapine, quetiapine, ziprasidone, and clozapine) and two FGAs (perphenazine and fluphenazine) in treating schizophrenia. Findings from phases 1 and 2 have been published or presented (Table 1),^2,8-9 and results from phase 3 are awaited.

Table 1
5 key findings from CATIE phases 1 and 2

Olanzapine was more effective than the four other antipsychotics (risperidone, quetiapine, ziprasidone, and perphenazine) in phase 1.2 Perphenazine—a first-generation antipsychotic—was as effective as risperidone, quetiapine and ziprasidone in phase 1.2 Neurocognitive function was no different whether patients were treated with perphenazine or SGAs, but adjunctive anticholinergic treatment worsened cognitive function.8 In phase 2, clozapine was more effective than other SGAs in patients who discontinued phase 1 because of inadequate efficacy.9 Antipsychotics differed in their adverse effect profiles, but no significant differences were observed between perphenazine and the SGAs in EPS rates or use of anticholinergic agents.2

CATIE phase 1 found no difference in efficacy, safety/tolerability, or effectiveness among perphenazine, risperidone, ziprasidone, and quetiapine. Soon-to-be-published data also will show no significant difference in cognitive effects among patients receiving perphenazine or any of four SGAs (risperidone, olanzapine, quetiapine, or ziprasidone).⁸ Because no FGA was used in CATIE phase 2,^9-11 its results added little to phase 1 observations about how “typical” and “atypical” antipsychotics compare.

‘Atypicals’ and EPS. By definition, a reduced tendency to cause EPS (such as parkinsonism, dystonia, akathisia, and akinesia) distinguishes SGAs from FGAs. In fact, SGAs were called “atypical” because they disproved the belief that EPS are an unavoidable consequence of drugs that produce an antipsychotic effect.^12,13 The CATIE trial’s inability to detect a difference in EPS rates between typical and atypical antipsychotics (Table 2)² is therefore the study’s most surprising finding.

Table 2
CATIE: Similar EPS rates with perphenazine and SGAs*

EPS measurement	Perphenazine-treated patients	SGA-treated patients
Increased mean Simpson-Angus Scale score	6%	4% to 8%
Increased AIMS global severity score	17%	13% to 16%
Increased Barnes Akathisia Rating Scale score	7%	5% to 9%
Anticholinergic added	10%	3% to 9%
* Differences were not statistically significant
EPS: extrapyramidal side effects
SGA: second-generation antipsychotic
AIMS: Abnormal Involuntary Movement Scale
Source: Reference 2

Making sense of catie

Most studies suggest consistent differences between FGAs and SGAs in risk of EPS and tardive dyskinesia.^14-16 One explanation for CATIE’s discrepant findings may be that the use of high-dose, high-potency haloperidol as the typical comparator in pre-CATIE studies magnified differences between FGAs and SGAs.^17,18

Conversely, CATIE researchers minimized this difference by studying a population of schizophrenia patients at an unusually low risk for EPS. The study design:

• assigned 231 patients with a history of tardive dyskinesia to an SGA, without the opportunity to be randomly assigned to an FGA

• excluded patients with first-episode schizophrenia

• enrolled patients who had been treated with antipsychotics for an average of 14 years without a history of significant adverse effects from study treatments.¹⁹

Just as prior studies might have exaggerated the EPS advantage for SGAs, CATIE might have minimized the FGA-SGA difference by studying a low-risk cohort in a way that reduced the trial’s ability to detect such differences.

Interpretation. How can we reconcile the absence of a difference between FGAs and SGAs in EPS liability in CATIE with the preponderance of data suggesting otherwise? It appears that SGAs may be less likely to cause EPS than FGAs, but this difference is not evident in all populations. Furthermore, SGAs and FGAs differ in their ability to provide an adequate antipsychotic effect without EPS.

Among FGAs, low-potency agents are less likely to cause EPS or require concomitant anticholinergics than high-potency agents. Among SGAs, the gradient of EPS liability appears to be risperidone > olanzapine, aripiprazole, ziprasidone > quetiapine > clozapine (Figure). Clinically, these pharmacologic differences interact with physiologic differences in EPS vulnerability—some patients are more liable to develop EPS than others. Individuals who are more susceptible to developing EPS are more likely to benefit from antipsychotics with lower EPS liability.

CATIE found no difference among the various FGAs and SGAs with regard to overall efficacy, effects on cognition, and occurrence of tardive dyskinesia in treating chronic schizophrenia. Perhaps it was CATIE’s failure to find a difference in EPS that explains its inability to demonstrate FGA-SGA differences in cognition and other effectiveness domains.

The clinical pearl Avoiding EPS and anticholinergics appears to be the key to improving cognition, dysphoria, and negative symptoms with FGAs and SGAs. SGAs’ ability to achieve an equivalent antipsychotic effect without EPS also seems related to their lower risk of tardive dyskinesia. SGAs’ main advantage may be their greater ease of achieving an adequate antipsychotic effect without EPS or the need to add an anticholinergic to treat or prevent EPS. This comes from the broader separation between dosages at which SGAs produce their antipsychotic versus EPS effects, compared with FGAs (Figure).13 In clinical practice, then, we must achieve an adequate antipsychotic effect for our patients without EPS—whether we are using FGAs or SGAs—to obtain “atypical” benefits. The purported benefits of an “atypical” antipsychotic are not unique to a particular class of agents but relate to achieving a good antipsychotic effect without EPS—and the SGAs are better able to accomplish this than the FGAs. Careful EPS monitoring is crucial to achieving optimal antipsychotic therapy. Reduced emphasis on EPS in the past decade (in awareness of EPS and training to detect symptoms) and overlap between behavioral aspects of EPS and psychopathology need to be addressed. CATIE confirms clinical observations that: no antipsychotic is always superior schizophrenia therapy must be individualized.23,24 Different agents are associated with different adverse effects, which can make achieving maximum efficacy and safety/tolerability challenging. But differences among antipsychotics and heterogeneity in individual response and vulnerabilities may allow us to optimize treatment. Different agents at different dosages may provide the best outcomes for individual patients, and the optimal agent and/or dosage can vary in the same patient at different stages of the illness. The CATIE trial contributes to evidence that guides our efforts to provide optimal antipsychotic treatment of schizophrenia (Table 3). Its “surprising” findings are most useful when considered in the context of the database to which it adds.25 Table 3 Treating chronic schizophrenia: 4 clinical tips from CATIE   Minimizing extrapyramidal symptoms (EPS) is essential, whether using FGAs or SGAs     Avoiding EPS and not using adjunctive anticholinergics is the key to SGAs’ purported benefits, such better cognition, less dysphoria, lower negative symptom burden, and lower risk of tardive dyskinesia     Antipsychotic dosing is key to accomplishing an adequate antipsychotic effect without EPS     Match the antipsychotic choice and dosage to the individual patient’s vulnerability, then make adjustments based on response   Related resources Tandon R. Comparative effectiveness of antipsychotics in the treatment of schizophrenia: What does CATIE tell us? Parts 1 and 2. Int Drug Ther Newsl 2006;41:51-8;67-74. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study. www.catie.unc.edu/schizophrenia. Disclosures The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. References Nasrallah HA. CATIE’s surprises. Current Psychiatry 2006;5(2):48–65. Lieberman JA, Stroup ST, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209–23. Kane JM, Leucht S, Carpenter D, et al. The expert consensus guideline series: optimizing pharmacologic treatment of psychotic disorders. J Clin Psychiatry 2003;64(suppl 12):1–100. Miller AL, Hall CS, Buchanan RW, et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2003 update. J Clin Psychiatry 2004;65:500–8. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, 2nd ed. Am J Psychiatry 2004;161(suppl 2):1–56. Kane JM. Commentary on the CATIE trial. J Clin Psychiatry 2006;67:831–2. Glick ID. Understanding the results of CATIE in the context of the field. CNS Spectrums 2006;1(suppl 7):40–7. Keefe RSE. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial.Paper presented at: 61st Society of Biological Psychiatry annual meeting; May 18-20, 2006; Toronto, Canada. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior antipsychotic treatment. Am J Psychiatry 2006;163:600–10. Stroup TS, Lieberman JA, McEvoy JP, et al. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry 2006;163:611–22. Buckley PF. Which antipsychotic do I choose next? CATIE phase 2 offers insights on efficacy and tolerability. Current Psychiatry 2006;5(9):27–43. Casey DE. Motor and mental aspects of EPS. Int Clin Psychopharmacol 1995;10:105–14. Jibson MD, Tandon R. New atypical antipsychotic medications. J Psychiatr Res 1998;32:215–28. Pierre JM. Extrapyramidal symptoms with atypical antipsychotics. Drug Safety 2005;28:191–208. Kelly DL, Conley RR, Carpenter WT. First-episode schizophrenia: A focus on pharmacological treatment and safety considerations. Drugs 2005;65:1113–38. Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry 2004;161:414–25. Geddes J, Freemantle N, Harrison P, et al. Atypical antipsychotics in the treatment of schizophrenia: a systematic overview and meta-regression analysis. BMJ 2000;231:1371–6. Hugenholtz GW, Heerdink ER, Stolker JJ, et al. Haloperidol dose when used as active comparator in randomized controlled trials with atypical antipsychotics in schizophrenia: comparison with officially recommended doses. J Clin Psychiatry 2006;67:897–903. Casey D. Implications of the CATIE trial on treatment: extrapyramidal symptoms. CNS Spectrums 2006;11(suppl 7):25–31. Tandon R. Jibson MD: Extrapyramidal side effects of antipsychotic treatment: Scope of problem and impact on outcome. Ann Clin Psychiatry 2002;14:123–9. Thornton AE, Snellenberg JXV, Sepehry AA, Honer WG. The impact of atypical antipsychotic medications on long-term memory dysfunction in schizophrenia spectrum disorder: a quantitative review. J Psychopharmacol 2006;20:335–46. Carpenter WT, Gold JM. Another view of therapy for cognition in schizophrenia. Biol Psychiatry 2002;51:972–8. Davis JM, Chen N. Dose response and dose equivalence of antipsychotics. J Clin Psychopharmacol 2004;24:192–208. Tandon R, Nasrallah HA. Subjecting meta-analyses to closer scrutiny: Little support for differential efficacy among second-generation antipsychotics at equivalent doses. Arch Gen Psychiatry 2006;62:935–7. Tandon R. Comparing antipsychotic efficacy. Am J Psychiatry 2006;163:1645. Current Psychiatry ©2006 Dowden Health Media  ( Si ringrazia per la politica della libera diffusione di questo articolo) (n.d.c.)

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Current Psychiatry ©2006 Dowden Health Media Vol. 5, No. 11 / November 2006

Richard C. Shelton, MD
6 safety rules for tapering antidepressants

Side effects to discontinuing serotonin reuptake inhibitor (SRI) treatment are common and may be severe.1 Patients who are not prepared for these reactions may attribute symptoms to other causes such as a medical illness. Educate your patient about potential side effects to mitigate problems such as relapse or patient distress.

1 Warn your patient.
Alert patients to potential discontinuation reactions when prescribing any antidepressant, particularly SRIs because they seem to cause more discontinuation problems than other classes of drugs. Although reactions appear to be more common and severe with short-acting drugs such as venlafaxine and paroxetine, they can occur with longer half-life agents such as fluoxetine and sertraline.

Warn patients about discontinuation effects when starting treatment and before the planned drug taper. In particular, caution them against missing doses or stopping a drug without informing you.

2 Know the symptoms.
Common discontinuation symptoms can be grouped into six areas:

Neurosensory—vertigo, paresthesias, shock-like reactions, myalgia

Neuromotor—tremor, myoclonus, ataxia, visual changes, piloerection

Gastrointestinal—nausea, vomiting, diarrhea

Psychiatric—anxiety, depressed mood, suicidal ideation, irritability

Vasomotor—flushing, diaphoresis

Other neuropsychiatric—anorexia, insomnia, vivid dreams, asthenia, chills.2

Typical onset is rapid, and symptoms usually resolve in 2 to 3 weeks or if treatment is restarted.

3 Distinguish discontinuation reactions from relapse.
Although depressed mood and anxiety may occur during taper, these symptoms tend to be transient in most patients. Severe or persistent symptoms—including emerging suicidal ideation—may indicate a relapse.

4 Reduce medication slowly.
Tapering is recommended for all antidepressants but should be particularly slow for certain drugs—including venlafaxine, paroxetine, and clomipramine—which can cause significant discontinuation effects. For example, venlafaxine at 225 mg/d could be reduced by 75 mg/d every 1 to 2 weeks, with a final step at 37.5 mg/d for at least 1 week.

If discontinuation reactions are a problem, ultimate discontinuation may require substituting a longer-acting medication such as fluoxetine during the tapering period. For example, add fluoxetine, 10 to 20 mg/d, for 1 week, then stop both antidepressants or discontinue the first medication and continue fluoxetine for 2 to 3 weeks until the risk of reactions passes.

Clinicians often are concerned about serotonin syndrome caused by combining SRIs. Isolated cases have been reported, but the small, finite chance of serotonin syndrome is much lower than the risk of severe discontinuation reactions.

5 Titrate up and taper down.
When switching to another SRI, titrate the second drug upward while tapering off the first. Remember that changing to a drug that does not act on serotonin, such as bupropion, can protect against discontinuation effects.

6 Allow for pregnancy.
Infants born to mothers taking antidepressants can exhibit discontinuation symptoms,2 particularly with shorter-acting drugs such as paroxetine or venlafaxine. Consider tapering the antidepressant early in the patient’s third trimester, then re-institute treatment after delivery. If an antidepressant is required during pregnancy, try using one with a longer half-life such as fluoxetine.
References
Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry 2006;67 (suppl 4):27–30.
Shelton RC. The nature of the discontinuation syndrome associated with antidepressant drugs. J Clin Psychiatry 2006;67(suppl 4):3–7.
Dr. Sheltonis the James G. Blakemore Research Professor and vice-chair for research, department of psychiatry, and professor of pharmacology, Vanderbilt University, Nashville, TN.

Current Psychiatry ©2006 Dowden Health Media ( Si ringrazia per la politica della libera diffusione di questo articolo) (n.d.c.)

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FDA Approves the First Drug to Treat Irritability Associated with Autism, Risperdal

The U.S. Food and Drug Administration (FDA) today approved Risperdal (risperidone) orally disintegrating tablets, an adult antipsychotic drug, for the symptomatic treatment of irritability in autistic children and adolescents. The approval is the first for the use of a drug to treat behaviors associated with autism in children. These behaviors are included under the general heading of irritability, and include aggression, deliberate self-injury, and temper tantrums.

"This approval should benefit many autistic children as well as their parents and other care givers," said Steven Galson, M.D., director of FDA’s Center for Drug Evaluation and Research. "Our agency strongly encourages the development of appropriate pediatric labeling for adult drugs, and Risperdal is a welcome addition to the growing number of such products that have been shown to have an appropriate risk-benefit profile when tested in children."

Risperdal has been approved since 1993 for the short-term treatment of adults with schizophrenia, and since 2003 for the short-term treatment of adults with acute manic or mixed episodes associated with extreme mood swings.

The product’s effectiveness in the symptomatic treatment of irritability associated with pediatric autistic disorders was established in two 8-week, placebo-controlled trials in 156 patients aged 5 to 16 years, 90 percent of whom were 5-12 years old. The results, which were evaluated using two assessment scales, showed that children on Risperdal achieved significantly improved scores for certain behavioral symptoms of autism compared to children on placebo. The most common side effects of the use of Risperdal included drowsiness, constipation, fatigue and weight gain.

Risperdal is marketed by Janssen, L.P. in Titusville, NJ.

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FDA news

Effexor XR (venlafaxine HCl) Extended-Release Capsules
Effexor (venlafaxine HCl) Tablets
Audience: Neuropsychiatric and other healthcare professionals
[Posted 10/25/2006] Wyeth and FDA notified healthcare professionals of revisions to the OVERDOSAGE/Human Experience section of the prescribing information for Effexor (venlafaxine HCl), indicated for treatment of major depressive disorder. In postmarketing experience, there have been reports of overdose with venlafaxine, occurring predominantly in combination with alcohol and/or other drugs. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcome compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Healthcare professionals are advised to prescribe Effexor and Effexor XR in the smallest quantity of capsules consistent with good patient management to reduce the risk of overdose.

[October 17, 2006 - Letter - Wyeth]
[August, 2006 - Effexor Label - Wyeth]
[August, 2006 - Effexor XR Label - Wyeth]

Lamictal (lamotrigine)
Audience: Neurologists, obstetricians, other healthcare professionals, and patients
[Posted 09/29/2006] The FDA notified healthcare professionals and patients of new preliminary information from the North American Antiepileptic Drug Pregnancy Registry that suggests that babies exposed to Lamictal, indicated to treat seizures and bipolar disorder, during the first three months of pregnancy may have a higher chance of being born with a cleft lip or cleft palate. More research is needed to be sure about the possibility of the increased chance of cleft lip or cleft palate developing in babies of pregnant women who take Lamictal. Women who take Lamictal and are pregnant or are thinking of becoming pregnant should talk with their doctor. Patients should not start or stop using Lamictal without talking to their doctor.

[September 28, 2006 - Patient Information Sheet - FDA]
[September 28, 2006 - Healthcare Professional Sheet - FDA]
 

FDA Alerts and Related Information SSRI
Persistent Pulmonary Hypertension (7/2006)
The results of a study that looked at the use of antidepressant medicines during pregnancy in mothers of babies born with a serious condition called persistent pulmonary hypertension of the newborn (PPHN) were recently published in a medical journal.
Babies born with PPHN have abnormal blood flow through the heart and lungs and do not get enough oxygen to their bodies. Babies with PPHN can be very sick and may die.
The study results showed that:
babies born to mothers who took selective serotonin reuptake inhibitors (SSRIs), the family of medicines Paxil ( paroxetina n.d.r.)belongs to,
20 weeks or later in their pregnancies,
had a higher chance (were 6 times as likely) to have persistent pulmonary hypertension (PPHN),
than babies born to mothers who did not take antidepressants during pregnancy.

Healthcare Professional Sheet with FDA Alert [HTML] [PDF]
Public Health Advisory: SSRIs and Persistent Pulmonary Hypertension (7/2006)

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In Inghilterra l’antidepressivo Venlafaxina associato ad un’alta incidenza di mortalità

BBC News ha riportato i dati dell’Office of National Statistics che hanno mostrato, tra il 1993 e il 2002, che 118 persone in Inghilterra e Galles, che stavano assumendo la Venlafaxina ( Effexor/ Efexor ), sono morte.

Nella decade studiata ci sono stati 4.767 morti associati a farmaci antidepressivi.
Otto su 10 erano suicidi.

Gli antidepressivi triciclici erano associati a circa 4.000 morti.

Tra i più nuovi antidepressivi, la Venlafaxina, un SNRI ( inibitore selettivo del recettore della serotonina e della noradrenalina ) è risultato il farmaco con la più alta incidenza di mortalità associata, superiore rispetto agli SSRI ( inibitori selettivi del riassorbimento della serotonina ).

Gli SSRI erano associati a 310 morti.

Secondo Wyeth, che produce la Venlafaxina, le statistiche non tengono conto della gravità dello stato depressivo.

Fonte: BBC News, 2004

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Schizophrenia Bulletin Advance Access originally published online on March 15, 2006
Schizophrenia Bulletin 2006 32(4):715-723;
 

© The Author 2006. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: [email protected].
 

Randomized Controlled Trial of Effect of Prescription of Clozapine Versus Other Second-Generation Antipsychotic Drugs in Resistant Schizophrenia

Shôn W. Lewis^1,2, Thomas R. E. Barnes³, Linda Davies², Robin M. Murray⁴, Graham Dunn², Karen P. Hayhurst², Alison Markwick², Helen Lloyd³ and Peter B. Jones^5
2 University of Manchester
³ Imperial College, London
⁴ Institute of Psychiatry, London
⁵ University of Cambridge

¹To whom correspondence should be addressed; e-mail: [email protected]

There is good evidence that clozapine is more efficacious than first-generation antipsychotic drugs in resistant schizophrenia. It is less clear if clozapine is more effective than the other second-generation antipsychotic (SGA) drugs. A noncommercially funded, pragmatic, open, multisite, randomized controlled trial was conducted in the United Kingdom National Health Service (NHS). Participants were 136 people aged 18–65 with DSM-IV schizophrenia and related disorders whose medication was being changed because of poor clinical response to 2 or more previous antipsychotic drugs. Participants were randomly allocated to clozapine or to one of the class of other SGA drugs (risperidone, olanzapine, quetiapine, amisulpride) as selected by the managing clinician. Outcomes were assessed blind to treatment allocation. One-year assessments were carried out in 87% of the sample. The intent to treat comparison showed no statistically significant advantage for commencing clozapine in Quality of Life score (3.63 points; CI: 0.46–7.71; p = .08) but did show an advantage in Positive and Negative Syndrome Scale (PANSS) total score that was statistically significant (–4.93 points; CI: –8.82 to –1.05; p = .013) during follow-up. Clozapine showed a trend toward having fewer total extrapyramidal side effects. At 12 weeks participants who were receiving clozapine reported that their mental health was significantly better compared with those receiving other SGA drugs. In conclusion, in people with schizophrenia with poor treatment response to 2 or more antipsychotic drugs, there is an advantage to commencing clozapine rather than other SGA drugs in terms of symptom improvement over 1 year.

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^{American Journal of Psychiatry 163:600-610, April 2006
doi: 10.1176/appi.ajp.163.4.600
© 2006 American Psychiatric Association
Effectiveness of Clozapine Versus Olanzapine, Quetiapine, and Risperidone in Patients With Chronic Schizophrenia Who Did Not Respond to Prior Atypical Antipsychotic Treatment
Joseph P. McEvoy, M.D., Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., Sonia M. Davis, Dr.P.H., Herbert Y. Meltzer, M.D., Robert A. Rosenheck, M.D., Marvin S. Swartz, M.D., Diana O. Perkins, M.D., M.P.H., Richard S.E. Keefe, Ph.D., Clarence E. Davis, Ph.D., Joanne Severe, M.S., John K. Hsiao, M.D. for the CATIE Investigators
OBJECTIVE: When a schizophrenia patient has an inadequate response to treatment with an antipsychotic drug, it is unclear what other antipsychotic to switch to and when to use clozapine. In this study, the authors compared switching to clozapine with switching to another atypical antipsychotic in patients who had discontinued treatment with a newer atypical antipsychotic in the context of the Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) investigation. METHOD: Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone in phase 1 or 1B of the trials, primarily because of inadequate efficacy, were randomly assigned to open-label treatment with clozapine (N=49) or blinded treatment with another newer atypical antipsychotic not previously received in the trial (olanzapine [N=19], quetiapine [N=15], or risperidone [N=16]). RESULTS: Time until treatment discontinuation for any reason was significantly longer for clozapine (median=10.5 months) than for quetiapine (median=3.3), or risperidone (median=2.8), but not for olanzapine (median=2.7). Time to discontinuation because of inadequate therapeutic effect was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone. At 3-month assessments, Positive and Negative Syndrome Scale total scores had decreased more in patients treated with clozapine than in patients treated with quetiapine or risperidone but not olanzapine. One patient treated with clozapine developed agranulocytosis, and another developed eosinophilia; both required treatment discontinuation. CONCLUSIONS: For these patients with schizophrenia who prospectively failed to improve with an atypical antipsychotic, clozapine was more effective than switching to another newer atypical antipsychotic. Safety monitoring is necessary to detect and manage clozapine’s serious side effects.}

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Effectiveness of Olanzapine, Quetiapine, Risperidone, and Ziprasidone in Patients With Chronic Schizophrenia Following Discontinuation of a Previous Atypical Antipsychotic

T. Scott Stroup, M.D., M.P.H., Jeffrey A. Lieberman, M.D., Joseph P. McEvoy, M.D., Marvin S. Swartz, M.D., Sonia M. Davis, Dr.P.H., Robert A. Rosenheck, M.D., Diana O. Perkins, M.D., M.P.H., Richard S.E. Keefe, Ph.D., Clarence E. Davis, Ph.D., Joanne Severe, M.S., John K. Hsiao, M.D. for the CATIE Investigators

Background: In the treatment of schizophrenia, changing antipsychotics is common when one treatment is suboptimally effective, but the relative effectiveness of drugs used in this strategy is unknown. This randomized, double-blind study compared olanzapine, quetiapine, risperidone, and ziprasidone in patients who had just discontinued a different atypical antipsychotic. METHOD: Subjects with schizophrenia (N=444) who had discontinued the atypical antipsychotic randomly assigned during phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) investigation were randomly reassigned to double-blind treatment with a different antipsychotic (olanzapine, 7.5–30 mg/day [N=66]; quetiapine, 200–800 mg/day [N=63]; risperidone, 1.5–6.0 mg/day [N=69]; or ziprasidone, 40–160 mg/day [N=135]). The primary aim was to determine if there were differences between these four treatments in effectiveness measured by time until discontinuation for any reason. RESULTS: The time to treatment discontinuation was longer for patients treated with risperidone (median: 7.0 months) and olanzapine (6.3 months) than with quetiapine (4.0 months) and ziprasidone (2.8 months). Among patients who discontinued their previous antipsychotic because of inefficacy (N=184), olanzapine was more effective than quetiapine and ziprasidone, and risperidone was more effective than quetiapine. There were no significant differences between antipsychotics among those who discontinued their previous treatment because of intolerability (N=168). CONCLUSIONS: Among this group of patients with chronic schizophrenia who had just discontinued treatment with an atypical antipsychotic, risperidone and olanzapine were more effective than quetiapine and ziprasidone as reflected by longer time until discontinuation for any reason

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American Journal of Psychiatry 163:563-565, April 2006 doi: 10.1176/appi.ajp.163.4.563 © 2006 American Psychiatric Association Editorial Practical Treatment Information for Schizophrenia Carol A. Tamminga, M.D. Schizophrenia, with itspervasive life impairments and the woeful lack of knowledge regarding its molecular pathophysiology, is a distressing mental illness. Its treatments have been empiric and serendipitously discovered, not rationally understood. Moreover, the treatments are partial, in that psychosis is the treatment-responsive symptom domain, whereas cognition and negative symptoms respond minimally. Successful treatments for schizophrenia, inadequate as they are, have been rather recent. Delay et al. first reported the efficacy of chlorpromazine in 1952 (1), and Carlsson and Lindquist identified the mechanism of that action only in 1963 (2). It is this group of dopamine receptor antagonists—direct and indirect, complex and simple, first and second generation—that we have today as our main treatment tools. While we are quick to point out the inadequacies of these medications, it is certainly true that they are far better than pre-1950 approaches (3). We are at a point where we can ask which, among the multiple antipsychotic treatments, are best for effectiveness, efficacy, and tolerability. The Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) study, sponsored by NIMH, was carried out to answer these questions. The CATIE investigation is a multicenter, multiphase, multidrug study of most of the actively marketed antipsychotics. A total of 1,493 patients entered phase 1 of the CATIE study, the results of which suggested a superiority of olanzapine in length of time to drug discontinuation (4). The hope that other new antipsychotics with fewer metabolic side effects might offer a similar effect was not fulfilled. Some have pointed out that older drugs like perphenazine, with their lower costs, may now once again become rational first-line therapies. The memory of patients with tardive dyskinesia still haunts many clinicians, however. The debate over less expensive first-generation drugs obscures the sobering results of phase 1. That first report thus also showed once again the stark reality of antipsychotic drugs—their therapeutic limitations and their problematic side effects, especially the metabolic effects. In this issue of the Journal, the CATIE story is continued. Stroup et al. report on the CATIE phase 2 "tolerability" study, which compared three second-generation antipsychotics (olanzapine, quetiapine, and risperidone) with ziprasidone (new enough to have missed phase 1) in individuals who had stopped their phase 1 medications for tolerability reasons. In addition, McEvoy et al. report on the CATIE phase 2 "efficacy" comparison of clozapine with second-generation antipsychotics in individuals who had stopped their phase 1 medications for poor efficacy. The CATIE studies are a naturalistic design, purportedly closer to what is done in the "real world" of clinical practice than the industry registration trials. They should more directly inform clinical drug use. The Stroup study began with 43% of the original cohort and sustained a 74% dropout rate between its study start and end (6 months). Although the dropout rates are substantial, they can be understood in light of a challenging methodology, which allowed patients to continue only as long as they and their doctors thought that they could be successfully treated with the drug selected for them. Both olanzapine and risperidone showed superiority in length of time to drug discontinuation, with quetiapine and ziprasidone lagging behind. The relative side effect profiles reflect those seen in the phase 1 study, showing olanzapine with prominent weight gain and metabolic changes (increased cholesterol and triglycerides), risperidone with hyperprolactinemia, and no differences across drugs in ECG (including QT interval) measures. Because many clinicians consider the relative dose levels unbalanced, the effectiveness comparisons are difficult to fully benchmark. But, the side effect outcomes are staggering in their magnitude and extent and demonstrate the significant medication burden for persons with schizophrenia. The McEvoy study began with only 9% of the original cohort (selected from those whose treatment failed efficacy in phase 1); 69% dropped out of the phase 2 between study start and end. The treatment cohort resembles a "treatment nonresponder" group, in that they were predominantly male, older, and had more previous hospitalizations and higher pretreatment psychopathology scores. In contrast to all previous CATIE reports, this "effectiveness" study shows a clear difference in outcome across study groups. Clozapine showed nearly a three-fold increase in time until drug discontinuation compared with the three new antipsychotics olanzapine, risperidone, and quetiapine (10.5 months for clozapine, compared with an average of 2.9 months for the others). Efficacy outcomes are consistent with the time-to-discontinuation measure. The data help answer the critical clinical question, "What to do if a new antipsychotic fails?" The evidence, clearer than many clinicians might have believed, is that clozapine is the only rational alternative. This answer is only tempered by the significantly greater side effect burden with clozapine, again demonstrated: weight gain, increased metabolic measures, sialorrhea, sedation, and the agranulocytosis that we all know to add in (even though adequate surveillance methodology is now in place). But this is a side effect risk profile that is positively balanced by clozapine’s increased efficacy and effectiveness. The suggestion by McEvoy and colleagues that we should "develop models of service delivery that would encourage its [clozapine’s] greater use" is an idea that is certainly timely. This study strongly confirms what we have seen before, that clozapine is our most effective drug for schizophrenic psychosis. Several aspects of these two studies may create controversy and challenge us to think creatively about solutions. The possibility of a dose disparity across the administered study drugs, often cited (even in these two articles themselves) as possibly accounting for outcome differences, highlights the crudeness of our dosing measures. To develop equivalent dose ranges across drugs, one needs an objective measure of drug action (other than merely clinical effect); such a goal is currently feasible using human molecular imaging techniques and should be undertaken. Because we know some sites of the molecular site of action (i.e., the dopamine and serotonin receptors), objective dose-equivalence estimates could be derived with additional research. Remington et al.’s report in the March issue of the Journal, which used PET imaging to establish a dose range for long-acting risperidone, is an example of such research (5). Also, to aid translation to practice, the CATIE study utilized a new operational definition of effectiveness: treatment discontinuation for any reason. Sky-high drug discontinuation rates were seen, suggesting rampant drug dissatisfaction and inefficacy. However, in the context of this multiphase study, such a high switching rate may reflect the real behavior of conscientious clinicians working with inadequate medications in a setting where drug-switching options are invited. Treatment discontinuation for any reason might be more a measure of physician hopefulness for a next medication than an estimate of failure of the current treatment. There has not been a previous set of treatment studies that has so clearly shown the tradeoffs for persons who need antipsychotic medication. There is no clear "winner" among the second generation of antipsychotics, weighing effectiveness and efficacy against side effects, nor a clear "loser." It is only clozapine that is superior, although its side effects are clearly challenging. These data make it abundantly clear that the risks and benefits of any single medication need to be weighed individually with each patient, and that side effect risk needs to be weighed repeatedly during treatment. Side effects need to be continuously monitored and medication adjusted to maintain optimal medical and psychiatric health in the individual person. The CATIE results are packed full of timely, pertinent, interesting, and provocative data pointing up issues about how we should treat, monitor, and advise our patients with schizophrenia in order to help them maximize their health and recovery. The metabolic and other somatic effects of olanzapine and clozapine also have implications for psychiatric practice. As long as psychotropic medications were considered relatively free of side effects, psychiatrists could practice in settings appropriate to other mental health counselors. However, medication treatments with high side effect burden demand clinical settings that are capable of detecting and managing serious side effects. This knowledge means that the clinician’s office needs to be equipped to efficiently monitor antipsychotic drug side effects. Blood pressure cuffs, scales, body tape measures, a process for plasma chemistry monitoring and electrocardiograms, and qualified consultants for medical questions become important components of practice. Dynamic information of drug side effects needs to take a prominent place in a patient’s psychiatric chart. Medical consequences of psychiatric drugs are real, preventable, and require focused monitoring. Clinicians will need to have systems for the effective monitoring of drug side effects to maintain and promote physical health among patients as well as psychiatric health. That these studies were NIMH-funded increases our confidence that they are as free from marketing or other bias or "spin" as possible. However, we do notice that the results of the CATIE studies, although broader and denser than our previous knowledge, are confirmatory of the efficacy and side effect data that we already know—data derived from pharmaceutical studies. This observation should increase our confidence in the results of drug registration studies, limited as they are to the comparative efficacy of one (possibly two) compounds. Of course, these studies point up the great medical need of schizophrenia. Only knowledge of the molecular basis of this psychotic illness will facilitate rational treatment development. Much remains to be learned. We will have to respond actively to the critical need for new schizophrenia treatments and a real understanding of disease mechanisms with creative research, bold leaps of creativity, and astute clinical observation. The time is right for innovative collaborations between clinicians, basic and translational neuroscientists, and industry to identify research strategies and successful molecular understanding, thereby promoting rational treatments. Moreover, the field must create and sustain teams of people to test innovative treatments, represented most recently by the CATIE consortium.    Footnotes   Address reprint requests to Dr. Tamminga, UT Southwestern Medical Center, Department of Psychiatry, 5323 Harry Hines Blvd., #NC5.914, Dallas, TX 75390-9070; [email protected] (e-mail). Dr. Tamminga reports an ad hoc consulting relationship with Jansen Pharmaceuticals. Dr. Freedman has reviewed this editorial and found no evidence of influence from this relationship.    References     Delay J, Deniker P, Harl J-M: Traitement des états d’excitation et d’agitation par une méthode médicamenteuse derivee de l’hibernothérapie. Ann Med Psychol 1952; 110:267–273 Carlsson A, Lindquist M: Effect of chlorpromazine and haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 1963; 20:140–144[Medline] Tamminga CA: Development in somatic treatments. Am J Psychiatry 1994; 151(June suppl):216-219 Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209–1223[Abstract/Free Full Text] Remington G, Mamo D, Labelle A, Reiss J, Shammi C, Mannaert E, Mann S, Kapur S: A PET study evaluating dopamine D2 receptor occupancy for long-acting injectable risperidone. Am J Psychiatry 2006; 163:396–401[Abstract/Free Full Text]

CNS Drugs. 2006;20(4):293-301.

The SOHO (Schizophrenia Outpatient Health Outcome) Study : Implications for the Treatment of Schizophrenia.

Haro JM, Salvador-Carulla L.

Sant Joan de Deu-SSM, Fundacio Sant Joan de Deu, Sant Boi de Llobregat, Barcelona, Spain.

The European SOHO (Schizophrenia Outpatient Health Outcome) study is an observational, naturalistic study of the outpatient treatment of schizophrenia. The patient recruitment and assessment began in September 2000 and finished in early 2005. A total of 10 972 adult patients from ten European countries who were initiating or changing antipsychotic medication for the treatment of schizophrenia within the normal course of care have been enrolled. The patients have been followed at regular intervals over the 3-year timeframe of the study. Evaluation includes clinical severity, measured with the Clinical Global Impression (CGI) scale; health-related quality of life; social functioning; and medication tolerability.The 6- and 12-month results have been published so far and have demonstrated that the patients in whom treatment was initiated with olanzapine or clozapine or who were started on more than one antipsychotic of any class at baseline tended to have somewhat greater improvement than patients treated with other atypical or typical antipsychotics, both in terms of symptoms measured with the CGI and quality of life. Numbers of social contacts increased with the treatment, but other aspects of social functioning did not show any significant change.Atypical antipsychotics as a class were associated with a lower frequency of extrapyramidal symptoms (EPS) and anticholinergic use than typical antipsychotics. The frequency of EPS was lowest in the clozapine-, quetiapine- and olanzapine-treated patients, at around 10%. The atypical antipsychotics also conferred a lower risk for tardive dyskinesia than the typical antipsychotics. Weight gain occurred in all treatment cohorts over the first 12 months of treatment and was statistically significantly greater in the patients who started treatment with olanzapine and clozapine. Prolactin- and sexually-related adverse events were frequent at baseline assessment: amenorrhoea was present in around one- third of women, impotence in around 40% of men, and loss of libido in 50% of both male and female patients. Patients treated with olanzapine, clozapine and quetiapine were significantly less likely to have sexual/endocrine-related dysfunctions after 6 months of treatment (the 12-month results of this parameter are yet to be published) than those in the other treatment cohorts (typical antipsychotics, risperidone and amisulpride). Concomitant medication use during the study has been high, ranging from 5% to 29% for anticholinergics, 8% to 23% for antidepressants, 22% to 37% for anxiolytics and 7% to 19% for mood stabilisers, depending on the type of antipsychotic prescribed. Fewer olanzapine-, quetiapine- and clozapine-treated patients used concomitant anticholinergics or anxiolytics/hypnotics.The current results from the SOHO study indicate that differences in effectiveness and tolerability do exist between the antipsychotics. Future results from the study will be published during the coming months and years, and will allow patterns of antipsychotic use in routine clinical practice (including how often and why changes are made) to be determined. This important information is likely to impact on the future use of antipsychotics and will assist clinicians in refining the use of these drugs and improving the outcome of patients to whom they are prescribed.

PMID: 16599647 [PubMed - in process]

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The New England Journal of Medicine

Volume 353:1209-1223 September 22, 2005 Number 12

Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia
 

Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., Joseph P. McEvoy, M.D., Marvin S. Swartz, M.D., Robert A. Rosenheck, M.D., Diana O. Perkins, M.D., M.P.H., Richard S.E. Keefe, Ph.D., Sonia M. Davis, Dr.P.H., Clarence E. Davis, Ph.D., Barry D. Lebowitz, Ph.D., Joanne Severe, M.S., John K. Hsiao, M.D., for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators

 

ABSTRACT

Background The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study.

Methods A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments.

Results Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects.

Conclusions The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.

Source Information

From the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, New York (J.A.L.); the Department of Psychiatry, School of Medicine (T.S.S., D.O.P.), and the Department of Biostatistics, School of Public Health (S.M.D., C.E.D.), University of North Carolina at Chapel Hill, Chapel Hill; Quintiles, Research Triangle Park, N.C. (S.M.D.); the Department of Biological Psychiatry, John Umstead Hospital, Butner, N.C. (J.P.M.); the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, N.C. (J.P.M., M.S.S., R.S.E.K.); the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (R.A.R.); and the Division of Services and Intervention Research, National Institute of Mental Health, National Institutes of Health, Bethesda, Md. (B.D.L., J.S., J.K.H.).

Address reprint requests to Dr. Lieberman at the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, 1051 Riverside Dr., New York, NY 10032, or at [email protected] .

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Helsinki, della Conferenza Ministeriale Europea dell’ O.M.S. sulla Salute Mentale (12-15 febbraio 2005

"Non c'è salute senza salute mentale:
La salute mentale e il benessere mentale di una persona sono fondamentali per la qualità della sua vita. Incidono sulla produttività degli individui, delle famiglie, delle comunità e delle nazioni. Rendono le persone capaci di sperimentare il vero significato della vita. Permettono loro di esprimere la propria creatività e di essere dei cittadini partecipi e attivi"

Così si sono espressi i ministri della salute dei 52 paesi europei membri dell'Organizzazione mondiale della sanità (OMS) che, in un accordo siglato ad Helsinki  hanno sottoscritto una dichiarazione sulla salute mentale.

Insieme alla dichiarazione, è stato firmato anche un piano d'azione per l'Europa perché, dalle parole, si passi ai fatti. Come indicato dallo stesso direttore europeo dell'OMS, questo accordo è uno storico e importante punto di partenza. Il risultato di anni di esperienza e di lavoro nell'ambito della difesa dei diritti umani e della cura, trattamento e prevenzione della salute mentale.

Alla stesura dell'accordo hanno partecipato anche medici, psicologi, ricercatori. Insieme a persone e familiari di persone che usano i servizi per la salute mentale dei diversi sistemi sanitari europei.

Tra le priorità stabilite dall'OMS ci sono la necessità di promuovere la salute mentale e quella di aiutare la prevenzione, il trattamento, la cura e la riabilitazione dei problemi di malattia mentale. Il programma d'azione prevede di aumentare gli investimenti per la salute mentale e stabilire politiche sanitarie e leggi basate sulle attuali conoscenze e considerazioni sui diritti umani.

Molti aspetti riguardanti le politiche sulla salute mentale e i relativi servizi connessi stanno subendo una trasformazione in Europa. Politiche e servizi stanno acquisendo una valenza sociale ed equa, tenendo sempre più conto del rapporto tra bisogni e benefici.

Secondo quanto stabilito dall'accordo, politiche e pratica nella cura della salute mentale dovrebbero essere focalizzate a promuovere il benessere mentale, contrastare la discriminazione e l'emarginazione sociale, prevenire i problemi di salute mentale, fornire servizi efficaci e adeguati, favorire il reinserimento in società delle persone che hanno sperimentato seri disturbi di salute mentale.

Lo sforzo deve essere comunitario ma tener conto delle differenze locali esistenti nei diversi paesi europei. Deve, in sostanza, esserci una piattaforma comune di riforma che tenga conto e faciliti la condivisione delle esperienze dei singoli paesi.

La dichiarazione dell'OMS mette la salute mentale al centro del potenziale umano, sociale ed economico delle diverse nazioni ed esorta gli stati a considerarla come parte integrante delle proprie politiche sociali. Al pari della difesa dei diritti umani, dell'educazione e dello sviluppo.

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Journal of Psychopharmacology, Vol. 19, No. 4, 408-413 (2005)
DOI: 10.1177/0269881105053308
© 2005 British Association for Psychopharmacology

The place of partial agonism in psychiatry: recent developments

R. I. Ohlsen

Institute of Psychiatry, De Crespigny Park, London, UK., [email protected]

L. S. Pilowsky

Institute of Psychiatry, De Crespigny Park, London, UK.

Drugs used to treat psychiatric disorders, although effective, are often restricted by adverse events. The use of partial agonists for treating hypertension was found to limit some of the side-effects in some patients. This led to the investigation of partial agonists as a treatment modality in psychiatric disorders. Partial agonists have a lower intrinsic efficacy than full agonists leading to reduced maximum response. They can act as antagonists by competing for receptor binding with full agonists. The level of activity depends on the level of endogenous receptor activity. Buprenorphine, a partial agonist at the mu-opioid receptor, is used to treat patients with addiction and decreases the symptoms of withdrawal and risks of overdose and intoxication. The anxiolytic buspirone shows partial agonism at 5-HT_1A receptors, and this seems to provide anxioselective effects, without inducing extrapyramidal side-effects, convulsions, tolerance or withdrawal reactions. In schizophrenia, partial dopamine agonism results in antagonistic effects at sites activated by high concentrations of dopamine and agonistic effects at sites activated by low concentrations of dopamine. This stabilizes the dopamine system to effect antipsychotic action without inducing adverse motor or hormonal events. Aripiprazole is the first ‘dopamine system stabilizer’, and the data are promising, with efficacy at least equivalent to that with current atypical antipsychotics but fewer of the troublesome side-effects. Partial agonists seem to provide a way to fine-tune the treatment of psychiatric disorders by maximizing the treatment effect while minimizing undesirable adverse events.

 

Key Words: addiction • anxiety • aripiprazole • buprenorphine • partial agonist • psychiatric disorders • schizophrenia

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La Direzione Centrale delle Prestazioni dell'INPS con circolare n. 191 del 12 dicembre 2003 ha indicato gli importi e i limiti di reddito relativi alle provvidenze economiche a favore degli invalidi civili, dei ciechi civili e dei sordomuti per l'anno 2004.
Vi invitiamo a prendere visione del documento direttamente nel sito Handilex, dove è riportato il quadro riassuntivo comprendente sia gli importi che i nuovi limiti di reddito comparati con quelli dello scorso anno.

Introdotta la figura dell' amministratore di sostegno (vai al link)

 

Ricorsi amministrativi: prorogati i termini di abrogazione


8 gennaio 2004 (Roma)
L'articolo 42 della Legge 326/2003 ha soppresso la possibilità di presentare ricorsi amministrativi contro i verbali emessi dalle Commissioni ASL di accertamento di invalidità e di handicap. I ricorsi potranno essere solo di fronte al giudice ordinario.
Il Decreto Legge 355 del 24 dicembre 2003 ha tuttavia posticipato l'efficacia di questa disposizione al 31 dicembre 2004.
Pertanto per tutto il 2004 sarà ancora possibile presentare i ricorsi amministrativi relativi ai verbali di accertamento dell'invalidità e di handicap. 8 gennaio 2004

Decredto Legge 24 dicembre 2003, n.355

"Proroga di termini previsti da disposizioni legislative".
(pubblicato in Gazzetta Ufficiale 29 dicembre 2003, n.300)
(omissis)
Art. 23
(omissis)
2. L'efficacia delle disposizioni di cui all'articolo 42, comma 3, del decreto legge 30 settembre 2003, n.269, convertito, con modificazioni, dalla legge 24 novembre 2003, n.326, è differita al 31 dicembre 2004. A tal fine è autorizzata la spesa di 2.000.000 di euro per l'anno 2004.
(omissis)

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Protocollo di monitoraggio progetto CRONOS


28 marzo 2003 (Comunicazione della Commissione Unica del Farmaco)
La Direzione Generale della Valutazione dei Medicinali e della Farmacovigilanza comunica che:


"Con il 31 marzo 2003 viene a cessare esclusivamente la obbligatorietà della compilazione e dell’invio delle schede di valutazione dei pazienti; continuano il funzionamento e le attività espletate dalle Unità di Valutazione Alzheimer (UVA); rimangono inalterate le modalità prescrittive e distributive dei farmaci (donepezil, rivastigmina, galantamina); restano immutati i prezzi vigenti e la fornitura gratuita dei medicinali da parte delle Aziende secondo quanto previsto dal DM 20 luglio 2000 pubblicato sul supplemento ordinario alla Gazzetta Ufficiale del 1 settembre 2000, fino a nuova negoziazione e conseguente decisione della CUF."

 

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Rischio iperglicemia e diabete con i farmaci antipsicotici atipici

L’FDA ( Food and Drug Administration ) ha modificato le schede tecniche dei farmaci antipsicotici atipici: Olanzapina ( Zyprexa ), Quetiapina ( Seroquel ), Clozapina ( Clozaril ), Aripiprazolo ( Abilify ).

Nei pazienti trattati con antipsicotici atipici sono stati segnalati casi di iperglicemia, talora grave ed associata a chetoacidosi o coma iperosmolare e morte.

La valutazione di una diretta correlazione tra impiego di antipsicotici atipici e l’insorgenza di alterazioni del metabolismo del glucosio è complessa per il fatto che i pazienti con schizofrenia sono a rischio di diabete mellito.

Tuttavia studi epidemiologici hanno indicato un aumento del rischio di eventi avversi correlati con l’iperglicemia nei pazienti che assumono farmaci antipsicotici atipici.

Pertanto i pazienti con una diagnosi di diabete mellito, che stanno assumendo antipsicotici atipici dovrebbero essere monitorati regolarmente per un possibile peggioramento del controllo glicemico.

I pazienti con fattori di rischio per il diabete mellito ( es. pazienti obesi, pazienti con storia familiare di diabete ) trattamento con antipsicotici atipici dovrebbero essere sottoposti al controllo della glicemia a digiuno , e tenuti sotto osservazione per il presentarsi dei sintomi tipici dell’iperglicemia ( polidipsia, poliuria, polifagia, senso di debolezza ).

Poiché l’Aripiprazolo è un antipsicotico atipico di recente impiego, esistono al riguardo poche segnalazioni di iperglicemia e nessun caso di diabete mellito.
Tuttavia anche la scheda tecnica dell’Aripiprazolo è stata modificata e sono state inserite le avvertenze riguardo al rischio di iperglicemia e di diabete mellito.


Fonte: FDA  2004
 

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Farmaci antipsicotici nei pazienti anziani

Gli antipsicotici sono ampiamente utilizzati nei disturbi psichiatrici geriatrici.

Ricercatori della Cornell University hanno cercato di fornire raccomandazioni sull’impiego dei farmaci antipsicotici nei pazienti anziani ( 65 anni ed oltre ).

E’ stato elaborato un questionario con 47 item e 1.411 opzioni, ed è stato inviato a 52 Esperti statunitensi, 38 psichiatri geriatri, 14 internisti geriatri / medici di famiglia.

Il 92% ( n = 48 ) ha risposto all’indagine.

Gli Esperti non raccomandano l’impiego degli antipsicotici nel disturbo da panico, nel disturbo d’ansia generalizzato, nella depressione maggiore non-psicotica, nell’ipocondriasi, nel dolore neuropatico, nella grave nausea, nel mal di viaggio, nell’irritabilità, ostilità e nei disturbi del sonno in assenza di una sindrome psichiatrica maggiore.

Nella demenza agitata con delusioni, la raccomandazione degli Esperti è il trattamento in monoterapia con un farmaco antipsicotico: Risperidone ( Risperdal ) ( 0,5 – 2 mg/die ) come prima scelta, seguito da Quetiapina ( Seroquel ) ( 50 – 150 mg/die ) ed Olanzapina ( Zyprexa ) ( 5 – 7,5 mg/die ), come opzioni di seconda scelta.

Nella demenza agitata senza delusioni non è stato indicato alcun antipsicotico come farmaco di prima scelta.

Nella schizofrenia ad insorgenza tardiva il farmaco di prima scelta dovrebbe essere il Risperidone ( 1,25-3,5 mg/die ), mentre la Quetiapina ( 100-300 mg/die ), Olanzapina ( 7,5-15 mg/die ) e l’Aripiprazolo ( Abilify ) ( 15-30 mg/die ) sono di seconda linea.

Per la depressione maggiore non-psicotica, agitata, gli Esperti raccomandano come prima scelta solo un farmaco antidepressivo, e come opzione secondaria un antidepressivo associato ad un antipsicotico, la terapia elettroconvulsiva, un antidepressivo associato ad una benzodiazepina ed un antidepressivo ed uno stabilizzatore dell’umore.

Per la depressione maggiore non-psicotica con grave stato d’ansia, g li Esperti raccomandano nella maggior parte dei casi solo un antidepressivo, eventualmente associato ad una benzodiazepina o ad uno stabilizzatore dell’umore.

Il trattamento di scelta per la depressione maggiore psicotica è rappresentato da un antipsicotico e da un antidepressivo.
Un’altra opzione di prima linea è la terapia elettroconvulsiva.

Per la mania lieve non-psicotica è raccomandato uno stabilizzatore dell’umore.
Qualora il paziente sia in trattamento con un antidepressivo, gli Esperti consigliano di prendere in considerazione l’interruzione del farmaco antidepressivo.

Per la forma grave della mania non-psicotica, gli Esperti raccomandano uno stabilizzatore dell’umore associato ad un antipsicotico, o solamente uno stabilizzatore dell’umore, eventualmente interrompendo l’antidepressivo se il paziente lo sta assumendo.

Per la mania psicotica, il trattamento di scelta è uno stabilizzatore dell’umore associato ad uno antipsicotico.
Il Risperidone ( 1,25-3 mg/die ) e l’Olanzapina ( 5-15 mg/die ) rappresentano i farmaci di primo impiego in combinazione con uno stabilizzatore dell’umore.
La Quetiapina ( 50-250 mg/die ) è un farmaco di seconda scelta.

Per i pazienti con diabete, dislipidemia o obesità, gli Esperti consigliano di evitare Clozapina ( Clozaril/Leponex ), Olanzapina e gli antipsicotici convenzionali.

La Quetiapina rappresenta il farmaco di prima scelta nei pazienti con malattia di Parkinson.

La Clozapina, lo Ziprasidone e gli antipsicotici convenzionali dovrebbero essere evitati nei pazienti con prolungamento del QTc o insufficienza cardiaca congestizia.

Alexopoulos GS et al, J Clin Psichiatry 2004; 65 Suppl 2: 5-99

NELLA PAGINA AIFA TROVI RECENTI INDICAZIONI PER L'USO DEI PSICOFARMACI NEI DISTURBI COMPORTAMENTALI NELLA DEMENZA

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Le indicazioni del NICE sui nuovi farmaci per il trattamento del disturbo bipolare di tipo 1

Il NICE ( National Institute for Clinical Excellence ) ha emesso un parere positivo sull’impiego di due nuovi farmaci nel trattamento della mania acuta associata a disturbi bipolari di tipo 1.

La scelta del trattamento dell’episodio maniacale acuto dovrebbe essere fatta dal medico sentendo il parere del paziente sulla base dei benefici e degli effetti indesiderati di ciascun farmaco.

Il disturbo bipolare è una malattia psichiatrica cronica, caratterizzata dall’alternanza di episodi maniacali e di depressione.
Si distinguono principalmente due tipi di disturbi bipolari: disturbo bipolare di tipo 1 e di tipo 2.

Il disturbo bipolare di tipo 1 è caratterizzato da un decorso clinico con episodi maniacali o misti, dove gli episodi maniacali sono gravi e causano danni funzionali e frequentemente richiedono l’ospedalizzazione del paziente.

Nel disturbo bipolare di tipo 2 prevale l’ipomania.
L’ipomania è distinta dalla mania dall’assenza di sintomi psicotici e minor danno funzionale.
I soggetti con ipomania di norma non richiedono l’ospedalizzazione.

Il rischio di suicidio negli individui con disturbo bipolare varia tra il 15 ed il 19%.
Gli uomini presentano un maggiori rischio di suicidio rispetto alle donne, e questo avviene più frequentemente durante un episodio depressivo.

Comunemente gli individui con disturbo bipolare presentano disturbi psichiatrici concomitanti o fanno abuso di sostanze stupefacenti o di alcool.

Alcuni farmaci impiegati nel trattamento del disturbo bipolare di tipo 1 agiscono sia sugli episodi maniacali che nella prevenzione delle recidive.
I farmaci che sono impiegati per trattare la fase maniacale acuta vengono anche assunti durante la remissione con lo scopo di prevenire o ritardare la comparsa delle recidive.

I sali di Litio sono stati per molto tempo i farmaci di prima scelta nel trattamento e nella profilassi della mania, della malattia maniaco-depre ssiva e delle recidive di depressione.
Tuttavia il Litio non presenta un buon profilo di sicurezza, e richiede frequenti aggiustamenti del dosaggio.

Gli anticonvulsivanti come il Valproato e la Carbamazepina sono impiegati come alternativa al Litio.

Riguardo all’episodio maniacale acuto non c’è consenso su quale sia il trattamento più appropriato.

L’impiego dei farmaci per la profilassi può avvenire sia singolarmente che in combinazione.
Questi farmaci possono essere assunti in modo concomitante con un farmaco che controlla i sintomi acuti della mania.

Una strategia alternativa è quella di iniziare il farmaco profilattico una volta che l’umore del paziente è stato stabilizzato da un farmaco antimaniacale.

Le benzodiazepine sono spesso impiegate negli stadi iniziali della fase acuta della mania.

Gli antipsicotici possono essere suddivisi in due classi: i più vecchi antipsicotici, detti “tipici” ed i più nuovi o “atipici” ( es. Olanzapina ).

Tutti gli antipsicotici sono associati ad effetti indesiderati.
Gli effetti indesiderati comprendono i sintomi extrapiramidali ( come parkinsonismo, distonia, acatisia, discinesia tardiva ) effetti autonomici ( come offuscamento visivo, aumento della pressione intraoculare, secchezza della fauci ed oculare, costipazione e ritenzione urinaria ), aumentati livelli di prolattina, convulsioni, sedazione, alterazioni elettriche del cuore ed aumento di peso.

Un grave effetto indesiderato con l’uso degli antipsicotici è la discinesia tardiva ( movimenti involontari del tronco ed orofacciali ), che può essere irreversibile e può peggiorare sospendendo il trattamento.

Sebbene l’incidenza degli effetti indesiderati sia associata alla dose somministrata, gli antipsicotici atipici in generale presentano una più bassa incidenza di sintomi extrapiramidali rispetto agli antipsicotici tipici.

Secondo il NICE l’Olanzapina ( Zyprexa ) ed il Valproato  dovrebbero essere considerati come opzioni nel trattamento dei sintomi acuti della mania associati al disturbo bipolare di tipo I.

Fonte: NICE 2003

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Olanzapine Shows No Advantage Over Haloperidol for Schizophrenia

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Psychopharmacology: Prescribing for Patients With Hepatic or Renal Dysfunction

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Decoding Schizophrenia (Scientific American, dicembre 2003)

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 Vibo Valentia  Chiesa di San Michele  (Campanile del Peruzzi)