Trust me I'm a Ducktor

Updated on 12-5-2012

This is a comment that I left on the Mad in America website:

Being unethical doesn’t mean it does not happen. It does. In my opinion, off label prescriptions of psychotropic drugs, particularly prescriptions which are not based on clinical trial evidence, or even minimally supported by data about the drugs’ safety and effectiveness, (which is more common than not, in psychiatry) is Human Experimentation. Calling it “Off Label” instead of calling it what it is, is deceptive; and I believe it is done to deceive. This off label prescribing is theoretically supposed to be based on actual evidence of safety and efficacy, even if it is not from drug trials; the drugs have been in use for a very long time and STILL there is not the evidence available that what is being done in Standard Clinical practice is supported by EVIDENCE. So how the hell did this become a STANDARD PRACTICE? By a using a quasi-democratic process of collaboration and consensus of a few followed by the vote of a few more. A group of people in effect have determined that voting on their own educated opinions and reaching a consensus is how to develop an "Evidence Base" for psychopharmacology. Consensus is evidence of agreetment, it is not a substitute for the empirical data required to ethically justify implementing any medical care standard. It is a dishonest and not at all ethical to use a collection of subjective opinions and observations AS IF they become scientific evidence by virtue of the number or "importance" of the individuals offering them. Subjective observation is used to SUPPORT objective information NOT replace it... What are the Standards of Care in psychiatry, ie. practice parameters, treatment algorithms, etc. if they are not science-based ethical medical standards? What the Standards of Care in psychiatry are is an affirmative defense for allegations of medical malpractice. In effect, and in fact, Human Experimentation without the knowledge or the consent of the human participants is standard practice it's "psycho" pharmacology!

beginning of original blog post

Recently the disappointing outcome of a study using 4 neuroleptic drugs, called "atypical antipsychotics," was reported by UC San Diego and published in the online Journal of Clinical Psychiatry. When I first read about this study at 1 Boring Old Man's blog, something seemed seriously wrong; but I couldn't put my finger on it right away. After doing a little digging, I realized what was bothering me. It appears the study was a seeding trial, conducted in an (unsucessful) attempt to "legitimize" gain FDA approval for what is being done in standard practice, the off-label prescription use of the drugs known to be ineffective for treating PTSD, Alzheimer's Disease, and Dementia. All four drugs have an FDA Block Box Warning for increased mortality when used to treat dementia; i.e. dementia is not an FDA approved indication for the drugs used in this trial. Another condition mentioned by the UC San Diego press release is PTSD; PTSD is not an FDA approved indication for the drugs either. In fact, PTSD is not even mentioned among the three conditions listed for intervention with this drug study at ClinicalTrials.gov.

via UC San Diego Health System:

Four Common Antipsychotic Drugs Found to Lack Safety and Effectiveness in Older Adults

some excerpts:

"In older adults, antipsychotic drugs are commonly prescribed off-label for a number of disorders outside of their Food and Drug Administration (FDA)-approved indications – schizophrenia and bipolar disorder. The largest number of antipsychotic prescriptions in older adults is for behavioral disturbances associated with dementia, some of which carry FDA warnings on prescription information for these drugs." (emhasis mine)

The study looked at four atypical antipsychotics (AAPs) – aripiprazole (Abilify), olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal) – in 332 patients over the age of 40 diagnosed with psychosis associated with schizophrenia, mood disorders, PTSD, or dementia. (emphasis mine)

“Our study suggests that off-label use of these drugs in older people should be short-term, and undertaken with caution,” said Dilip V. Jeste, MD, Estelle and Edgar Levi Chair in Aging, Distinguished Professor of Psychiatry and Neurosciences, and director of the Stein Institute for Research on Aging at UC San Diego.

"Results of the five-year study led by Jeste, who is also current president of the American Psychiatric Association (which was not involved in this research), showed that within one year of treatment, one-third of the patients enrolled in the study developed metabolic syndrome (medical disorders that can increase the risk of cardiovascular disease or diabetes). Within two years, nearly a quarter of the patients developed serious adverse effects and just over half developed non-serious adverse effects." here

The FDA approved indications for the 4 drugs used in this study are here

All of the drugs used in this drug trial have black box warnings from the FDA for causing increased mortality for elderly with dementia. The UC San Diego article states, some of the drugs, "carry FDA warnings." The actual number of participants enrolled in the trial was 406, according to the ClinicalTrials.gov website; why would the the UC San Diego announcement state there were only 332? PTSD and mood disorders are not listed with the conditions participants were to be treated for on the Clinical Trials website; schizophrenia, Alzheimer's Disease, and dementia are the conditions listed. The only one that is an FDA approved condition is schizophrenia. The end points were safety and efficacy, which is standard for an "investigational" drug trial, Clinical Trials.gov states this was an investigational Phase 1 trial for the first few years of the trial.

On October 18, 2012 "Active Control" was deleted from the list of design characteristics for this study. The responsible party, Dilip V. Jeste, and UCSD was changed to "sponsor" on the same date. On April 11, 2009 the Seroquel arm was discontinued, and the answer for the "accepts healthy volunteers" question was changed from "NO" to "Yes." A Data Monitoring Committee was also added at the same time. On February 29, 2008 the classification for this trial was changed from a Phase 1 drug trial to a Phase 4 drug trial; The lead sponsor was changed from being listed as the NIMH to being listed as UCSD; and Dilip V. Jeste, at UCSD, was listed as now being the responsible party, usually the responsible party the lead investigator, would also be the lead author, but in this case Dilip V. Jeste, the President of the American Psychiatric Association, is said to be the lead investigator but is not the lead author. This study started with The Veterans Medical Research Foundation as the lead sponsor, then the lead sponsor was the NIMH, and upon the study's conclusion, the VMRF is once again listed as the lead sponsor and the NIMH is listed as a collaborator.

"The bottom line is no solid evidence-based treatment exists for psychosis or agitation in dementia. Atypical antipsychotics carry a black-box warning for increased risk of death and cerebrovascular events in dementia, although typical antipsychotics appear no safer." Thomas W. Meeks, M.D. and Dilip V. Jeste, M.D. in Beyond the Black Box: What is The Role for Antipsychotics in Dementia? 2008

via Physicians Postgraduate Press:
Use of Clinical Markers to Identify Metabolic Syndrome in Antipsychotic-Treated Patients

Hua Jin, MD; Jonathan Meyer, MD; Sunder Mudaliar, MD; Robert Henry, MD; Srikrishna Khandrika, PhD; Danielle K. Glorioso, MSW; Helena Kraemer, PhD; and Dilip Jeste, MD

J Clin Psychiatry 2010;71(10):1273–1278

10.4088/JCP.09m05414yel

Objective: Metabolic syndrome (MetS) is prevalent among antipsychotic-treated patients; however, in psychiatric clinics, scarce resources often limit the feasibility of monitoring all 5 criteria that are necessary for diagnosing MetS. As one goal of the MetS definition is to facilitate the clinical identification of insulin-resistant individuals, other biomarkers of insulin resistance have been explored. However, there are relatively few data from antipsychotic-treated patients, especially on the association between these markers and the clinical MetS diagnosis.

Method: We analyzed data from 196 psychiatric patients over age 40 years enrolled in an ongoing study of antipsychotic-related metabolic effects that began in August 2005. here

Black Box Warning from The U.S. Department of Health and Human Services FDA

Public Health Advisory: Deaths with Antipsychotics in Elderly Patients with Behavioral Disturbances

4/11/2005

The Food and Drug Administration has determined that the treatment of behavioral disorders in elderly patients with dementia with atypical (second generation) antipsychotic medications is associated with increased mortality. Of a total of seventeen placebo controlled trials performed with olanzapine (Zyprexa), aripiprazole (Abilify), risperidone (Risperdal), or quetiapine (Seroquel) in elderly demented patients with behavioral disorders, fifteen showed numerical increases in mortality in the drug-treated group compared to the placebo-treated patients. These studies enrolled a total of 5106 patients, and several analyses have demonstrated an approximately 1.6-1.7 fold increase in mortality in these studies. Examination of the specific causes of these deaths revealed that most were either due to heart related events (e.g., heart failure, sudden death) or infections (mostly pneumonia). read the rest here

via Physician's Post Graduate Press:

Comparison of Longer-Term Safety and Effectiveness of 4 Atypical Antipsychotics in Patients Over Age 40: A Trial Using Equipoise-Stratified Randomization

Hua Jin, MD; Pei-an Betty Shih, PhD; Shahrokh Golshan, PhD; Sunder Mudaliar, MD; Robert Henry, MD; Danielle K. Glorioso, MSW; Stephan Arndt, PhD; Helena C. Kraemer, PhD; and Dilip V. Jeste, MD

J Clin Psychiatry

10.4088/JCP.12m08001

Objective: To compare longer-term safety and effectiveness of the 4 most commonly used atypical antipsychotics (aripiprazole, olanzapine, quetiapine, and risperidone) in 332 patients, aged > 40 years, having psychosis associated with schizophrenia, mood disorders, posttraumatic stress disorder, or dementia, diagnosed using DSM-IV-TR criteria.

Method: We used equipoise-stratified randomization (a hybrid of complete randomization and clinician’s choice methods) that allowed patients or their treating psychiatrists to exclude 1 or 2 of the study atypical antipsychotics due to past experience or anticipated risk. Patients were followed for up to 2 years, with assessments at baseline, 6 weeks, 12 weeks, and every 12 weeks thereafter. Medications were administered employing open-label design and flexible dosages, but with blind raters. The study was conducted from October 2005 to October 2010.

Outcome Measures: Primary metabolic markers (body mass index, blood pressure, fasting blood glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), percentage of patients who stay on the randomly assigned atypical antipsychotic for at least 6 months, psychopathology, percentage of patients who develop metabolic syndrome, and percentage of patients who develop serious and nonserious adverse events.

Results: Because of a high incidence of serious adverse events, quetiapine was discontinued midway through the trial. There were significant differences among patients willing to be randomized to different atypical antipsychotics (P < .01), suggesting that treating clinicians tended to exclude olanzapine and prefer aripiprazole as one of the possible choices in patients with metabolic problems. Yet, the atypical antipsychotic groups did not differ in longitudinal changes in metabolic parameters or on most other outcome measures. Overall results suggested a high discontinuation rate (median duration 26 weeks prior to discontinuation), lack of significant improvement in psychopathology, and high cumulative incidence of metabolic syndrome (36.5% in 1 year) and of serious (23.7%) and nonserious (50.8%) adverse events for all atypical antipsychotics in the study.

Conclusions: Employing a study design that closely mimicked clinical practice, we found a lack of effectiveness and a high incidence of side effects with 4 commonly prescribed atypical antipsychotics across diagnostic groups in patients over age 40, with relatively few differences among the drugs. Caution in the use of these drugs is warranted in middle-aged and older patients. here

via ClinicalTrials.gov:

Side Effects of Newer Antipsychotics in Older Adults

Purpose

This study will compare four atypical antipsychotic medications in terms of the risk of specific side effects each of them presents in middle-aged and elderly individuals.

Condition Intervention Phase
Schizophrenia Drug: Aripiprazole Phase 4
Alzheimer's Disease Drug: Olanzapine
Dementia Drug: Risperidone

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Metabolic Effects of Newer Antipsychotics in Older Patients

Detailed Description:

Atypical antipsychotic medications introduced within the last decade have been used increasingly for the treatment of several types of psychotic disorders and severe behavioral disturbances in older individuals. This trend is primarily due to a decrease in side effects caused by the new medications, as compared to conventional neuroleptic medications. There is a lower risk for developing tardive dyskinesia and extrapyramidal symptoms, both of which are movement abnormalities, with new antipsychotic medications. However, there has been a growing concern that the newer medications can cause a different set of potentially serious adverse side effects. Specifically, they may cause long-term metabolic, cardiovascular, and cerebrovascular effects, which may result in weight gain, diabetes, or stroke. This study will compare four atypical antipsychotic medications in terms of the risk of metabolic, cardiovascular, and cerebrovascular side effects that each presents in middle-aged and elderly individuals.

Participants in this open-label study will be randomly assigned to receive one of three atypical antipsychotic medications: aripiprazole; olanzapine; or risperidone. Although assignment is random, a technique that may reflect the participant's own interests or the researcher's knowledge of relevant participant characteristics will be used to assign the participant to a medication. Dosing will be determined by each participant's psychiatrist. Participants will be followed for up to 5 years to assess the side effects of the study medications, with study visits at baseline, Week 6, and every 3 months thereafter.

Ages Eligible for Study: 40 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: Yes

Criteria
Inclusion Criteria:
DSM-IV diagnosis of a disease or disorder that requires treatment with an atypical antipsychotic medication

Exclusion Criteria:
N/A here

photo credit Just Ducks