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Posted on Tuesday 4 January 2011

Some years back, I jokingly referred to clinical drug trials as "the grid." What I was referring to was the fact that they were putting all the possible psychiatric diagnoses on the top row of a table and all the psychiatric drugs in the left column – then filling in the blanks with clinical trials. I meant it to be funny, that the drug companies were testing everything in everything – hardly consistent with the buzz words, "evidence based" medicine. I had no idea that my bad joke was actually true. Then I got to looking at Seroquel and the clinical trials on ClinicalTrials.gov. When it was introduced, Seroquel was an Atypical Antipsychotic to be used for Schizophrenia. Since then, the drug has been approved for:

add-on treatment to an antidepressant for patients with Major Depressive Disorder [MDD] who did not have an adequate response to antidepressant therapy
acute Depressive episodes in Bipolar disorder
acute Manic or mixed episodes in Bipolar Disorder alone or with lithium or divalproex
long-term treatment of Bipolar Disorder with lithium or divalproex
Schizophrenia

So the grid has being partially filled in already. On ClinicalTrials.gov, there are 314 trials listed for Seroquel, 100 of them currently "open" [meaning recruiting subjects]. Of that 100, 30 of the open studies are sponsored by the drug’s manufacturer, AstraZeneca. Of those 30, 17 [57%] are related to pushing the XR form of the drug – the one with the longest remaining time with an exclusive patent. Looking at the diagnostic groups studied, 60% are studying some aspect of the use of Seroquel in the already approved areas [Schizophrenia 17%, MDD 10%, BPD 33%] mostly establishing a place for the extended release [XR] dosage. The remaining 37% are looking for creative new uses for the drug shown in the table below:

^STUDY

^{• Seroquel Extended Release (XR) for the Management of Borderline Personality Disorder (BPD)}

^{• Open Label Seroquel Study for TR IBS [irritable bowel syndrome]}

^{• A Study of Quetiapine SR (Seroquel SR) to Treat SSRI-Resistant Comorbid Panic Disorder Patients}

^{• Quetiapine Extended Release (XR) for the Management of Psychotic Aggression or Agitation in Adult Acute Psychiatry}

^{• Open-Label Pilot Study to Examine the Value of Substituting Quetiapine for Benzodiazepines}

^{• Quetiapine in Specific Phobia}

^{• Flushing in Social Anxiety Disorder on Seroquel}

^{• Comparative Efficacy and Tolerability of Quetiapine XR and Amitriptyline in the Treatment of Fibromyalgia}

^{• Quetiapine for the Treatment of Insomnia in Alzheimer’s Disease}

^{• Quetiapine for the Reduction of Cocaine Use}

^{• Quetiapine Augmentation for Primary Anxiety Disorder or Mood Disorders With Co-Morbid Anxiety Symptoms}

That pretty much completes "the grid" I was talking about. It’s approved already for the Major Psychiatric Disorders [Schizophrenia, Manic-Depressive Illnesses]. It’s being given out like candy for PTSD in the VAH. These clinical trials add Personality Disorders, Anxiety States, Psychosomatic symptoms, Dementia, Addiction, Fibromyalgia, Phobias, and are even checking to see if it can be substituted for Valium. There’s very little left.

Obviously, the motive here is to get Seroquel on the docket as good for any and everything psychiatric as a way to boost their already soaring sales, before AstraZeneca loses exclusive patent rights. We’re so used to such things in the modern pharmaceutical world that it doesn’t occur to us that this is an absolutely ridiculous story.

Seroquel is a not-very-potent antipsychotic that was specifically approved for Schizophrenia because it holds out the hope of having less neurologic consequences – eg tardive dyskinesia. As it turns out, the high propensity for weight gain and type 2 diabetes may over-ride that hoped for advantage. Antipsychotics have long been used in Mania or Psychotic Depression, so those indications are understandable. The approval as an antidepressant isn’t something that I can confirm. The studies are flaky and I don’t see that improvement in the office. The patients on it for that indication are using it as a sleeping pill, best I can tell. And none of that stuff in the table above makes any sense to me. It’s being used as if it were Valium or Xanax, a non-specific "calmer-downer." So there’s not much in the way of science driving those studies.

Drug companies are in the business of making money, so there’s no reason to complain about their motives. But there’s good reason to question whether it’s reasonable to put human volunteers in the situation of taking a Major Tranquillizer with potential toxic side effects as part of a fishing trip to try push up sales. Not only is there no scientific rationale to do a lot of these studies, there’s little likelihood of success. And even if some of these studies showed statistical improvement, it would be unlikely that the FDA would approve such a drug for most of the conditions being studied. For example, the incidence of Irritable Bowel Syndrome is between 10% and 20% of the population. It is a benign condition. The notion of treating a benign symptom in a major segment of our population using an antipsychotic drug with a difficult side effect profile seems like going after a mouse in the kitchen with a 12 gauge shotgun and a hand grenade. This "grid" approach to evaluate medications is just one more indicator that our system for approving drugs and regulating clinical trials is both out of control and irrational.

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