Thursday, October 8, 2009

Is Seroquel XR better than generic quetiapine?

A supplement written by Christoph Correll for The Canadian Journal of Diagnosis (September 2009) was delivered--free--into my office mailbox the other day.

It starts off describing the receptor-binding profiles of different atypical antipsychotic drugs. A table is presented early on.

First of all, the table as presented is almost meaningless: it merely shows the concentrations of the different drugs required to block 50% of the given receptors. These so-called "Ki" concentrations have little meaning, particularly for comparing between one drug and another, UNLESS one has a clear idea of what concentrations the given drugs actually reach when administered at typical doses.

So, of course, quetiapine has much higher Ki concentrations for most receptors, compared to risperidone -- this is related to the fact that quetiapine doses are in the hundreds of milligrams, whereas risperidone doses are less than ten milligrams (these dose differences are not reflective of anything clinically relevant, and only pertain to the size of the tablet needed).

A much more meaningful chart would show one of the following:

1) the receptor blockades for each drug when the drug is administered at typical doses

2) the relative receptor blockade compared to a common receptor (so, for example, the ratio between receptor blockades of H1 or M1 or 5-HT2 compared to D2, for each drug).

The article goes on to explore a variety of other interesting differences between antipsychotics. Many of the statements made were theoretical propositions, not necessarily well-proven empirically. But in general I found this discussion valuable.

Despite apparent efforts for the author to be fair and balanced regarding the different antipsychotics, I note a few things:

1) there are two charts in this article showing symptom improvements in bipolar disorder among patients taking quetiapine extended-release (Seroquel XR).

2) one large figure appears to show that quetiapine has superior efficacy in treating schizophrenia, compared to olanzapine and risperidone (the only "p<.05 asterisk" was for quetiapine!) -- this figure was based on a single 2005 meta-analysis, published in a minor journal, before the CATIE results were published. No other figures were shown based on more recent results, nor was clozapine included in any figure.

I think quetiapine is a good drug. BUT -- I don't see any evidence that quetiapine extended release is actually any better, in any regard, than regular quetiapine. In fact, I have seen several patients for whom regular quetiapine suited them better than extended-release, and for whom a smaller total daily dose was needed.

Here is a reference to one study, done by Astra-Zeneca, comparing Seroquel with Seroquel XR, in healthy subjects: http://www.ncbi.nlm.nih.gov/pubmed/19393840 It shows that subjects given regular quetiapine were much more sedated 1 hour after dosing, compared to those given the same dose of Seroquel XR. It implies that the extended release drug was superior in terms of side-effects. Here is my critique of this study: first of all, sedation is often a goal in giving quetiapine, particularly in the treatment of psychosis or mania. Secondly, problematic sedation is usually the type that persists 12 hours or more after the dose, as opposed to one hour after the dose. In this study, the two different formulations did not differ in a statistically significant way with respect to sedation 7, 8 or 14 hours after dosing. In fact, if you look closely at the tables presented within the article, you can see that the Seroquel XR group actually had slightly higher sedation scores 14 hours after dosing. Thirdly, dosing of any drug can be titrated to optimal effect. Regular quetiapine need not be given at exactly the same dose as quetiapine XR--to give both drugs at the same dose, rather than at the optimally effective dose for each, is likely to bias the results greatly. Fourth, this study lasted only 5 days for each drug ! In order to meaningfully compare effectiveness or side-effects between two different drugs, it is necessary to look at differences after a month, or after a year, of continuous treatment. For most sedating drugs, problematic sedation diminishes after a period of weeks or months. Once again, if immediate sedation is the measure of side-effect adversity, then this study is biased in favour of Seroquel XR. Fifth, the study was done in healthy subjects who did not have active symptoms to treat. This reminds me of giving insulin to non-diabetic subjects, and comparing the side-effects of the different insulin preparations: the choice of population is an obvious strong bias!


Regular quetiapine has gone generic.

Quetiapine extended-release (Seroquel XR) has not.

I am bothered by the possibility of bias in Correll's article.

It is noted, in small print at the very end of this article, that Dr. Correll is "an advisor or consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Organon, Ortho McNeill-Janssen, Otsuka, Pfizer, Solvay, Supernus, and Vanda." AstraZeneca is the company which manufactures Seroquel XR.

In conlusion, I agree that there are obviously differences in receptor binding profiles between these different drugs. There are some side-effect differences.

Differences in actual effectiveness, as shown in comparative studies, are minimal. But probably olanzapine, and especially clozapine, are slightly better than the others, in terms of symptom control.

Quetiapine can be an excellent drug. Seroquel XR can be an excellent formulation of quetiapine, and might suit some people better.

BUT -- there is no evidence that brand-name Seroquel XR is superior to generic regular quetiapine.

One individual might respond better to one drug, compared to another.

The author, despite including 40 references, seems to have left out many important research studies on differences between antipsychotics, such as from CATIE and SOHO.

(see my previous post on antipsychotics: http://garthkroeker.blogspot.com/2008/12/antipsychotic-medications.html )

Monday, October 5, 2009

Hallucinations

Hallucinations are perceptions which take place in the absence of a stimulus from the peripheral or sensory nervous system.

They may be classified in a variety of different ways (this is an incomplete list):
1)by sensory modality
a) auditory: these are most common, and may be perceived as voices speaking or mumbling; musical sounds; or other more cacophonous sounds
b) visual: these can occur more commonly in delirious states or medical illnesses affecting the brain. Many people experience normal, but unsettling, visual hallucinations, just when falling asleep or waking up.
c) tactile: these are most common in chemical intoxication syndromes, such as with cocaine.
d) olfactory: more common in medical illness

2) by positionality
-when describing hallucinated voices, if the voices are perceived to originate inside the head, or to not have any perceived origin, then they could be called "pseudohallucinations." If the voices are perceived to originate from a particular place, such as from the ceiling or from across the room, then they could be called "hallucinations" or "true hallucinations." This terminology has been used to distinguish between the hallucinations in schizophrenia and psychotic mood disorders (which are typically "true hallucinations") and those experienced in non-psychotic disorders (pseudohallucinations are more typically--though not invariably--associated with dissociative disorders, borderline personality, or PTSD).

3) by insight
An individual experiencing a "psychotic hallucination" will attribute the phenomenon to stimuli outside of the brain. An individual experiencing a "non-psychotic hallucination" will attribute the phenomenon to his or her own brain activity, and recognize the absence of an external stimulus to account for the experience. In most cases, "insight" fluctuates on a continuum, and many individuals experiencing hallucinations will have some intellectual understanding of their perceptions being hallucinatory, but still feel on a visceral level that the perceptions are "real."

4) by character
Voices in particular can be described in a variety of ways. So-called "first rank symptoms of schizophrenia" include hallucinated voices which comment on a person's behavior, or include several voices which converse with each other.
The quality of the voice can vary, with harsh, angry, critical tones more common in psychotic depression, and neutral emotionality more common in schizophrenic states.


--all of these above descriptions are incomplete, and associations between one type of hallucination and a specific "diagnosis" are imperfect. A great deal of variation exists--

It is probably true that some hallucinations are factitious (i.e. the person is not actually hallucinating, despite claiming to), but of course this would be virtually impossible to prove. Something like functional brain imaging might be an interesting, though impractical, tool, to examine this phenomenon. People with psychotic disorders or borderline personality might at times describe factitious hallucinatory phenomena in order to communicate emotional distress or need to caregivers. Or sometimes the phenomena may convey some type of figurative meaning. The motivation to do this might not always be conscious.

There are a variety of ways to treat hallucinations.

In my opinion, the single most effective treatment is an antipsychotic medication. Hallucinations due to almost any cause are likely to diminish with antipsychotic medication treatment.

There is evolving evidence that CBT and other psychotherapy can help with hallucinations. Here are some references:
http://www.ncbi.nlm.nih.gov/pubmed/19176275
http://www.ncbi.nlm.nih.gov/pubmed/9827323

Some individuals may not be bothered by their hallucinations. In this case, it may sometimes be more the physician's agenda than the patient's to "treat" the symptom. Yet, it is probably true that active hallucinations in psychotic disorders are harbingers of other worsening symptoms, so it may be important to treat the symptom early, even if it is not troublesome.

Other types of behavioral tactics can help, including listening to music, wearing ear plugs, other distractions, etc. In dealing with pseudohallucinations or non-psychotic hallucinations, "mindfulness" exercises may be quite important. A well-boundaried psychodynamically-oriented therapy structure could be very helpful for non-psychotic hallucinations or pseudohallucinations associated with borderline personality dynamics or PTSD. Care would need to be taken, in these cases, not to focus excessively or "deeply" on the hallucinations, particularly without the patient's clear consent, since such a dialog could intensify the symptoms.

Mediterranean diet is good for your brain

In this month's Archives of General Psychiatry, a study by Sanchez-Villegas et al. is published showing a strong association between lower rates of depression, and consuming a Mediterranean diet (lots of vegetables, fruits, nuts, whole grains, and fish, with low intake of meat, moderate intake of alcohol & dairy, and lots of monounsaturated fatty acids compared to saturated fatty acids). Data was gathered prospectively during a period averaging over 4 years, and was based on following about 10 000 initially healthy students in Spain who reported food intake on questionnaires.

I'll have to look closely at the full text of the article. I'm interested to consider the question of whether the results strongly suggest causation, or whether the results could be due to non-causal association. That is, perhaps people in Spain with a higher tendency to become depressed tend to choose non-Mediterranean diets. Another issue is cultural: the study was done in Spain, where a Mediterranean diet may be associated with certain--perhaps more traditional--cultural or subcultural features, and this cultural factor may then mediate the association with depressive risk.

In any case, in the meantime, given the preponderance of other data showing health benefits from a Mediterranean-style diet, I wholeheartedly (!) recommend consuming more nuts, vegetables, olive oil, fish, whole grains, and fruit; and less red meat.

The need for CME

Here's another article from "the last psychiatrist" on CME:
http://thelastpsychiatrist.com/2009/07/who_should_pay_for_continuing.html#more

Another insightful article, but pretty cynical!

But here are some of my opinions on this one:

1) I think that, without formalized CME documentation requirements, there would be some doctors who would fall farther and farther behind in understanding current trends of practice, current research evidence, etc.
2) In the education of intelligent individuals, I have long felt that process is much more important than content. A particular article with accompanying quiz is bound to convey a certain biased perspective. It is my hope that most professionals are capable of understanding and resisting such biases. In this modern age, I do think that most of us have a greater understanding of bias, of being "sold" something. Anyway, I think that the process of working through such an article is a structure to contemplate a particular subject, and perhaps to raise certain questions or a debate in one's mind about it, to reflect further upon, or to research further, later on. Yet, I agree that there are many psychiatrists who might be more easily swayed in a non-critical manner, by a biased presentation of information. The subsequent quiz, and the individual's high marks on the quiz, become reinforcers for learning biased information.
3) After accurately critiquing a problem, we should then move on and try to work together to make more imaginative, creative educational programs which are stimulating, enjoyable, fair, and as free of bias as possible.

I think this concludes my little journey through this other blog. While interesting, I find it excessively cynical. It reminds me of someone in the back seat of my car continuously telling me--accurately, and perhaps even with some insightful humour--all the things I'm doing wrong. Maybe I need to hear this kind of feedback periodically--but small doses are preferable! Actually, I find my own writing at this moment becoming more cynical than I want it to be.

Opinions on mistakes psychiatrists make

Here's another interesting link from "the last psychiatrist" blog:

http://thelastpsychiatrist.com/2006/11/post_2.html#more


I agree with many of his points.

But here are a few counterpoints, in order:

1.) I think some psychiatrists talk too little. There's a difference between nervous or inappropriate chatter diluting or interrupting a patient's opportunity to speak, and an engaged dialog focusing on process or content of a problem. There is a trend in psychiatric practice, founded or emphasized by psychoanalysis, that the therapist is to be nearly silent. Sometimes I think these silences are unhelpful, unnecessary, inefficient, even harmful. There are some patients I can think of for whom silence in a social context is extremely uncomfortable, and certainly not an opportunity for them to learn in therapy. Therapy in some settings can be an exercise in meaningful dialog, active social skills practice, or simply a chance to converse or laugh spontaneously.

I probably speak too much, myself--and I need to keep my mouth shut a little more often. I have to keep an eye on this one.

It is probably better for most psychiatrists to err on the side of speaking too little, I would agree. An inappropriately overtalkative therapist is probably worse than an inappropriately undertalkative one. But I think many of us have been taught to be so silent that we cannot be fully present, intuitively, personally, intellectually, to help someone optimally. In these cases, sometimes the tradition of therapeutic silence can suppress healthy spontaneity, positivity, and humour in a way which only delays or obstructs a patient's therapy experience.

2) I agree strongly with this one--especially when history details are ruminated about interminably during the first few sessions.
However, I do think that a framework to be comprehensive is important. And sometimes it is valuable, in my opinion, to entirely review the whole history, after seeing a patient for a year, or for many years. There is so much focus on comprehensive history-taking during the first few sessions, or the first hour, that we forget to revisit or deepen this understanding after knowing a patient much better, later on. Sometimes whole elements of a patient's history can be forgotten, because they were only talked about once, during the first session.

There is a professional standard of doing a "comprehensive psychiatric history" in a single interview of no longer than 55 minutes. There may even be a certain bravado among residents, or an admiration for someone who can "get the most information" in that single hour. I object to this being a dogmatic standard. A psychiatric history, as a personal story, may take years to understand well, and even then the story is never complete. It can be quite arrogant to assume that a single brief interview (which, if optimal exchange of "facts" is to take place, can sound like an interrogation) can lead to a comprehensive understanding of a patient.

I do believe, though, that certain elements of comprehensiveness should be aimed for, and aimed for early. For example, it is very important to ask about someone's medical ailments, about substance use, about various symptoms the person may be too embarrassed to mention unless asked directly, etc. Otherwise an underlying problem could be entirely missed, and the ensuing therapy could be very ineffective or even deleterious.

Also, some individual patients may feel a benefit or relief to go through a very comprehensive historical review in the first few sessions, with the structure of the dialog supplied mainly from the therapist. Other individual patients may feel more comfortable, or find it more beneficial, to supply the structure of their story themselves. So maybe it's important not to make strong imperative statements on this question: as with so many other things in psychiatry, a lot depends on the individual situation.

3. I think it's important not to ignore ANY habitual behavior that could be harmful. Yet perhaps some times are better than others to address or push for things like smoking or soft-drink cessation: a person with a chronically unstable mood disorder may require improved mood stability (some of which may actually come from cigarette smoking, in a short-term sense anyway), before they are able to embark on a quit-smoking plan.

4. not much to add here
5. Well, point taken. I've written a post about psychiatry and politics before, and suggested a kind of detached, "monastic role." But on the other hand, any person or group may have a certain influence--the article here suggests basically that it's none of psychiatry's business to deal with political or social policy. Maybe not. But the fact is, psychiatry does have some influence to effect social change. And, in my opinion, it is obvious that social and political dynamics are driven by forces that are similar to the dynamics which operate in a single family, or in an individual's mind. So, if there is any wisdom in psychiatry, it could certainly be applicable to the political arena. Unfortunately, it appears to me that psychiatrists I have seen getting involved in politics or other group dynamics are just as swept up in dysfunctional conflict, etc. as anyone else.
But if there's something that psychiatry can do to help with war or world hunger, etc. -- why not? In some historic situations an unlikely organized group has come to the great aid of a marginalized or persecuted group in need of relief or justice, even though the organized group didn't necessarily have any specialized knowledge of the matter they were dealing with.

6. I strongly agree. I prefer to offer therapy to most people I see. And I think most people do not have adequate opportunities to experience therapy. Yet I do also observe that many individuals could be treated with a medication prescribed by a gp, and simply experience resolution of their symptoms. Subsequent "therapy" is done by the individual in their daily life, and does not require a "therapist." In these cases, the medication may not be needed anymore, maybe after a year or so. Sometimes therapists may end up offering something that isn't really needed, or may aggrandize the role or importance of "therapy" (we studied all those years to learn to be therapists, after all--therefore a therapist's view on the matter may be quite biased), when occasionally the best therapy of all could simply be self-provided. Yet, of course, many situations are not so simple at all, and that's where a therapy experience can be very, very important. I support the idea of respecting the patient's individual wishes on this matter, after providing the best possible presentation of benefits and risks of different options. Of course, we're all biased in how we understand this benefit/risk profile.
7. some interesting points here...but subject to debate. Addressing these complex subjects in an imperative manner makes me uncomfortable.
8. polypharmacy should certainly not be a norm, though intelligent use of combination therapies, in conjunction with a clear understanding of side-effect risks, can sometimes be helpful. Some of the statements made in this section have actually not been studied well, for example it makes no pharmacological sense to combine two different SSRI antidepressants at the same time. But there has not been a body of research data PROVING that such a combination is in fact ineffectual. Therefore, before we scoff at the practitioner who prescribes two SSRIs at once, I think we should look at the empirical result--since there are no prospective randomized studies, the best we can do is see whether the individual patient is feeling better, or not.
9. I'm not a big fan of "diagnosis", but sometimes, and for some individuals, it can be part of a very helpful therapy experience, to be able to give a set of problems a name. This name, this category, may lead the person to understand more about causes & solutions. Narrative therapy makes a good use, I think, of "naming" (a variant of "diagnosing") as a very useful therapeutic construct.

10. There isn't a number 10 here, but the comments at the end of this article were good.