Transcript Functional Contextual Pharmacology #2

Assumptions, coherence, effectiveness
Behavioral
Pharmacology
Mentalistic/Cognitivistic
Psychopharmacology
A Philosophical Structure for Psychiatry
Kenneth S. Kendler AJP 2005
Seeks a coherent conceptual and philosophical framework for
psychiatry that consists of eight major propositions:
1.
Grounded in mental experiences – thoughts, feelings, etc
2.
Cartesian dualism is false (see however 3, 4, 6, 7)
3.
Epiphenomenalism is false. thoughts, feelings, and impulses matter to
science because they do things / have causal efficacy in the (real) world
4.
Brain-mind & mind-brain causality real.
Mental phenomena have causal efficacy in the world. They affect
our brains and bodies & through them the outside world.
RE – 2. Cartesian dualism is false
We need to reject definitively the belief that mind and brain reflect two
fundamentally different and ultimately incommensurable kinds of "stuff."
in accord with overwhelming clinical and scientific
evidence, we conclude that the human first-person world
of subjective experience emerges from and is entirely
dependent upon brain functioning…
The mental world does not exist independently of its
physical instantiation in the brain.
To accept monism means to no longer consider the mental (or
functional) to be a fundamentally different thing from the
biological (or organic)… the mental and the biological
become different ways of viewing and/or
different levels of analysis of the mind-brain system.
A Philosophical Structure for Psychiatry 2
5. Psychiatric disorders are etiologically complex
6. Explanatory pluralism preferable to monistic explanatory
approaches, especially biological reductionism (?2)
7. Psychiatry needs to move from a prescientific "battle of
paradigms" toward a more mature approach that embraces
complexity along with empirically rigorous and pluralistic
explanatory models. “Ways of viewing a mind-brain system”
8. Need to accept "patchy reductionism" with the goal of
piecemeal integration in explaining complex etiological
pathways to psychiatric illness a little bit at a time.
… eliminating incoherence in assumptions?
What kinds of things are psychiatric disorders?
Kendler, Zachar and Craver, Psychological Medicine, 22 Sep 2010
Depts of Psychiatry, Psychology, and Philosophy -Neuroscience-Psychology
Program
Psychiatry  etiology & underlying mechanisms: thus (MPC) kinds

Mechanistic Property Cluster (MPC) kinds; “a kind is real, the cluster of
properties is lawfully connected independently of our classifications.”
“…we take ourselves to be investigating an objective causal structure that
is independent of our investigative and instrumental practices.”
Complex, mutually reinforcing networks of causal mechanisms,
objectively grounded features of causal structure of the mind/brain,
fuzzy sets - mechanisms at multiple levels that act and interact
Defining our disorders at the level of property clusters under-girded by
dysfunctional but self-sustaining mechanisms is a practical goal.
Indeed, we are seeing early signs of success of uncovering such
mechanisms in contemporary research. (? C.f. actual evidence)
Philosophy of Psychopharmalogy. CUP 2008
Dan Stein. Previous work with David Kupfer, Schatzberg, Stephen Stahl
Chapter 3 – How to think about science - Larger questions about science,
language, medicine, and even about philosophy
“What is a medical disorder?”, and perhaps the most important question in
philosophy of psychiatry: “What is a psychiatric disorder?” 2 approaches
(the classical approach) - well-delineated formal definitions of disorder
(the critical approach) - arguments that no scientific response is possible
(synthetic or integrative position) taken here draws on cognitiveaffective science and emphasizes that the brain-mind is embodied
sensorimotor-affective neuronal circuitry allows humans to interact with
their physical and social world… (Conceptual Nervous System!)
development of basic-level and abstract cognitive-affective maps (or
metaphors) for understanding the world. (Mentalist CNS!!)
NIMH Research Domain Criteria (RDoC)
project – AJPsychiatry Editorial July 2010
RDoC classification rests on three assumptions.
1.
mental illnesses are brain disorders – i.e. disorders of brain circuits.
2.
dysfunction in neural circuits can be identified with the tools of clinical
neuroscience, eg electrophysiology, functional neuroimaging, and new
methods for quantifying connections in vivo.
3.
data from genetics and clinical neuroscience will yield biosignatures that
will augment clinical symptoms and signs for clinical management.
Example of circuitry-behavior relationships and future clinical
use:…"anxiety disorder" and data from imaging, genomic sequencing, &
laboratory measures of fear conditioning and extinction to determine
prognosis and appropriate treatment, as in “Proper Medicine” now 
Key unspoken assumptions: healthy normality, ontological reality,
correspondence based mechanist/biologist “truth”, objective science
i
CHEMICAL IMBALANCES – OR NOT
After 40 years of research, in contradiction to prevailing beliefs,
neurotransmitter theories have failed to achieve empirical support.
“Although it is often stated with great confidence that depressed people
have a serotonin or norepinephrine deficiency, the evidence actually
contradicts these claims” Professor of Neuroscience E.Valenstein
“…there is no “real” monoamine deficit” Psychiatrist Stephen M. Stahl
“We have hunted for big simple neurochemical explanations for psychiatric
disorders and have not found them” Kenneth Kendler
“Thus… currently available agents likely restore mood by modulating distinct
processes that are unrelated to the primary pathology of depression”
Krishnan and Nestler, AJP in press 2010
NEUROCHEMICAL MECHANISMS?
Linking Molecules to Mood - New Insight Into the Biology of Depression
Krishnan and Nestler, American Journal of Psychiatry October 2010

after more than a decade of PET studies (positioned aptly to
quantitatively measure receptor and transporter numbers and occupancy),
monoamine depletion studies (which transiently and experimentally
reduce brain monoamine levels) , and genetic association analyses of
polymorphisms in monoaminergic genes…

there is little evidence to implicate true deficits in serotonergic,
noradrenergic, or dopaminergic neurotransmission in the
pathophysiology of depression. (i.e. unrelated to the primary pathology)
Molecular neuropharmacology. 2009 Nestler, Hyman and Malenka
“Neurotransmitter-related hypotheses explaining the aetiology of
schizophrenia are based purely upon pharmacological evidence, and
thus are likely to be incomplete or misleading. … aberrations in these
systems do not necessarily underlie psychotic disorders”
Psych0pharmacology – usual “truths”
1955 - Thorazine arrived, and allowed the Asylums to empty in a
psychopharmacological revolution, a step forward, and around the
same time tricyclics discovered – ANTI psychotics/depressants
Chemical imbalances – the presumption from drug neurochemical
mechanisms to illness causes – excess dopamine, lack of serotonin
1987 – Prozac – the SSRI revolution, a major step forward
1988-91 – Risperidone, Clozapine – the atypical revolution
1999 – US Surgeon General Mental Health : A Report – “a wide variety
of treatments of well-documented efficacy for the array of clearly
defined mental and behavioral disorders … across the life span”
… and further “advances in neurosciences and molecular biology”…
Psychopharmacology – historical facts
Asylums emptied before drugs, those with drugs earlier - emptied later!
No evidence for any role of dopamine excess or lack of serotonin etc
1955 – about 365,000 mentally ill in US asylums – 1 in 470 people
1987 – SSI / SSDI recipients: 1.25 million – 1 in 184 people ($800 million)
2007 – SSI / SSDI recipients 4 million – a tripling ($30 billion, now $40 b)
Every day in US 850 adults added to SSI / SSDI
1987 – 16,000 kids on SSI/SSDI – this is an apples to apples comparison 
2007 – 600,000 kids on SSI/SSDI – 35 times as many
THE PUZZLE – A REVOLUTIONARY ADVANCE
AND AN EXPLOSION OF DISABILITY DUE TO MENTAL ILLNESS
New Zealand, Australia, Iceland
NZ 2000  2010
rise of 23,142  48,899 18 - 64 year olds I.E. from 1 in every 168 to 1 in every 90 on
government disability (sickness or invalid benefits) in New Zealand due to psychiatric
conditions
% total disability due to psychiatric conditions 26%  34%
total disability count rose 56,161 adults, 46% due to psychiatric conditions.

" bipolar spectrum disorder" US 4.4%, NZ 3.9%, India 0.1%, Bulgaria 0.3%.
AUSTRALIA 2001  2010
rise of 140,965  227,420 adults I.E. rise of 1 in every 137 to 1 in every 98 on disability
due a psychiatric disorder
% total disability due to psychiatric conditions 22.6%  28.7%
of the total disability count increase, 51% due to psychiatric conditions.
ICELAND 1992  2007
rise from 84 per 100,000 to 217 per 100,000 population in the new cases of disability
annually due to mental and behavioral disorders
Recent effectiveness data
STAR*D "largest antidepressant effectiveness trial ever conducted”
NIMH trumpeted results – 67% remission, a great achievement
The facts - 4041 started SSRI, and after 4 trials, only 108 in remission
and did not either have a relapse and/or dropped out by the end of 12
months of continuing care  2.7% 12 month remission
The real results "point to a lack of long-term efficacy for antidepressants."
Fake results said medications "far more effective" than placebo
CATIE – maximum 20% continued meds over a year
CUTLASS – older drugs better tolerated and better quality of life
JAMA – haloperidol = olanzapine, with less cost, less fatal s/e’s
Sz outcomes declined since 1970’s, now = 100 YEARS AGO.
STAR D – author responds to review
"The overall cumulative
remission rate was 67%“
Whereas the review found…
“4041 patients started, 108 had a
remission and did not either
relapse and/or drop out by 12
months - i.e. only 2.7%”
“I think their analysis is
reasonable and not
incompatible with what
we had reported“
STAR-D more spin from authors
Every drug, and combination of drugs showed same
effect as every other drug, and drug combination.
Despite making use of a wide gamut of medications,
switching patients from a drug with one
neurochemical action to another did not produce
differential outcomes
In contradiction to their data, the STAR*D authors
claimed, “The findings are suggestive that major
depressive disorder is biologically heterogeneous
… different treatments differ in the likelihood of
achieving remission in different patients”
STAR D – a small sample of the key
authors’ financial disclosures…
SCHIZOPHRENIA OUTCOMES – Harrow et
al, NEJM 2007, NIMH funded, no publicity…
Manic-depression outcome change…
good poor in 40 years of drugs
“in the era prior to pharmacotherapy, poor outcome in mania was
relatively rare. . .
…modern outcome studies found majority of bipolar patients with high
rates of functional impairment.”
“medication-induced changes” may be at least partly responsible.
Antidepressants may cause a “worsening of the course of illness” and
Antipsychotics “depressive episodes” and “lower functional recovery”
Drug side effects, may “explain the cognitive deficits”
HARVARD UNIVERSITY and ELI LILLY ARTICLE 2000
Manic-depression –good prognosis to poor
over 40 years of the modern drug era
“prognosis for bipolar disorder was once relatively
favourable, but contemporary findings suggest that
disability and poor outcomes are prevalent.”
“neuropharmacological-neurotoxic factors” might be
causing “cognitive deficits in bipolar disorder patients.”
“As few as 1/3 of BPD patients achieve full social and
occupational functional recovery to their own
premorbid levels.”
Further - Bipolar patients today suffer from a host of
physical illnesses--cardiovascular problems, obesity,
thyroid dysfunction, etc.--which, researchers admit,
may be due to “toxicity from medications.”
Psychotropics and children
Stimulants – no evidence of long term functional improvement
“associated with worse hyperactivity-impulsivity and with oppositional
defiant disorder symptoms,”
and greater “overall functional impairment.”
Anti-depressants - “recommending (any antidepressant) as a treatment
option, let alone as first-line treatment, would be inappropriate.”
Use of stimulants and antidepressants ? juvenile “bipolar illness”
Until the 1990s, bipolar illness was rarely diagnosed in teenagers and
virtually never in prepubertal children.
Then… Stimulants and antidepressants to children  psychotic and manic
reactions  and were then diagnosed with bipolar disorder.
Child bipolar patients treated with antipsychotic meds “were significantly
less likely to recover than those who did not receive a neuroleptic.”
CLINICAL GUIDELINE MANIPULATION
American Psychiatric Association clinical practice
guidelines for schizophrenia, bipolar disorder,
and major depressive disorder
90% of authors had a financial tie to companies
whose products were specifically considered or
included in the guideline they authored.
All of the companies whose drugs were listed as
“optimal medications” for major depressive
disorder provided funding to the authors of the
guidelines for major depressive disorder.
Like old men often do...1boringoldman
I am a psychoanalyst, a group that was disenfranchised with the rise of
the psychopharmacological focus of modern psychiatry, but that didn’t
hurt me personally, and it has been true for thirty years without
getting me stirred up.
The thing that brought me out of the woodwork is that I’m
mad as hell about being being lied to. And I have been
lied to, as have our patients.
There’s nothing wrong with having drugs to use that are symptomatic
rather than curative, weaker than we’d prefer, or more toxic than we’d
choose. That’s true of medicine no matter what the specialty.
It’s why medical training goes on so long [like a lifetime] – learning to get
the most out of what’s available without hurting people. It’s the state
of the art as they say. But as a doctor seeing patients, to do that, I have
to have access to accurate information about medications.
I have been lied to, as have our patients
I needed to know about medications after years of a
psychotherapy practice away from the medication world. I
went to "bone up." What I found was just not credible.
In fact, a lot of it was just plain lies.
The antidepressants sometimes cause akisthisia and suicidal
ideation; regularly produce dreadful withdrawal symptoms;
aren’t useful in kids; and are nowhere near as effective as
advertised. I’m not mad about that.
The drugs are what they are. I’m mad that I had to find out
those things by myself. My colleagues in high places and the
companies making the drugs knew about all of that, and they
didn’t tell me. In many cases, they tried to keep me and my
patients from knowing.
Lying in a situation where the truth is vital
I’m not mad that the Atypical Antipsychotics aren’t as good as
we’d hoped. They’re no more efficacious than our older drugs;
cause obesity and sometimes diabetes; have neurotoxicity not
too different from the older neuroleptics; and produce
withdrawal syndromes just like the antidepressants. I had to
find out about those things all by myself. Same complaint –
betrayed by formerly trusted resources, on purpose.
That’s not a complaint about neuropsychopharmacologists or
neuroscientists. It’s not a complaint about the pharmaceutical
industry or even capitalism. It’s a complaint about people
betraying the the only standard that separates medicine
from the fantastic. It’s a complaint about lying in a situation
where the truth is vital.
Crises aren’t just a time for growth or a change in direction
They’re a time for correcting what’s been wrong
As the egregious scandals have swept through psychiatry and
psychopharmacology, our organizations have been way too passive,
way too defensive, way too uninvolved and slow to embrace much
needed reform. The known sinners in high places are still there. There’s
a big difference between protecting one’s own kind and colluding with
misbehavior that needs to be addressed decisively.
Universities, Medical Schools, Professional Organizations, Scientific
Colleges, even Governmental Agencies have ignored loud symptoms of
ongoing disease during a time of epidemic. It looks from the outside
like they’ve been bought out. I hope that’s not true, but whatever the
case, the ball’s in their court now. No matter the cause for their failures
in enforcement of ethical standards, this growing crisis is a time for
new directions there too. We don’t need much reflection to know what
needs changing in that department. We can’t move forward without
acknowledging and addressing the failures of the recent past. There’s
just no room for liars and entrepreneurs in a healthy psychiatry.
URGENT NEED FOR AN ALTERNATIVE
“the drug effect on behavior was related to the schedule … the
schedule is, as it were, the score of the symphony… These
changes are sufficient to change the music profoundly, making
slow themes into fast and soft interludes into loud, even though
the drugs do not affect the symphony or the quality of the
instruments. (Peter Dews, 1964)
BEHAVIORAL PHARMACOLOGY
Behavioral pharmacology uses methods and concepts from behavior
analysis to explore and explain the behavioral effects of drugs.
Behavior analysis is a unique natural science approach to the study of
behavior developed by B. F. Skinner, but since then refined and
clarified philosophically (Steven Hayes, Aaron Brownstein, Linda Hayes,
Dermot Barnes-Holmes, Kelly Wilson, etc)
Because behavior analysis forms the theoretical and methodological
foundation of behavioral pharmacology, it deserves careful attention.
Because contextual behavioral science is our foundation, likewise attention
The following review may clarify possibilities, and some of the
reasons for the assumptions of functional contextualism,
the position taken, why our flag is planted just here.
In contrast to the dead ends of reductive mechanistic biologism.