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Adderall and Vyvanse for Schizophrenia? :
Seeing Schizophrenia as a Cognitive and Attentional Deficit Disorder
Cormac Quinn Rada
Professor Earl Thomas
Psychopharmacology
4/17/15
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Introduction
Atypical anti-psychotics, the most commonly prescribed anti-psychotics, show efficacy
in improving positive symptoms of schizophrenia, but have had lesser effects on negative and
disorganized symptoms. This ameliorative incongruence has provoked the potential thought that
by studying the underlying cognitive deficits in disorganized thought, researchers will have a
better understanding of the complex neural networks at work in schizophrenia. A better
understanding of these networks and deficiencies will contribute to a more accurate model of
schizophrenia and better pharmacological treatment. The examination of schizophrenia as a
cognitive disorder has wider implications on how we: view our current dopamine model of
schizophrenia, deploy standardization of cognitive tests, and the development and definition of
effective drugs.
History
As a History major, I believe it is beneficial to refer to the past to see how
methods of thinking on schizophrenia have evolved, and as a consequence have prioritized
narratives and models that have directly impacted the development of drugs and current
treatment. This paper seeks to endorse an underappreciated lens used to intervene in how
researches view schizophrenia in a particular way in order to enter into new discussions and
treatments.
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“mental efficiency is always diminished to a considerable degree” and that “patients are
distracted, inattentive, they cannot keep the thought in mind”1
-Kraeplin (1913)
Kraepelin’s classification of schizophrenia as dementia praecox diagnoses it as a
progressive cognitive disease that leads to dementia. Implicit in this theory is the idea that a
major symptom of schizophrenia is cognitive dysfunctionality. In 1934, Vigotsky argued that
dysfunction in abstract or conceptual thinking was observed in schizophrenia. In 1944, Hunt and
Cofer observed that intelligence quotients of schizophrenics were lower than that of controls.2
These dysfunctionalities had and continually have been explicated by other studies to
convincingly show deficiencies in executive functioning, attention, memory, and other cognitive
components.
Yet, when conventional neuroleptics were first introduced, the focus of schizophrenia
research, treatment, and care shifted solely to the treatment of positive symptoms. It has only
been in the past two decades that cognitive dysfunction and deficits have once again been
acknowledged as fundamental to schizophrenia, and furethermore, for its potential association to
and possible source of negative symptoms. And thanks to “a number of studies since the early
1990s , that have found that cognitive deficits are the best predictor of functional status across a
number of outcome domains and patient characteristics”, has the shift in schizophrenic treatment
been directed towards cognition.
Kraepelin E. (1913). “Section IX, die endogenen verblödungen. Die dementia
praecox,” in Psychiatrie. Ein Lehrbuch für Studierende und Ärzte, ed. Kraepelin von Dr. Emil.,
III, editor. (Leipzig: Barth; ), 746–749
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2
Jablensky A. The diagnostic concept of schizophrenia: its history, evolution, and future
prospects. Dialogues Clin Neurosci. 2010;12:271–287.
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Cognitive Deficits
On the curtails of this historic shift, in 1999, Braver et al. concluded that patients with
schizophrenia exhibited cognitive impairments in distractibility, loose associations, disorganized
or socially inappropriate behavior, and disorders of Executive functioning. also, a metanalysis
done by Heinrichs and Zakzanis examined the mean effect size of 204 studies to “index
schizophrenia versus control differences in global and selective verbal memory, nonverbal
memory, bilateral and unilateral motor performance, visual and auditory attention, general
intelligence, spatial ability, executive function, language, and interhemispheric tactile-transfer
test performance”.3 The results concluded that schizophrenics’ cognitive performance were a
standard deviation of 1.5 below the norm of healthy adults.
Executive Functioning Deficits
Additionally, schizophrenics, particularly first episode non-medicated populations
relatives and those at high risk for developing schizophrenia, exhibit moderate to severe
deficiencies in executive functioning. Executive function is “ a set of abilities that allow us to
invoke voluntary control of our behavioral responses.”4 Orellana and Slachevsky state that
executive functioning enables humans to “develop and carry out plans, make up analogies, obey
social rules, solve problems, adapt to unexpected circumstances, do many tasks simultaneously,
and locate episodes in time and place”. Researchers have attempted to fraction executive
functioning into parts such as divided attention, sustained attention, working memory, set-
3
Heinrichs RW., Zakzanis KK. Neurocognitive deficit in schizophrenia: a quantitative review of
the evidence. Neuropsychology. 1998;12:426–445. [PubMed]
4
Orellana G., Slachevsky A. (2013). Executive functioning in schizophrenia. Front.
Psychiatry4:35. 10.3389/fpsyt.2013.00035
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shifting, flexibility, planning, and the regulation of appropriate goal directed behavior, as a
means to measure mechanical disruptions and relations.
One such feature of executive functioning is executive attention. Executive attention
includes different processes that “depend on three different yet closely related neural networks:
(i) alert, which underlies the ability to achieve and maintain a vigil and aware state, (ii)
orientation to sensory events, which underlies the ability to select information from sensory
inputs (i.e., selective attention), and (iii) executive control of thoughts and feelings (i.e., so-called
executive attention)”5.
Executive attention is related to and measured by set shifting, which refers to “the ability
to shift attentional sets between multiple tasks, operations or ideas via the ability to disengage
from an irrelevant stimulus and engage with a relevant one”. The Wisconsin Card Sorting Task
(WCST) is the most commonly test to measure this component of executive functioning, and is
most often used to assess brain injured populations and schizophrenics. Typically,
schizophrenics see general impairments in WSCT performance.
This pattern of performance pointed towards a potential neuroanatomical location of
these deficiencies. Shafritz et al. (2005) found that brain areas activated during set shifting task
include the DLPFC, ACC, and intraparietal sulcus. This research has been expanded upon by a
meta-analysis by Minzenberg et al., in which they found that “healthy adults and schizophrenic
patients activate a qualitatively similar cortico-subcortical neural network during executive task
performance, consistent with the engagement of a general-purpose cognitive control network,
Posner M. I., Fan J. (2009). “Attention as an organ system,” inTopics in Integrative
Neuroscience: From Cells to Cognition, ed. Pomerantz J., editor. (Cambridge: Cambridge
University Press; ), 31–61
5
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with critical nodes in the DLPFC and ACC. But, patients with schizophrenia show altered
activity with deficits in the DLPFC, ACC, and mediodorsal nucleus of the thalamus”.6
However, the WCST has come under criticism as being problematic as an instrument to
measure general executive functioning in schizophrenia, because cognitive impairments are
discreet, specific and selective rather than generalized and global, as well as diverse in
incorporating many brain regions and connections. 7
Importance
Proper cognitive testing and sub-typing have the potential to contribute new model and
pharmacological treatment of negative symptoms and cognitive deficiencies, which is and has
been equally important to the treatment of positive symptoms. This is incredibly important
because research shows that cognitive performance predicted by scores on a performance-based
measure of skills account for the variance in functional outcomes such as work skills, community
activities, and interpersonal functions of schizophrenics.8 Furthermore, cognitive performance
has been shown to have “associations with different aspects of clinical symptoms, limited
learning in rehabilitation programs, and functional outcome in schizophrenia”, and could thereby
lead to more successful anti-psychotic treatment as well as a more accurate ideology of what
drugs are declared as successfully effective, and an awareness of the future implication of such a
definition9.
6
Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC Arch Gen Psychiatry. 2009 Aug;
66(8):811-22.
7
Grady
Bowie PD, Harvey PB. Cognitive deficits and functional outcome in
schizophrenia. Neuropsychiatry Dis Treat. 2006;2(4):531–536.
8
9
Sharma T, Antonova L.Cognitive function in schizophrenia. Deficits, functional consequences,
and future treatment. Psychiatr Clin North Am. 2003 Mar;26(1):25-40. Review
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Theories
As we have learned, current atypical antipsychotics act primarily on dopamine systems
and other neurotransmitters like serotonin. Stip et al. (2005) concluded that atypical
antipsychotics work on the prefrontal cortex and the hippocampus by increasing acetylcholine
release. This cholinergic belief adequately responds to a finding by Tandon et al. (1991) that
concluded that positive symptoms are the result of decreased cholinergic activity, explaining
how atypical antipsychotics have a large effect on positive symptoms. While studies have found
areas of association between positive and negative symptoms, the most supported model of
schizophrenia as “three uncorrelated and independent symptom factors” and the lack of an effect
by current anti-psychotics on negative and disorganized symptoms leads one to believe that other
systems besides the cholinergic system may be responsible.
Increased muscarinic Ach activity has been suggested by Tandon et al. (1991) to exert a
compensatory response that dampens the influence of dopamine hyperactivity seen in positive
symptoms, and thereby modifying the DA/Ach balance, which brings about and intensifies
negative symptoms.
The existing literature has provided a myriad of theories describing the underlying
systematic substrates of disorganized symptoms, and therefore inconclusive understandings of
the precariously entangled and complex role of cognitive functions in schizophrenia. However
inconclusive this data may be, there is evidence that anticholinergic agents effects on
cholinesterase inhibitors responsible for executive functioning show an improvement of
performance in areas such as planning and sustained attention. In addition, studies on the
glutamatergic system, specifically with NMDA receptor agonists, have shown promising results
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in decreasing negative symptoms and cognitive deficits. Other studies show the noradrenergic
system involved in prefrontal functionality ultimately responsible for the majority of these
cognitive functions, and in particular executive functions, due to its influence through its
projections on locus ceruleus to the prefrontal cortex.
The MATRICS Project and the Future
The NIMH has supported an initiative called the MATRICS Project to “facilitate the
development of pharmacological agents for enhancing neurocognition in patients with
schizophrenia”. The collective group has delineated obstacles to more streamlined drug
development that include issues such as:
“(i) the lack of a well-accepted instrument for measuring neurocognition in clinical trials;
(ii) the lack of a consensus on the best molecular target or targets for drug development; (iii) the
lack of a consensus regarding the optimal trial design for either comedication that improves
cognition when added to an antipsychotic or a broad spectrum agent that improves cognition
and treats psychosis; and (iv) the approaches of regulatory agencies such as the US Food and
Drug Administration to approving and labeling a new agent”10.
The mission of this project is to change the narrative of schizophrenic treatment by
emphasizing the need and priority of treating these cognitive impairments that have been
pervasive and severe, yet are suggested to be potentially modifiable. With this optimism,
attempts have been made and research is being conducted to prescribe atypical anti-psychotics
and adjunctive cognitive enhancers such as guanfacine, cetylcholinesterase inhibitors, glycine,
stimulants, nicotinic agents, and serotonergic agents. The results are limited and inconclusive,
but other compounds are being synthesized and tested with the hopes to provide a more complete
and effective treatment for negative and dysfunctional symptoms in schizophrenia.
10
Marder SR. The NIMH-MATRICS project for developing cognition-enhancing agents for
schizophrenia. Dialogues Clin Neurosci. 2006;8:109–113.