CHAPTER 1

Psychiatric Disorders an
Overview
KATHRYN M. CONNOR AND DAVID MICHELSON*
Merck Research Laboratories, UG4C-018, Box 1000, North Wales,
PA 19454, USA
*Email: David_michelson@merck.com
1.1 Introduction
The psychiatric illnesses represent, collectively, a group of brain disorders
characterized by behavioural and cognitive abnormalities and dysfunction.
That psychiatric disorders exist and are abnormal states has been recognized
throughout history, though, as with the history of illness generally, the
meanings attributed to them have varied considerably across cultures and eras.
Today psychiatric disorders are understood as behavioural and cognitive
syndromes that reect specic alterations or abnormalities in brain function,
and comprise several distinct categories. Some of the more common psychiatric
disorders include the psychotic illnesses, which are associated with gross dis-
ruptions of normal cognitive functioning such as hallucinations, thought dis-
orders and delusions; aective disorders, which are characterized by marked
extremes of mood states such as severe depressed mood or mania and/or
disruptive oscillations between dierent mood states; anxiety disorders, char-
acterized by hypervigilance, arousal or fear out of proportion to external sti-
muli, as well as disorders of impulse control such as ADHD, substance use
disorders and eating disorders.
It is important to recognize that even within a given diagnostic category,
psychiatric disorders generally are classied on the basis of observed signs
RSC Drug Discovery Series No. 28
Drug Discovery for Psychiatric Disorders
Edited by Zoran Rankovic, Matilda Bingham, Eric J. Nestler and Richard Hargreaves
r The Royal Society of Chemistry 2012
Published by the Royal Society of Chemistry, www.rsc.org
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and symptoms these are syndromal diagnoses. The Diagnostic and Statistical
Manual for Mental Disorders, 4th edition Text Revision (DSM-IV-TR)
1
states:
[In DSM-IV] there is no assumption that all individuals having the same
mental disorder are alike in all important ways. The clinician using DSM-IV
should therefore consider that individuals sharing a diagnosis are likely to be
heterogeneous. . . (p. xxxi).
This heterogeneity means that two individuals with, for example, schizo-
phrenia can present with quite dierent sets of signs and symptoms: one patient
may experience paranoid delusions and auditory hallucinations, while another
may present with disorganized thinking and loose associations. To complicate
matters further, this heterogeneity is not conned to disease phenotype it may
also be that the pathogenesis and pathophysiology of a given psychiatric dis-
order vary among dierent individuals who share that diagnosis. From the
perspective of drug discovery and drug development this is of particular
importance, as it suggests that dierent patients with the same diagnosis may
have quite dierent responses to a particular intervention.
Our current understanding of the etiology of most psychiatric disorders is
imperfect. Characteristic alterations in certain laboratory or other biological
measures have been shown is some disorders, but few psychiatric disorders have
been associated with broadly reproducible pathophysiological ndings that sug-
gest a clear link to disease pathogenesis and etiology. With respect to the genetic
bases of disease, many psychiatric disorders have been shown to have high her-
itability, and studies have suggested that some specic gene polymorphisms
appear to be associated with increased risk for particular disorders. However,
even for the genes with the strongest evidence of association to particular ill-
nesses, the contribution to the overall observed phenotype attributable is likely to
be small, suggesting that most psychiatric illness are the product of a complex
interaction of genetic and environmental factors. Finally, most psychiatric dis-
orders appear to have important developmental components in which experience
and gene-environment interactions act together in disease pathogenesis.
1.2 Diagnostic Considerations
As noted above, and in contrast to other elds of medicine where diagnosis is
based on pathophysiology or etiology, psychiatric diagnoses or diseases are
predominantly syndromes. While the psychiatric research community continues
to work toward dening specic mental illnesses based on pathophysiology and
etiology, this goal has only been achieved for a limited number of disorders,
such as many of the dementias (e.g., Alzheimers, multi-infarct or those due to
other general medical conditions), delirium and substance-induced syndromes.
The process of diagnosis in psychiatry has been formalized through the
development of structured classication systems. The most widely used classi-
cation systems are those based on the DSM-IV-TR
1
and the International
Classication of Diseases (ICD-10) Classication of Mental and Behavioural
Disorders,
2
both of which are currently under revision. These systems enable a
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consistent and comprehensive approach for diagnosing psychiatric disorders.
Within each system, the psychiatric diagnoses are categorized based on the most
salient features, with further summary of each diagnosis including specication
of the symptoms required to make a given diagnosis. Using these frameworks for
psychiatric diagnosis serves several functions, notably reducing the complexity
of these clinical phenomena, facilitating communication between clinicians and
researchers, assisting in prediction of outcome and determination of appropriate
treatment alternatives. Table 1.1 provides a listing of the various categories of
psychiatric disorders as described in DSM-IV-TR.
Table 1.1 DSM-IV-TR Classication.
1
Disorders usually rst diagnosed in infancy, childhood or adolescence
Mental retardation
Learning disorders
Motor skill disorder
Communication disorders
Pervasive Developmental Disorder
Attention-Decit and Disruptive Behaviour Disorders
Feeding and eating disorders of infancy or early childhood
Tic disorders
Elimination disorders
Other disorders of infancy, childhood, or adolescence
Delirum, dementia, amnestic and other cognitive disorders
Mental disorders due to a general medical condition not elsewhere classied
Substance-related disorders
Schizophrenia and other psychotic disorders
Mood disorders
Depressive disorders
Bipolar disorders
Anxiety disorders
Somatoform disorders
Factitious disorders
Dissociative disorders
Sexual and gender identify disorders
Sexual dysfunctions
Gender identity disorders
Eating disorders
Sleep disorders
Primary sleep disorders dyssomnias, parasomnias
Sleep disorders related to another mental disorder
Other sleep disorders
Impulse-control disorders not elsewhere classied
Adjustment disorders
Personality disorders
Other disorders that may be a focus of clinical attention
3 Psychiatric Disorders an Overview
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1.3 Treatment Options
At the present time, pharmacologically based approaches are considered the
foundation of treatment for most psychiatric disorders. Developments in the
eld of psychopharmacology since the 1950s have provided considerable
advances for the treatment of psychiatric illness. These developments have also
served as tools for expanding our understanding of neurochemistry and for
developing new disease classications based on responses to specic drugs
manipulating specic neurochemical targets in brain. Pharmacologic treatment
considerations for some of the more common psychiatric disorders are as
follows.
1.3.1 Schizophrenia
Antipsychotics have been the mainstay of treatment for schizophrenia since the
development of chlorpromazine in the 1950s and the recognition of the role of
dopamine in this chronic and debilitating disorder. Working primarily through
dopamine receptor blockade, the rst-generation antipsychotics represented an
important advance in the treatment of schizophrenia, improving the positive
symptoms which are hallmarks of the disorder (i.e. delusions, disordered
thought and speech and perceptual disturbances), with benets observed within
one to two weeks. However, these drugs have little impact on the negative
symptoms (i.e. blunted aect, alogia, anhedonia, asociality and avoliton) and
cognitive dysfunction, which are also characteristic of the disorder. The newer,
atypical antipsychotics also demonstrate serotonergic acitivity, with less
dopaminergic activity and, arguably, improved tolerability. Nonetheless, all
antipsychotics have signicant and unpleasant sideeects which can limit their
utility, including the following: extra-pyramidal symptoms and risk of tardive
dyskinesia; weight gain, diabetes, dyslipidemia and risk of metabolic syndrome;
galactorhea and sexual dysfunction; haematologic eects (e.g., agranulocy-
tosis); and neuroleptic malignant syndrome. Clearly, alternative treatments
with better tolerability and a broader spectrum of activity, improving both
positive and negative symptoms as well as cognition, are needed. In recent
years, considerable research interest has focused on the development of drugs
targeting glutamatergic pathways; however, no successful development pro-
grams have emerged to date.
1.3.2 Major Depression
Approved pharmacologic treatments for depression act primarily through
increasing synaptic availability of monoamines and/or direct interaction with
monoaminergic receptors. In comparison to older generation tricyclic anti-
depressants (TCAs) and monoamine oxidase (MAO) inhibitors, the selective
serotonin reuptake and serotonin norepinephrine reuptake inhibitors (SSRI
and SNRI, respectively) and other newer antidepressants have broader ther-
apeutic indices, thereby allowing for marked expansion of psychiatric
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treatment into primary care settings. The full benet of treatment may take 6 to
12 weeks, with initial improvement generally reported within 2 weeks. While
awaiting the antidepressant response, short-term anxiolytic treatment may be
co-administered. For patients who fail to respond to an optimal dose of an
antidepressant, another class of antidepressant may be tried or the anti-
depressant can be augmented with another drug. As with antipsychotics,
antidepressants are also associated with a number of treatment-limiting side-
eects including sexual dysfunction, weight gain, insomnia, sedation, other
psychiatric and neurologic symptoms, dietary restrictions (MAO inhibitors),
lethality in overdose (TCAs and MAO inhibitors), increased risk of suicidal
ideation and behaviour and discontinuation symptoms with abrupt dis-
continuation. Preclinical and clinical observations over the last several decades
have implicated other neurochemical systems as therapeutic targets for
depression, with potential roles for the following: hippocampal neurogenesis
(neurotrophins); hypothalamic-pituitary axis dysfunction (CRF antagonists);
immunologic dysfunction, with activation of pro-inammatory cytokines; cir-
cadian dysfunction; and the role of oestrogen, given the increased prevalence of
depression in women and alterations in mood that are observed during the
reproductive years.
1.3.3 Anxiety Disorders
Pharmacologic treatment of anxiety primarily targets reducing the increased
arousal and fear associated with the various anxiety disorders. Available
pharmacologic agents that have demonstrated ecacy for anxiety disorders
work primarily through increasing GABAergic tone and/or modulating ser-
otonergic and noradrenergic transmission. Benzodiazepines have rapid onset of
action, an important attribute for an anxiolytic, with variable duration of eect
based on a given drugs half-life and metabolic prole (e.g., presence of active
metabolites), and many of these drugs need to be taken several times a day.
Benzodiazepines can be associated with the development of tolerance, which, in
turn, can lead to the need for dose escalation. When administered chronically,
benzodiazepines are associated with withdrawal phenomena upon abrupt dis-
continuation and, therefore, tapering over time may be required for patients
who wish to discontinue these medications. Other untoward eects include
residual sedation, cognitive impairment, increased risk of falls in the elderly and
respiratory depression and potential lethality in overdose. With the develop-
ment of the TCA and SSRI/SNRI antidepressants, clinicians noted that
patients also reported improvement in symptoms of anxiety. Ecacy of several
antidepressants has subsequently been demonstrated for treating a variety of
anxiety disorders, including panic disorder, social anxiety disorder, obsessive-
compulsive disorder, post-traumatic stress disorder and generalized anxiety
disorder. Unlike the benzodiazepines, however, SSRI/SNRIs can be anxiogenic
upon initiation and onset of an anxiolytic eect may takes several weeks. The
other side-eects for SSRI and SNRI antidepressants described above are
frequently even less well tolerated in patients with anxiety disorders. For more
5 Psychiatric Disorders an Overview
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refractory cases, atypical antipsychotics or MAO inhibitors may be indicated.
The future of drug development for the treatment of anxiety disorders is
challenged by the absence of well-dened, novel targets.
1.3.4 Insomnia
Insomnia may be viewed as a primary disorder of sleep or, alternatively, as a
condition secondary to another underlying illness, such as sleep apnoea, major
depression or substance abuse or dependence, for example. Secondary insom-
nias are best treated by addressing the underlying condition. In contrast,
pharmacological treatment of primary insomnia is currently dominated by
benzodiazepines (BZD), non-BZD hypnotics acting at the benzodiazepine site,
sedating antidepressants such as trazodone and sedating non-prescription
medications which are readily available over the counter (e.g. sedating anti-
histamines). As noted above, benzodiazepines have a number of properties and
side-eects that have limited their use. In addition, the non-BZD treatments
also have issues with tolerability, including next-day cognitive impairment
related to residual eects of treatment. Recognizing the potential role of mel-
atonin in regulation of sleep/wake cycle, recent work with melatonin agonists
has shown benet in treating transient circadian disturbances (e.g., jet lag), but
appear less promising for insomnia. Recent identication of novel compounds
targeting orexigenic pathways directly linked to circadian biology oers pro-
mise for future therapies that overcome the limitations and disadvantages of
those aecting the GABA
A
receptor system.
1.3.5 Bipolar Disorder
Bipolar disorder is characterized by periodic alterations in mood states, cycling
between extremes of mood elevation and arousal, often accompanied by psy-
chosis and depression. Pharmacologic treatment targets stabilization of mood
and reducing the likelihood of cycling between mood states. The most widely
prescribed mood stabilizers are lithium and various anticonvulants (e.g.,
lamotrigine and sodium valproate). Atypical antipsychotics have also demon-
strated ecacy in treating mania. Antidepressants may be used in this popu-
lation in conjunction with mood stabilizers, but with caution, due to the risk of
precipitating mania.
1.3.6 Other Psychiatric Disorders
The development of pharmacologic treatments for other common psychiatric
disorders has been hampered by our limited understanding of the underlying
neurobiology and pathophysiology of these conditions and, thereby, inability
to identify neurochemical targets for drug development. For example:
Attention-decit hyperactivity disorder (ADHD) is the most common
neurobehavioral disorder in childhood, often manifesting during the early
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school years and adversely impacting academic performance and normal
psychosocial development and may persist into adulthood. The underlying
pathophysiology for ADHD is unknown, but currently approved phar-
macologic treatments include stimulants and, more recently, the selective
norepinephrine reuptake inhibitor atomoxetine. While limited data are
available regarding long-term outcomes associated with atomoxetine, sti-
mulants are controlled substances with potential for abuse and the safety of
their use in the long termcontinues to be a topic of debate and investigation.
Autism is a pervasive neurodevelopmental disorder manifesting within the
rst three years of life and aecting the brains normal development of
social and communication skills. Research suggests a complex etiology,
with contributions from genetic, neurophysiologic and environmental
inuences. There are currently no medications approved for treating
patients with autism. Thus, medications are prescribed primarily for the
symptomatic treatment of disruptive behaviours.
Addiction encompasses disorders of the brain and behaviour associated
with use, usually excessive, of psychoactive substances. Substances asso-
ciated with addiction include widely available products such as nicotine,
caeine and alcohol, as well as over-the-counter (e.g. ephredrine) and
prescription medications (e.g., BZD, opiates, stimulants) and illicit drugs
(e.g. cannabis, cocaine, heroin, methamphetamine, hallucinogenics). Dis-
orders associated with misuse of psychoactive compounds are classied in
psychiatry as substance-related disorders. These range from acute intox-
ication and withdrawal to more chronic abuse and dependence and are
associated with other psychiatric and medical co-morbidity and psycho-
social impairment. While researchers work to understand the biologic and
genetic underpinnings of addiction, including the role of neural pathways
associated with reward, pharmacologic treatment remains largely symp-
tomatic. Available treatments focus on the eects of substance withdrawal
in the absence of medications addressing prevention or progression of
disease, cravings and maintenance of abstinence.
While many patients with psychiatric illness benet from available treat-
ments, others may demonstrate only a partial response or may fail to respond
altogether. Positive outcomes are further challenged by the high rates of psy-
chiatric and other medical co-morbidities, which complicate proper diagnosis
and treatment. Currently available treatments are each associated with toler-
ability issues, which limit their utility in many patients. Poor tolerability, along
with impaired insight associated with many psychiatric disorders, in turn
contribute to treatment non-adherence and adversely impact outcome. Thus,
many unmet medical needs remain.
1.4 Unmet Medical Needs
Pharmacotherapy for psychiatric illnesses has advanced remarkably in the last
50 years. Eective treatments for schizophrenia, depression, bipolar disorder,
7 Psychiatric Disorders an Overview
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the anxiety disorders and other debilitating psychiatric conditions are now
available. Nonetheless, critical needs remain for new treatments. A very brief
and incomplete survey of these needs would include:
For schizophrenia, atypical antipsychotics can provide many patients with
good control of acute signs and symptoms with fewer side-eects com-
pared with rst-generation antipsychotics. However, for many patients the
most ecacious drugs are poorly tolerated or are associated with
unwanted consequences such as weight gain and metabolic changes.
Further, the more chronic and devastating sequelae of the illness, parti-
cularly decit or negative symptoms and cognitive impairment, are not
well treated by currently available drugs.
Todays antidepressants are safer and better tolerated compared with the
earlier drugs such as tricyclic reuptake inhibitors and monoamine oxidase
inhibitors. However, only about one-third of patients with depression
respond fully to todays pharmacologic treatments, and a similar number
have little or no response. Thus, new drugs that could, alone or in com-
bination with available drugs, induce a more complete and lasting
response in poor and partial responders are badly needed.
Patients with bipolar disorder have a number of mood stabilizers available
to them. However, for many of the drugs, such as lithium and atypical
antipsychotics, tolerability is a signicant problem, and many patients
have more complex presentations with symptoms that are inadequately
controlled with available drugs.
Most other psychiatric disorders have similar gaps in the current therapeutic
armamentarium, or in some cases, such as autism, have very little if anything
available as eective pharmacotherapy. In this context, there is a great
opportunity as a great challenge for those working to discover and develop new
drugs to treat psychiatric disorders. The variety of unmet needs supports a
number of dierent approaches. Thus, drugs that maintain todays ecacy but
improve safety and tolerability can be important in some disorders. In others,
drugs that can be added to existing treatments to increase response would be
highly valued by patients and physicians. And novel treatments, working
through new mechanisms that can provide new alternatives for patients and
especially for those patients who respond poorly or not at all to the drugs
available today, are also badly needed.
The opportunity for todays drug discoverers and developers is also a chal-
lenge. There are many promising and interesting mechanisms that could
potentially lead to new drugs. However, because of the complexity of psy-
chiatric disorders and the limits of current understanding of pathogenesis and
pathophysiology, many and perhaps most biologically plausible mechanisms
have little rigorous validation. Most psychiatric disorders have few clear ana-
logues in the animal world, so that models most commonly try to replicate
aspects of disorders, or particular symptom clusters, and few well-validated,
predictive animal models are available reliably to screen new mechanisms.
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References
1. American Psychiatric Association, Diagnostic and Statistical Manual for
Mental Disorders, American Psychiatric Association, Washington DC, 4th
edn, Text Revision, 2000.
2. The ICD-10 Classication of Mental and Behavioural Disorders, World
Health Organization, Geneva, 1993.
9 Psychiatric Disorders an Overview
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