Cyclothymia

Cyclothymia is marked by manic and depressive states,
yet neither are of sufficient intensity nor duration to
merit a diagnosis of bipolar disorder or major
depressive disorder. The diagnosis of cyclothymia is
appropriate if there is a history of hypomania, but no
prior episodes of mania or major depression (Table 4-
5). Longitudinal followup studies indicate that the risk
of bipolar disorder developing in patients with
cyclothymia is about 33 percent; although 33 times
greater than that for the general population, this rate of
risk still is too low to justify viewing cyclothymia as
merely an early manifestation of bipolar type I disorder
(Howland & Thase, 1993). .

Differential Diagnosis

Mood disorders are sometimes caused by general
medical conditions or medications. Classic examples
include the depressive syndromes associated with
dominant hemispheric strokes, hypothyroidism,
Cushing’s disease, and pancreatic cancer (DSM-IV).
Among medications associated with depression,
antihypertensives and oral contraceptives are the most
frequent examples. Transient depressive syndromes are
also common during withdrawal from alcohol and
various other drugs of abuse. Mania is not uncommon
during high-dose systemic therapy with glucocorticoids
and has been associated with intoxication by stimulant
and sympathomimetic drugs and with central nervous
system (CNS) lupus, CNS human immunodeficiency
viral (HIV) infections, and nondominant hemispheric
strokes or tumors. Together, mood disorders due to
known physiological or medical causes may account
for as many as 5 to 15 percent of all treated cases
(Quitkin et al., 1993b). They often go unrecognized
until after standard therapies have failed.

A challenge to diagnosticians is to balance their
search for relatively uncommon disorders with their
sensitivity to aspects of the medical history or review
of symptoms that might have etiologic significance. For
example, the onset of a depressive episode a few weeks
or months after the patient has begun taking a new
blood-pressure medication should raise the physician’
index of suspicion. Ultimately, occult or covert medical

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Adults and Mental Health

illnesses must always be considered when an
apparently clear-cut case of a mood disorder is
refractory to standard treatments (Depression Guideline
Panel, 1993). Cultural influences on the manifestation
and diagnosis of depression are also important for the

-diagnostician to identify (DSM-IV). As discussed in

Chapter 2, somatization is especially prevalent in
individuals from ethnic minority backgrounds (Lu et
al., 1995). Somatization is the expression of mental
distress in terms of physical suffering.

Etiology of Mood Disorders

The etiology of depression, the mood disorder most
frequently studied, is far from ideally understood.
Many cases of depression are triggered by stressful life
events, yet not everyone becomes depressed under such
circumstances. The intensity and duration of these
events, as well as each individual’s genetic endowment,
coping skills and reaction, and social support network
contribute to the likelihood of depression. That is why
depression and many other mental disorders are broadly
described as the product of a complex interaction
between biological and psychosocial factors (see
Chapter 2). The relative importance of biological and
psychosocial factors may vary across individuals and
across different types of depression.

This section of the chapter describes the biological,
genetic, and psychosocial factors—such as cognition,
personality, and gender—that correlate with, or
predispose to, depression. The discussion of genetic
factors also incorporates the latest findings about
bipolar disorder. Genes are implicated even more
strongly in bipolar disorder than they are in major
depression, galvanizing a worldwide search to identify
chromosomal regions where genes may be located and
ultimately to pinpoint the genes themselves (NIMH,
1998).

Biologic Factors in Depression

Much of the scientific effort expended over the past 40
years on the study of depression has been devoted to
the search for biologic alterations in brain function.
From the beginning, it has been recognized that the
clinical heterogeneity of depression disorders may
Mental Health: A Report of the Surgeon General

preclude the possibility of finding a single defect.
Researchers have detected abnormal concentrations of
many neurotransmitters and their metabolites in urine,
plasma, and cerebrospinal fluid in subgroups of patients
(Thase & Howland, 1995), dysregulation of the HPA
axis (Thase & Howland, 1995), elevated levels of
corticotropin-releasing factor (Nemeroff, 1992, 1998;
Mitchell, 1998); and, most recently, abnormalities in
second messenger systems and neuroimaging (Drevets,
1998: Rush et al., 1998, Steffens & Krishnan, 1998).
Much current research focuses on how the biological
abnormalities interrelate, how they correlate with
behavioral and emotional patterns that seem to
distinguish one subcategory of major depression from
another, and how they respond to diverse forms of
therapy.

In the search for biological changes with
depression, it must be understood that a biological
abnormality reliably associated with depression may
not actually be a causal factor. For example, a biologic
alteration could be a consequence of sleep deprivation
or weight loss. Any biological abnormality found in
conjunction with any mental disorder may be a cause,
a correlate, or a consequence, as discussed in Chapter
2. What drives research is the determination to find
which of the biological abnormalities in depression are
true causes, especially ones that might be detectable
and treatable before the onset of clinical symptoms.

Monoamine Hypothesis

For many years the prevailing hypothesis was that
depression was caused by an absolute or relative
deficiency of monoamine® transmitters in the brain.
This line of research was bolstered by the discovery
many years ago that reserpine, a medication for
hypertension, inadvertently caused depression. It did so
by depleting the brain of both serotonin and the three
principal catecholamines (dopamine, norepinephrine,
and epinephrine). Such findings led to the
“catecholamine hypothesis” and the “indoleamine (1.e.,

 

8 : : 7
Monoamine neurotransmitters are a chemical class that

includes catecholamines (norepinephrine, epinephrine, dopa-
mine) and indoleamines (serotonin).

252

serotonin) hypothesis,” which in due course led to an
integrated “monoamine hypothesis” (Thase &
Howland, 1995).

After more than 30 years of research, however, the
monoamine hypothesis has been found insufficient to
explain the complex etiology of depression. One
problem is that many other neurotransmitter systems
are altered in depression, including GABA and
acetylcholine (Rush et al., 1998). Another problem is
that improvement of monoamine neurotransmission
with medications and lifting of the clinical signs of
depression do not prove that depression actually is
caused by defective monoamine neurotransmission. For
example, diuretic medications do not specifically
correct the physiological defect underlying congestive
heart failure, but they do treat its symptoms. Neither
impairment of monoamine synthesis, nor excessive
degradation of monoamines, is consistently present in
association with depression; monoamine precursors do
not have consistent antidepressant effects, and a
definite temporal lag exists between the quick elevation
in monoamine levels and the symptom relief that does
not emerge until weeks later (Duman et al., 1997). To
account for these discrepancies, one new model of
depression proposes that depression results from
reductions in neurotrophic factors that are necessary for
the survival and function of particular neurons,
especially those found in the hippocampus (Duman et
al., 1997).

Despite the problems with the hypothesis that
monoamine depletion is the primary cause of
depression, monoamine impairment is certainly one of
the manifestations, or correlates, of depression.
Therefore, the monoamine hypothesis remains
important for treatment purposes. Many currently
available pharmacotherapies that relieve depression or
cause mania, or both, enhance monoamine activity. One
of the foremost classes of drugs for depression, SSRIs,
for example, boost the level of serotonin in the brain.

Evolving Views of Depression
An important shortcoming of the monoamine

hypothesis was its inattention to the psychosocial risk
factors that influence the onset and persistence of
depressive episodes. The nature and interpretation of,
and the response to, stress clearly have important
causal roles in depression. The following discussion
illustrates ongoing work aimed at understanding the
pathophysiology of depression. While incomplete, it
offers a coherent integration of the biological,
psychological, and social factors that have long been
associated clinically with this disorder.

Many decades ago, Hans Selye demonstrated the
damaging effects of chronic stress on the HPA axis, the

Adults and Mental Health

decreased sexual behavior and sleep, and other changes
(Sullivan et al., 1998). Furthermore, CRH is found in
higher concentrations in the cerebrospinal fluid of
depressed patients (Nemeroff, 1998). In autopsy studies
of depressed patients, CRH gene expression is elevated.

- and there are greater numbers of hypothalamic neurons

gastrointestinal tract, and the immune system of rats: —

adrenal hypertrophy, gastric ulceration, and involution
of the thymus and lymph nodes (Selye, 1956). Since
that time, researchers have provided ample evidence
that brain function, and perhaps even anatomic
structure, can be influenced by stress, interpretation of
stress, and learning (Weiss, 1991; Sapolsky, 1996;
McEwen, 1998). Much current research has been
directed at stress, the HPA axis, and CRH in the
genesis of depression.

Depression can be the outcome of severe and
prolonged stress (Brown et al., 1994; Frank et al., 1994;
Ingram et al., 1998). The acute stress response is
characterized by heightened arousal—the fi ght-or-flight
response—that entails mobilization of the sympathetic
nervous system and the HPA axis (see Etiology of
Anxiety). Many aspects of the acute stress response are
exaggerated, persistent, or dysregulated in depression
(Thase & Howland, 1995). Increased activity in the
HPA axis in depression is viewed as the “most
venerable finding in all of biological psychiatry”
(Nemeroff, 1998).

Increased activity of the HPA axis, however, may
be secondary to more primary causes, aS was the
problem with the monoamine hypothesis of depression.
For this reason, much attention has been focused on
CRH, which is hypersecreted in depression (Nemeroff,
1992, 1998). CRH is the neuropeptide that is released
by the hypothalamus to activate the pituitary in the
acute stress response. Yet there are many other sources
of CRH in the brain.

CRH injections into the brain of laboratory animals
produce the signs and symptoms found in depressed
patients, including decreased appetite and weight loss,

253

that express CRH (Nemeroff, 1998). These findings
have ignited research to uncover how CRH expression
in the hypothalamus is regulated, especially by other
brain centers such as the hippocampus (Mitchell,
1998). The hippocampus exerts control over the HPA
axis through feedback inhibition J acobson & Sapolsky,
1991). Shedding light on the regulation of CRH is
expected to hold dividends for understanding both
anxiety and depression.

Anxiety and Depression

Anxiety and depression frequently coexist, so much so
that patients with combinations of anxiety and
depression are the rule rather than the exception
(Barbee, 1998). And many of the medications used to
treat either one are often used to treat the other. Why
are anxiety and depression so interrelated?

Clues to answering this question are expected to
come from similarities in antecedents, correlates, and
consequences of each condition. Certainly, stressful
events are frequent, although not universal,
antecedents. Overlapping biochemical correlates are
found, most notably, an elevation in CRH (Arborelius
et al., 1999). Interestingly, one new line of research
finds that long-term consequences of anxiety and
depression are evident at the same anatomical site—the
hippocampus. Human imaging studies of the
hippocampus revealed it to have smaller volume in
patients with post-traumatic stress disorder (McEwen,
1998) and in patients with recurrent depression
(Sheline, 1996). In the latter study, the degree of
volume reduction was correlated with the duration of
major depression. In both conditions, excess
glucocorticoid exposure was thought to be the culprit
in inducing the atrophy of hippocampal neurons. But
the complete chain of events leading up to and
following the hippocampal damage is not yet known.
Mental Health: A Report of the Surgeon General

Psychosocial and Genetic Factors in Depression
If stressful events are the proximate causes of most

cases of depression, then why is it that not all people
become depressed in the face of stressful events? The
answer appears to be that social, psychological, and
genetic factors act together to predispose to, or protect
against, depression. This section first discusses
stressful life events, followed by a discussion of the
factors that shape our responses to them.

Stressful Life Events
Adult life can be rife with stressful events, as noted

earlier, and although not all people with depression can .

point to some precipitating event, many episodes of
depression are associated with some sort of acute or
chronic adversity (Brown et al., 1994; Frank et al.,
1994; Ingram et al., 1998). ,

The death of a loved one is viewed as one of the
most powerful life stressors. The grief that ensues is a
universal experience. Common symptoms associated
with bereavement include crying spells, appetite and
weight loss, and insomnia. Grief, in fact, has such
emotional impact that the diagnosis of depressive
disorder should not be made unless there are definite
complications such as incapacity, psychosis, or suicidal
thoughts.

The compelling impact of past parental neglect,
physical and sexual abuse, and other forms of
maltreatment on both adult emotional well-being and
brain function is now firmly established for depression.
Early disruption of attachment bonds can lead to
enduring problems in developing and maintaining
interpersonal relationships and problems with
depression and anxiety. Research in animals bears this
out as well. In both rodents and primates, maternal
deprivation stresses young animals, and a pattern of
repeated, severe, early trauma from maternal
deprivation may predispose an animal to a lifetime of
overreactivity to stress (Plotsky et al., 1995).
Conversely, early experience with mild, nontraumatic
stressors (such as gentle handling) may help to protect
or “immunize” animals against more pathologic
‘responses to subsequent severe stress.

Cognitive Factors
According to cognitive theories of depression, how
individuals view and interpret stressful events
contributes to whether or not they become depressed.
One prominent theory of depres sionstems from studies
of learned helplessness in animals. The theory posits
that depression arises from a cognitive state of
helplessness and entrapment (Seligman, 1991). The
theory was predicated on experiments in which animals
were trained in an enclosure in which shocks were
unavoidable and inescapable, régaydless of avoidance
measures that animals attempted. When they later were
placed in enclosures in which evasive action could have
succeeded, the animals were inactive, immobile, and
unable to learn avoidance maneuvers. The earlier
experience engendered a behavioral state of
helplessness, one in which actions were seen as
ineffectual.

In humans there is now ample evidence that the
impact of a stressor is moderated by the personal

_ meaning of the event or situation. In other words, the

254

critical factor is the person’s interpretation of the
stressor’s potential impact. Thus, an event interpreted
as a threat or danger elicits a nonspecific stress
response, and an event interpreted as a loss (of either an
attachment bond or a sense of competence) elicits more
grieflike depressive responses.

Heightened vulnerability to depression is linked to
a constellation of cognitive patterns that predispose to
distorted interpretations of a stressful event (Ingram et
al., 1998). For example, a romantic breakup will trigger
a much stronger emotional response if the affected
person believes, “I am incomplete and empty without
her love,” or “I will never find another who makes me
feel the way he does.” The cognitive patterns
associated with distorted interpretation of stress include
relatively harsh or rigid beliefs or attitudes about the
importance of romantic love or achievement (again, the
centrality of love and work) as well as the tendency to
attribute three specific qualities to adverse events: (1)
global impact—“This event will have a big effect on
me”: (2) internality—“/ should have done something to
prevent this,” or “This is my fault”; and @)
irreversibility—“T ll never be able to recover from this.”
According to a recent model of cognitive vulner-
ability to depression, negative cognitions by themselves
are not sufficient to engender depression. This model
postulates, on the basis of previously gathered
empirical evidence, that interactions between negative
cognitions and mildly depressed mood are important in
the etiology and recurrences of depression. Patterns or
styles of thinking stem from prior negative experiences.
When they are activated by adverse life events and a
mildly depressed mood, a downward spiral ensues,
leading to depression (Ingram et al., 1998).

Temperament and Personality
Responses to life events also can be linked to
personality (Hirschfeld & Shea, 1992). Personality may
be understood in terms of one’s attitudes and beliefs as
well as more enduring neurobehavioral predispositions
referred to as temperaments. The study of personality
and temperament is gaining momentum. Neuroticism (a
temperament discussed earlier in this chapter)
predisposes to anxiety and depression (Clark et al.,
1994), Having an easy-going temperament, on the other
hand, protects against depression (IOM, 1994). Further,
those with severe personality disorder are particularly
likely to have a_ history of early adversity or
maltreatment (Browne & Finkelhor, 1986).
Temperaments are not destiny, however. Parental
influences and individual life experiences may
determine whether a shy child remains vulnerable or
becomes a healthy, albeit somewhat reserved, adult. In
adults, several constellations of personality traits are
associated with mood disorders: avoidance,
dependence, and traits such as reactivity and
impulsivity (Hirschfeld & Shea, 1992). People who
have such personality traits not only cope less
effectively with stressors but also tend to provoke or
elicit adversity. A personality disorder of
temperamental disturbance may mediate the
relationship between stress and depression.

Gender

Major depressive disorder and dysthymia are more
prevalent among women than men, as noted earlier.
This difference appears in different cultures throughout

255

Adults and Mental Health

the world (Weissman et al., 1993). Understanding the
gender-related difference is complex and likely related
to the interaction of biological and psychosocial factors
(Blumenthal, 1994a), including differences in stressful
life events as well as to personality (Nolen-Hoeksema
et al., in press).

Keys to understanding the sex-related difference in
rates in the United States may be found in two types of
epidemiologic findings: (1) there are no sex-related
differences in rates of bipolar disorder (type 1) (NIMH,
1998) and, (2) within the agrarian culture of the Old
Order Amish of Lancaster, Pennsylvania, the rate of
major depressive disorder is both low (i.e., comparable
to that of bipolar disorder)’ and equivalent for men and
women (Egeland et al., 1983). Something about the
environment thus appears to interact with a woman’s
biology to cause a disproportionate incidence of
depressive episodes among women (Blumenthal,
1994a).

Research conducted in working-class
neighborhoods suggests that the combination of life
stress and inadequate social support contributes to
women’s greater susceptibility to depressive symptoms
(Brown et al., 1994). Because women tend to use more
ruminative ways of coping (e.g., thinking and talking
about a problem, rather than seeking out a distracting
activity) and, on average, have less economic power,
they may be more likely to perceive their problems as
less solvable. That perception increases the likelihood
of feeling helpless or entrapped by one’s problem.
Subtle sex-related differences in hemispheric
processing of emotional material may further
predispose women to experience emotional stressors
more intensely (Baxter et al., 1987). Women are also
more likely than men to have experienced past sexual
abuse; as noted earlier in this chapter, physical and
sexual abuse is strongly associated with the subsequent
development of major depressive disorder. Women’s
greater vulnerability to depression may be amplified by
endocrine and reproductive cycling, as well as by a

 

9 A small, albeit noteworthy, sex-related difference is seen in
the higher incidence of rapid-cycling bipolar disorder in women
(cited in Blumenthal, 1994),
Mental Health: A Report of the Surgeon General

greater susceptibility to hypothyroidism (Thase &
Howland, 1995). Menopause, on the other hand, has
little bearing on gender differences in depression.
Contrary to popular beliefs, menopause does not appear
to be associated with increased rates of depression in
women (Pearlstein et al., 1997). Untreated mental
health problems are likely to worsen at menopause, but
menopause by itself is not a risk factor for depression
(Pearce et al., 1995; Thacker, 1997). The increased risk
for depression prenatally or after childbirth suggests a
role for hormonal influences, although evidence also
exists for the role of stressful life events. In short,

psychosocial and environmental factors likely interact

with biological factors to account for greater
susceptibility to depression among women.

Poor young women (white, black, and Hispanic)
appear to be at the greatest risk for depression
compared with all other population groups (Miranda &
Green, 1999). They have disproportionately higher
rates of past exposure to trauma, including rape, sexual
abuse, crime victimization, and physical abuse; poorer
support systems; and greater barriers to treatment,
including financial hardship and lack of insurance
(Miranda & Green, 1999). Many of the same problems
apply to single mothers, whose risk of depression is
double that of married mothers (Brown & Moran,
1997).

The interaction between stressful life events,
individual experiences, and genetic factors also plays
a role in the etiology of depression in women. Some
research suggests that genetic factors, which are
discussed below, may alter women’s sensitivity to the
depression-inducing effect of stressful life events
(Kendler et al., 1995). A recent report of depression in
a sample of 2,662 twins found genetic factors in
depression to be stronger for women than men, for
whom depression was only weakly familial. For both
_ genders, individual environmental experiences played
a large role in depression (Bierut et al., 1999).

Genetic Factors in Depression and Bipolar
' Disorder

Depression, and especially bipolar disorder, clearly
tend to “run in families,” and a definite association has

256

been scientifically established (Tsuang & Faraone,
1990). Numerous investigators have documented that
susceptibility to a depressive disorder is twofold to
fourfold greater among the first-degree relatives of
patients with mood disorder than among other people
(Tsuang & Faraone, 1990). The risk among first-degree
relatives of people with bipolar disorder is about six to _
eight times greater. Some evidence indicates that first-
degree relatives of people with mood disorders are also
more susceptible than other people to anxiety and
substance abuse disorders (Tsuang & Faraone, 1990).

Remarkable as those statistics may be, they do not
by themselves prove a genetic connection. Inasmuch as
first-degree relatives typically live in the same
environment, share similar values and beliefs, and are
subject to similar stressors, the vulnerability to
depression could be due to nurture rather than nature.
One method to distinguish environmental from genetic
factors is to compare concordance rates among same-
sex twins. At least in terms of simple genetic theory, a
solely hereditary trait that appears in one member of a
set of identical (monozygotic) twins also should always
appear in the other twin, whereas the trait should
appear only 50 percent of the time in same-sex fraternal
(dizygotic) twins.

The results of studies comparing the prevalence of
depression among twins vary, depending on the specific
mood disorder, the age of the study population, and the
way the depression is defined. In all instances,
however, the reported concordance for mood disorders
is greater among monozygotic than among dizygotic
twins, and often the proportion is 2 to 1 (Tsuang &
Faraone, 1990). In Denmark, Bertelsen and colleagues
(1977) found that among 69 monozygotic twins with
bipolar illness, 46 co-twins also had bipolar disorder
and 14 other co-twins had psychoses, affective
personality disorders, or had died by suicide. In studies
of monozygotic twins reared separately (“adopted
away”), the results also revealed an increased risk of
depression and bipolar disorder compared with controls
(Mendlewicz & Rainer 1977; Wender et al., 1986).
Within the major depressive disorder grouping, greater
heritable risk has been associated with more severe,
recurrent, or psychotic forms of mood disorders
(Tsuang & Faraone, 1990). Those at greater heritable
risk also appear more vulnerable to stressful life events
(Kendler et al., 1995).

The availability of modern molecular genetic
methods now allows the translation of clinical
associations into identification of specific genes
(McInnis, 1993; Baron, 1997), Evidence collected to
date strongly suggests that vulnerability to mood
disorders may be associated with several genes
distributed among various chromosomes. For bipolar

Adults and Mental Health

treatment (Katon et al., 1992. Narrow et al., 1993;
Wells et al., 1994; Thase, 199¢. Nearly 40 percent of
people with bipolar disorder = untreated in 1 year,
according to the Epidemiologic Catchment Area survey
(Regier et al., 1993). Undertres=2ent of mood disorders

- stems from many factors, inc.zding societal stigma,

disorder, numerous distinct chromosomal regions ~

(called loci) show promise, yet the complex nature of
inheritance and methodological problems have
encumbered investigators (Baron, 1997). Heritability in
some cases may be sex linked or vary depending on
whether the affected parent is the father or mother of
the individual being studied. The genetic process of
anticipation (which has been associated with an
expansion of trinucleotide repeats) may further alter the
expression of illness across generations (McInnis,
1993). Thus, the genetic complexities of the common
depressive disorders ultimately may rival their clinical
heterogeneity (Tsuang & Faraone, 1990). |
Based on a comprehensive review of the genetics
literature, the National Institute of Mental Health
Genetics Workgroup recently evaluated several mood
disorders according to their readiness for large-scale
genetics research initiatives. Bipolar disorder was rated
in the highest category, meaning that the evidence was
strong enough to justify large-scale molecular genetic
studies. Depression, eating disorders, obsessive-
compulsive disorder, and panic disorder were rated in
the second highest category, which called for
nonmolecular genetic and/or epidemiological studies to

document further their estimated heritability (NIMH,
1998).

Treatment of Mood Disorders

So much is known about the assortment of

pharmacological and psychosocial treatments for mood

disorders that the most salient problem is not with

treatment, but rather with getting people into treatment.
Surveys consistently document that a majority of

individuals with depression receive no specific form of

257

financial barriers to treatmer:. underrecognition by
health care providers, and underappreciation by
consumers of the potential benefits of treatment (e.g.,
Regier et al., 1988; Wells et al.. 99-4: Hirschfeld et al.,
1997). The symptoms of depression. such as feelings of
worthlessness, excessive guilt. and lack of motivation,
also deter consumers from seking treatment; and
members of racial and ethnic minority groups often
encounter special barriers, as discussed in Chapter 2.
Mood disorders have profoundly deleterious
consequences on well-being: their toll on quality of life
and economic productivity matches that of heart
disease and is greater than that of peptic ulcer, arthritis,
hypertension, or diabetes (Wells et al., 1989).

Stages of Therapy ;
The treatment of mood disorders tS complex because it

involves several stages: acute. continuation, and
maintenance stages. The stages apply to
pharmacotherapy and psychosocial therapy alike. Most
patients pass through these stages to restore full
functioning.

Acute Phase Therapy
Acute phase treatment with cither psychotherapy or

pharmacotherapy covers the time period leading up to
an initial treatment response. A treatment response is
defined by a significant reduction (i.e. 2 50 percent) in
symptom severity, such that the patient no longer meets
syndromal criteria for the disorder (Frank et al.,
1991b). The acute phase for medication typically
requires 6 to 8 weeks (Depression Guideline Panel,
1993), during which patients are seen weekly or
biweekly for monitoring of symptoms, side effects,
dosage adjustments, and support (Fawcett et al., 1987).
Psychotherapies during the acute phase for depression
typically consist of 6 to 20 weekly visits.
Mental Health: A Report of the Surgeon General

Outpatient Treatment. In outpatient clinical trials,

about 50 to 70 percent of depressed patients who .

complete treatment respond to either antidepressants or
psychotherapies (Depression Guideline Panel, 1993).
An acute treatment response includes the effects of
placebo expectancy, spontaneous remission, and active
treatment. The magnitude of the active treatment effect
may be estimated from randomized clinical trials by
subtracting the placebo response rate from that of
active medication. Overall, the active treatment effect
for major depression typically ranges from 20 to 40
percent, after accounting for a placebo response rate of
about 30 percent (Depression Guideline Panel, 1993).
Although psychotherapy trials do not employ placebos
in the form of an inert pill, they do rely on comparisons
of active treatment with psychological placebos (e.g.,
a form of therapy inappropriate for a given disorder), a
comparison form of treatment, or wait list (i.e., no
therapy). The figures cited above must be understood
as rough averages. The efficacy of specific
pharmacotherapies and psychotherapies is covered later
in this section.

Acute phase therapy is ; often compromised by
patients leaving treatment. Attrition rates from clinical
trials often are as high as 30 to 40 percent, and rates of
nonadherence” are even higher (Depression Guideline
Panel, 1993). Medication side effects are a factor, as
are other factors such as inadequate psychoeducation
(resulting in unrealistic expectations about treatment),
ambivalence about seeing a therapist or taking
medication, and practical roadblocks (e.g., the cost or
accessibility of services).

Another problem is clinician failure to monitor
symptomatic response and to change treatments in a
timely manner. Antidepressants should be changed if
there is no clear effect within 4 to 6 weeks (Nierenberg
et al., 1995; Quitkin et al., 1996). Similar data are not
available for psychotherapies, but revisions to the
treatment plan should be considered, including the
addition of antidepressant medication, if there is no

 

' 10 Nonadherence is defined as lack of adherence to prescribed

activities such as keeping appointments, taking medication, and
completing assignments. :

258

symptomatic improvement within 3 or 4 months
(Depression Guideline Panel, 1993).

Acute Inpatient Treatment. Hospitalization for acute
treatment of depression is necessary for about 5 to 10
percent of major depressive episodes and for up to 50
percent of manic episodes. The principal reasons for
hospitalization are overwhelming severity of symptoms
and functional incapacity and suicidal or other life-
threatening behavior. Hospital median lengths of stay
now are about 5 to 7 days for depression and 9 to 14
days for mania. Such abbreviated stays have reduced
costs but necessitate greater transitional or aftercare
services. Few severely depressed or manic people are
in remission after only 1 to 2 weeks of treatment.

Electroconvulsive Therapy. As described above, first-
line treatment for most people with depression today
consists of antidepressant medication, psychotherapy,
or the combination (Potter et al., 1991; Depression
Guideline Panel, 1993). In situations where these
options are not effective or too slow (for example, in a

‘person with delusional depression and intense,

unremitting suicidality) electroconvulsive therapy
(ECT) may be considered. ECT, sometimes referred to
as electroshock or shock treatment, was developed in
the 1930s based on the mistaken belief that epilepsy
(seizure disorder) and schizophrenia could not exist at
the same time in an individual. Accumulated clinical
experience—later confirmed in controlled clinical
trials, which included the use of simulated or “sham”
ECT as a control (Janicak et al., 1985)—determined
ECT to be highly effective against severe depression,
some acute psychotic states, and mania (Small et al.,
1988). No controlled study has shown any other
treatment to have superior efficacy to ECT in the
treatment of depression (Janicak et al., 1985; Rudorfer
et al., 1997). ECT has not been demonstrated to be
effective in dysthymia, substance abuse, or anxiety or
personality disorders. The foregoing conclusions, and
many of those discussed below, are the products of
review of extensive research conducted over several
decades (Depression Guideline Panel, 1993; Rudorfer
et al., 1997) as well as by an independent panel of
scientists, practitioners, and consumers (NIH & NIMH
Consensus Conference, 1985).

ECT consists of a series of brief generalized
seizures induced by passing an electric current through
the brain by means of two electrodes placed on the
scalp. A typical course of ECT entails 6 to 12
treatments, administered at a rate of three times per
week, on either an inpatient or outpatient basis. The
exact mechanisms by which ECT exerts its therapeutic
effect are not yet known. The production of an
adequate, generalized seizure using the proper amount
of electrical stimulation at each treatment session is
required for therapeutic efficacy (Sackheim et al.,
1993). |

With the development of effective medications for
the treatment of major mental disorders a half-century
ago, the need for ECT lessened but did not disappear.
Prior to that time, ECT often had been administered for
a variety of conditions for which it is not effective, and
administered without anesthesia or neuromuscular
blockade. The result was grand mal seizures that could

produce injuries and even fractures. Despite the

availability of a range of effective antidepressant
medications and psychotherapies, as discussed above,
ECT continues to be used (Rosenbach et al., 1997),
occupying a narrower but important niche. It is
generally reserved for the special circumstances where
the usual first-line treatments are ineffective or cannot
be taken, or where ECT is known to be particularly
beneficial, such as depression or mania accompanied
by psychosis or catatonia (NIH & NIMH Consensus
Conference, 1985; Depression Guideline Panel, 1993;
Potter & Rudorfer, 1993). Examples of specific
indications include depression unresponsive to multiple
medication trials, or accompanied by a physical illness
or pregnancy, which renders the use of a usually
preferred antidepressant dangerous to the patient or to
a developing fetus. Under such circumstances, carefully
weighing risks and benefits, ECT may be the safest
treatment option for severe depression. It should be
administered under controlled conditions, with
appropriate personnel (Rudorfer et al., 1997).
Although the average 60 to 70 percent response
rate seen with ECT is comparable to that obtained with

259

Adults and Mental Health

pharmacotherapy, there is evidence that - the
antidepressant effect of ECT occurs faster than that
seen with medication, encouraging the use of ECT
where depression is accompanied by potentially
uncontrollable suicidal ideas and actions (Rudorfer et
al., 1997). However, ECT does not exert a long-term
protection against suicide. Indeed, it is now recognized
that a single course of ECT should be regarded as a
short-term treatment for an acute episode of illness. To
sustain the response to ECT, continuation treatment,
often in the form of antidepressant and/or mood
stabilizer medication, must be instituted (Sackeim,
1994). Individuals who repeatedly relapse following
ECT despite continuation medication may be
candidates for maintenance ECT, delivered on an
outpatient basis at a rate of one treatment weekly to as
infrequently as monthly (Sackeim, 1994; Rudorfer et
al., 1997).

The major risks of ECT are those of brief general
anesthesia, which was introduced along with muscle
relaxation and oxygenation to protect against injury and
to reduce patient anxiety. There are virtually no
absolute health contraindications precluding its use
where warranted (Potter & Rudorfer, 1993; Rudorfer et
al., 1997).

The most common adverse effects of this treatment
are confusion and memory loss for events surrounding
the period of ECT treatment. The confusion and
disorientation seen upon awakening after ECT typically
clear within an hour. More persistent memory problems
are variable. Most typical with standard, bilateral
electrode placement (one electrode on each side of the
head) has been a pattern of loss of memories for the
time of the ECT series and extending back an average
of 6 months, combined with impairment with learning
new information, which continues for perhaps 2 months
following ECT (NIH & NIMH Consensus Conference,
1985), Well-designed neuropsychological studies have
consistently shown that by several months after
completion of ECT, the ability to learn and remember
are normal (Calev, 1994). Although most patients
return to full functioning following successful ECT, the
degree of post-treatment memory impairment and
resulting impact on functioning are highly variable
Mental Health: A Report of the Surgeon General

across individuals (NIH & NIMH _ Consensus
Conference, 1985; CMHS, 1998). While clearly the
exception rather than the rule, no reliable data on the
incidence of severe post-ECT memory impairment are
available. Fears that ECT causes gross structural brain
pathology have not been supported by decades of
methodologically sound research in both humans and
animals (NIH & NIMH Consensus Conference, 1985;
Devanand et al., 1994; Weiner & Krystal, 1994;
Greenberg, 1997; CMHS, 1998). The decision to use
ECT must be evaluated for each individual, weighing
the potential benefits and known risks of all available
and appropriate treatments in the context of informed
consent (NIH & NIMH Consensus Conference, 1985).

Advances in treatment technique over the past
generation have enabled a reduction of adverse
cognitive effects of ECT (NIH & NIMH Consensus
Conference, 1985; Rudorfer et al., 1997). Nearly all
ECT devices deliver a lower current, brief-pulse
electrical stimulation, rather than the original sine wave
output; with a brief pulse electrical wave, a therapeutic
seizure may be induced with as little as one-third the
electrical power as with the older method, thereby
reducing the potential for confusion and memory
disturbance (Andrade et al., 1998). Placement of both
stimulus electrodes on one side of the head
(“unilateral” ECT), over the nondominant (generally
right) cerebral hemisphere, results in delivery of the
initial electrical stimulation away from the primary
learning and memory centers. According to several
controlled trials, unilateral ECT is associated with
virtually no detectable, persistent memory loss (Horne
et al., 1985; NIH Consensus Conference, 1985;
Rudorfer et al., 1997). However, most clinicians find
unilateral ECT less potent and more slowly acting an
intervention than conventional bilateral ECT,
particularly in the most severe cases of depression or in
" mania. One approach that is sometimes used is to begin
atrial of ECT with unilateral electrode placement and
switch to bilateral treatment after about six treatments
if there has been no response. Research has
demonstrated that the relationship of electrical dose to
clinical response differs depending on electrode
placement; for bilateral ECT, as long as an adequate

260

seizure is obtained, any additional dosage will merely
add to the cognitive toxicity, whereas for unilateral
electrode placement, a therapeutic effect will not be
achieved unless the electrical stimulus is more than
minimally above the seizure threshold (Sackeim et al.,
1993). Even a moderately high electrical dosage in
unilateral ECT still has fewer cognitive adverse effects
than bilateral ECT. On the other hand, high-dose
bilateral ECT may be unnecessarily risky and may be
a preventable cause of severe memory impairment.
Some types of medication, such as lithium, also add to
confusion and cognitive impairment when given during
a course of ECT and are best avoided. Medications that
raise the seizure threshold and make it harder to obtain
a therapeutic effect from ECT, including
anticonvulsants and some minor tranquilizers, may also
need to be tapered or discontinued.

Informed consent is an integral part of the ECT
process (NIH & NIMH Consensus Conference, 1985).
The potential benefits and risks of this treatment, and
of available alternative interventions, should be
carefully reviewed and discussed with patients and,
where appropriate, family or friends. Prospective
candidates for ECT should be informed, for example,
that its benefits are short-lived without active
continuation treatment, and that there may be some risk
of permanent severe memory loss after ECT. In most
cases of depression, the benefit-to-risk ratio will favor
the use of medication and/or psychotherapy as the
preferred course of action (Depression Guideline Panel,
1993). Where medication has not succeeded, or is
fraught with unusual risk, or where the potential
benefits of ECT are great, such as in delusional
depression, the balance of potential benefits to risks
may tilt in favor of ECT. Active discussion with the
treatment team, supplemented by the growing amount
of printed and videotaped information packages for
consumers, is necessary in the decisionmaking process,
both prior to and throughout a course of ECT. Consent
may be revoked at any time during a series of ECT
sessions.

Although many people have fears related to stories
of forced ECT in the past, the use of this modality on
an involuntary basis today is uncommon. Involuntary
ECT may not be initiated by a physician or family
member without a judicial proceeding. In every state,
the administration of ECT on an involuntary basis
requires such a judicial proceeding at which patients
may be represented by legal counsel. As a rule, such
petitions are granted only where the prompt institution
of ECT is regarded as potentially lifesaving, as in the
case of a person who is in grave danger because of lack
of food or fluid intake caused by catatonia. Recent
epidemiological surveys show that the modern use of
ECT is generally limited to evidence-based indications
(Hermann et al., 1999). Indeed, concern has been raised
that in some settings, particularly in the public sector
and outside major metropolitan areas, ECT may be
underutilized due to the wide variability in the
availability of this treatment across the country
(Hermann etal., 1995). Consequently, minority patients
tend to be underrepresented among those receiving
ECT (Rudorfer et al., 1997),

On balance, the evidence supports the conclusion
that modern ECT is among those treatments effective

Adults and Mental Health

remission). A remission is defined as a complete
resolution of affective symptoms to a level similar to
healthy people (Frank et al., 1991a). As residual
symptoms are associated with increased relapse risk
(Keller et al., 1992; Thase et al., 1992), recovery
should be achieved before withdrawing antidepressant
pharmacotherapy.

Many psychotherapists similarly taper a successful
course of treatment by scheduling several sessions

(every other week or monthly) prior to termination.

for the treatment of select severe mental disorders, .

when used in accord with current standards of care,
including appropriate informed consent.

Continuation Phase Therapy
Successful acute phase antidepressant pharmacotherapy
or ECT should almost always be followed by at least 6
months of continued treatment (Prien & Kupfer, 1986;
Depression Guideline Panel, 1993; Rudorfer et al.,
1997). During this phase, known as the continuation
phase, most patients are seen biweekly or monthly. The
primary goal of continuation pharmacotherapy is to
prevent relapse (ie., an exacerbation of symptoms
sufficient to meet syndromal criteria). Continuation
pharmacotherapy reduces the risk of relapse from 40-60
percent to 10-20 percent (Prien & Kupfer, 1986; Thase,
1993), Relapse despite continuation pharmacotherapy
might suggest either nonadherence (Myers &
Branthwaithe, 1992) or loss of a placebo response
(Quitkin et al., 1993a).

A second goal of continuation pharmacotherapy is
consolidation of a response into a complete remission
and subsequent recovery (i.e., 6 months of sustained

261

There is some evidence, albeit weak, that relapse is less
common following successful treatment with one type
of psychotherapy—cognitive-behavioral therapy—than
with antidepressants (Kovacs et al., 1981; Blackburn et
al., 1986; Simons et al., 1986; Evans et al., 1992). If
confirmed, this advantage may offset the greater short-
term costs of psychotherapy.

Maintenance Phase Therapies
Maintenance pharmacotherapy is intended to prevent
future recurrences of mood disorders (Kupfer, 1991;
Thase, 1993; Prien & Kocsis, 1995). A recurrence is
viewed as a new episode of illness, in contrast to
relapse, which represents reactivation of the index
episode (Frank et al., 1991a). Maintenance
pharmacotherapy is typically recommended for
individuals with a history of three or more depressive
episodes, chronic depression, or bipolar disorder
(Kupfer, 1991; Thase, 1993; Prien & Kocsis, 1995).
Maintenance pharmacotherapy, which may extend for
years, typically requires monthly or quarterly visits.
Longer term, preventive psychotherapy to prevent
recurrences has not been studied extensively. However,
in one study of patients with highly recurrent
depression, monthly sessions of interpersonal
psychotherapy were significantly more effective than
placebo but less effective than pharmacotherapy (Frank
et al., 199 1a).

Specific Treatments for Episodes of
Depression and Mania

This section describes specific types of pharmaco-
therapies and psychosocial therapies for episodes of
depression and mania. Treatment generally targets
Mental Health: A Report of the Surgeon General

symptom patterns rather than specific disorders.
Differences in the treatment strategy for unipolar and
bipolar depression are described where relevant.

Treatment of Major Depressive Episodes

Pharmacotherapies

Antidepressant medications are effective across the
full range of severity of major depressive episodes in
major depressive disorder and bipolar disorder
(American Psychiatric Association, 1993; Depression
Guideline Panel, 1993; Frank et al., 1993). The degree

of effectiveness, however, varies according to the.

intensity of the depressive episode. With mild
depressive episodes, the overall response rate is about
70 percent, including a placebo rate of about 60 percent
(Thase & Howland, 1995). With severe depressive
episodes, the overall response rate is much lower, as is
the placebo rate. For example, with psychotic
depression, the overall response rate to any one drug is
only about 20 to 40 percent (Spiker, 1985), including a
placebo response rate of less than 10 percent (Spiker &
Kupfer, 1988; Schatzberg & Rothschild, 1992).
Psychotic depression is treated with either an
antidepressant/antipsychotic combination or ECT
(Spiker, 1985; Schatzberg & Rothschild, 1992). .
There are four major classes of antidepressant
medications. The tricyclic and heterocyclic
antidepressants (TCAs and HCAs) are named for their
chemical structure. The MAOIs and SSRIs are
classified by their initial neurochemical effects. In
general, MAOIs and SSRIs increase the level of a target
neurotransmitter by two distinct mechanisms. But, as
discussed below, these classes of medications have
many other effects. They also have some differential
effects depending on the race or ethnicity of the patient.
The mode of action of antidepressants is complex
and only partly understood. Put simply, most
antidepressants are designed to heighten the level of a
target neurotransmitter at the neuronal synapse. This
can be accomplished by one or more of the following
_ therapeutic actions: boosting the neurotransmitter’s
synthesis, blocking its degradation, preventing its
' reuptake from the synapse into the presynaptic neuron,

262

or mimicking its binding to postsynaptic receptors. To
make matters more complicated, many antidepressant
drugs affect more than one neurotransmitter.
Explaining how any one drug alleviates depression
probably entails multiple therapeutic actions, direct and
indirect, on more than one neurotransmitter system
(Feighner, 1999).

Selection of a particular antidepressant for a
particular patient depends upon the patient’s past
treatment history, the likelihood of side effects, safety
in overdose, and expense (Depression Guideline Panel,
1993). A vast majority of U.S. psychiatrists favor the
SSRIs as “first-line” medications (Olfson & Klerman,

1993). These agents are viewed more favorably than

the TCAs because of their ease of use, more
manageable side effects, and safety in overdose (Kapur
et al., 1992; Preskorn & Burke, 1992). Perhaps the
major drawback of the SSRIs is their expense: they are
only available as name brands (until 2002 when they
begin to come off patent). At minimum, SSRI therapy
costs about $80 per month (Burke et al., 1994), and
patients taking higher doses face proportionally greater
costs.

Four SSRIs have been approved by the FDA for
treatment of depression: fluoxetine, sertraline,
paroxetine, and citalopram. A fifth SSRI, fluvoxamine,
is approved for treatment of obsessive-compulsive
disorder, yet is used off-label for depression.'' There
are few compelling reasons to pick one SSRI over
another for treatment of uncomplicated major
depression, because they are more similar than different
(Aguglia et al., 1993; Schone & Ludwig, 1993; Tignol,
1993; Preskorn, 1995). There are, however, several
distinguishing pharmacokinetic differences between
SSRIs, including elimination half-life (the time it takes
for the plasma level of the drug to decrease 50 percent
from steady-state), propensity for drug-drug
interactions (e.g., via inhibition of hepatic enzymes),
and antidepressant activity of metabolite(s) (DeVane,
1992). In general, SSRIs are more likely to be

 

\\ Technically, FDA approves drugs for a selected indication
(a disorder in a certain population), However, once the drug

is marketed, doctors are at liberty to prescribe it for unapproved
(off-label) indications.
metabolized more slowly by African Americans and
Asians, resulting in higher blood levels (Lin et al.,
1997).

The SSRIs as a class of drugs have their own class-
specific side effects, including nausea, diarrhea,
headache, tremor, daytime sedation, failure to achieve
orgasm, nervousness, and insomnia. Attrition from
acute phase therapy because of side effects is typically
10 to 20 percent (Preskorn & Burke, 1992). The
incidence of treatment-related suicidal thoughts for the
SSRIs is low and comparable to the rate observed for
other antidepressants (Beasley et al., 1991; Fava &
Rosenbaum, 1991), despite reports to the contrary
(Breggin & Breggin, 1994).

Some concern persists that the SSRIs are less
effective than the TCAs for treatment of severe
depressions, including melancholic and psychotic
subtypes (Potter et al., 1991; Nelson, 1994). Yet there
is no definitive answer (Danish University Anti-
depressant Group, 1986, 1990; Pande & Sayler, 1993;
Roose et al., 1994; Stuppaeck et al., 1994).

Side effects and potential lethality in overdose are
the major drawbacks of the TCAs. An overdose of as
little as 7-day supply of a TCA can result in potentially
fatal cardiac arrhythmias (Kapur et al., 1992). TCA
treatment is typically initiated at lower dosages and
titrated upward with careful attention to response and
side effects. Doses for African Americans and Asians
should be monitored more closely, because their slower
metabolism of TCAs can lead to higher blood
concentrations (Lin et al., 1997). Similarly, studies also
suggest that there may be gender differences in drug
metabolism and that plasma levels may change over the
course of the menstrual cycle (Blumenthal, 1994b).

In addition to the four major classes of anti-
depressants are bupropion, which is discussed below,
and three newer FDA-approved antidepressants that
have mixed or compound synaptic effects. Venlafaxine,
the first of these newer antidepressants, inhibits
reuptake of both serotonin and, at higher doses,
norepinephrine. In contrast to the TCAs, venlafaxine
has somewhat milder side effects (Bolden-Watson &
Richelson, 1993), which are like those of the SSRIs.

263

Adults and Mental Health

Venlafaxine also has a low risk of cardiotoxicity and,
although experience is limited, it appears to be less
toxic than the others in overdose. Venlafaxine has
shown promise in treatment of severe (Guelfi et al.,
1995) or refractory (Nierenberg et al., 1994) depres-
sive states and is superior to fluoxetine in one inpatient
study (Clerc et al., 1994). Venlafaxine also
occasionally causes increased blood pressure, and this
can be a particular concern at higher doses (Thase,
1998).

Nefazodone, the second newer antidepressant, is
unique in terms of both structure and neurochemical
effects (Taylor et al., 1995). In contrast to the SSRIs,
nefazodone improves sleep efficiency (Armitage et al.,
1994). Its side effect profile is comparable to the other
newer antidepressants, but it has the advantage of a
lower rate of sexual side effects (Preskorn, 1995). The
more recently FDA-approved antidepressant, mirta-
zapine, blocks two types of serotonin receptors, the 5-
HT, and 5-HT;, receptors (Feighner, 1999). Mirtazapine
is also a potent antihistamine and tends to be more
sedating than most other newer antidepressants. Weight
gain can be another troublesome side effect.

Figure 4-2 presents summary findings on newer
pharmacotherapies from a recent review of the
treatment of depression by the Agency for Health Care
Policy and Research (AHCPR, 1999). There have been
few studies of gender differences in clinical response to
treatments for depression. A recent report (Kornstein et
al., in press) found women with chronic depression to
respond better to a SSRI than a tricyclic, yet the oppo-
site for men. This effect was primarily in premeno-
pausal women. The AHCPR report (1999) also noted
that there were almost no data to address the efficacy of
pharmacotherapies in post partum or pregnant women.

Alternate Pharmacotherapies

Regardless of the initial choice of pharmacotherapy,
about 30 to 50 percent of patients do not respond to the
initial medication. It has not been established firmly
whether patients who respond poorly to one class of
antidepressants should be switched automatically to an
alternate class (Thase & Rush, 1997). Several studies
Mental Health: A Report of the Surgeon General

have examined the efficacy of the TCAs and SSRIs
when used in sequence (Peselow et al., 1989; Beasley
et al., 1990). Approximately 30 to 50 percent of those
not responsive to one class will respond to the other
(Thase & Rush, 1997).

Among other types of antidepressants, the MAOIs
and bupropion are important alternatives for SSRI and
TCA nonresponders (Thase & Rush, 1995). These
agents also may be relatively more effective than TCAs
or SSRIs for treatment of depressions characterized by
atypical or reversed vegetative symptoms (Goodnick &

Extein, 1989; Quitkin et al., 1993b; Thase et al., 1995). -

Bupropion and the MAOIs also are good choices to
treat bipolar depression (Himmelhoch et al., 1991;
Thase et al., 1992; Sachs et al., 1994). Bupropion also
has the advantage of a low rate of sexual side effects
(Gardner & Johnston, 1985; Walker et al., 1993).

Bupropion’ s efficacy and overall side effect profile
might justify its first-line use for all types of depression
(e.g., Kiev et al., 1994). Furthermore, bupropion has a
novel neurochemical profile in terms of effects on
dopamine and norepinephrine (Ascher et al., 1995).
However, worries about an increased risk of seizures
delayed bupropion’ s introduction to the U.S. market by
more than 5 years (Davidson, 1989). Although clearly
effective for a broad range of depressions, use of the
MAOIs has been limited for decades by concerns that
when taken with certain foods containing the chemical
tyramine (for example, some aged cheeses and red
wines); these medications may cause a potentially
lethal hypertensive reaction (Thase et al., 1995). There
has been continued interest in development of safer,
selective and reversible MAOIs.

Hypericum (St. John's Wort). The widespread publicity
and use of the botanical product from the yellow-
flowering Hypericum perforatum plant with or without
medical supervision is well ahead of the science
database supporting the effectiveness of this putative
antidepressant. Controlled trials, mainly in Germany,
have been positive in mild-to-moderate depression,
with only mild gastrointestinal side effects reported
(Linde et al., 1996). However, most of those studies
were methodologically flawed, -in areas including

264

 

Figure 4-2. Treatment of depression—newer
pharmacotherapies: Summary findings

= Newer antidepressant drugs” are effective
treatments for major depression and dysthymia.

* They are efficacious in primary care and specialty
mental health care settings:

— Major depression:
50 percent response to active agent
32 percent response to placebo

— Dysthymia (fluoxetine, sertraline, and
amisulpride): :
59 percent response to active agent
37 percent response to placebo

= Both older and newer antidepressants demonstrate
similar efficacy.

= Drop-out rates due to all causes combined are
similar for newer and older agents:

+ Drop-out rates due to adverse effects are slightly
higher for older agents.

+ Newer agents are often easier to use because of
single daily dosing and less titration.

 

*SSRIs and all other antidepressants marketed
subsequently.
Source: AHCPR, 1999.

 

 

 

diagnosis (more similar to adjustment disorder with
depressed mood than major depression), length of trial
(often an inadequate 4 weeks), and either lack of
placebo control or unusually low or high placebo
response rates (Salzman, 1998).

Post-marketing surveillance in Germany, which
found few adverse effects of Hypericum, depended
upon spontaneous reporting of side effects by patients,
an approach that would not be considered acceptable in
this country (Deltito & Beyer, 1998). In clinical use,
the most commonly encountered adverse effect noted
appears to be sensitivity to sunlight.

Basic questions about mechanism of action and
even the optimal formulation of a pharmaceutical
product from the plant remain; dosage in the
randomized German trials varied by sixfold (Linde et
al., 1996). Several pharmacologically active
components of St. John's wort, including hypericin,
have been identified (Nathan, 1999); although. their
long half-lives in theory should permit once daily
dosing, in practice a schedule of 300 mg three times a
time is most commonly used. While initial speculation
about significant MAO-inhibiting properties of
hypericum have been largely discounted, possible
serotonergic mechanisms suggest that combining this
agent with an SSRI or other serotonergic antidepressant
should be approached with caution. However, data
regarding safety of hypericum in preclinical models or
clinical samples are few (Nathan, 1999). At least two
placebo-controlled trials in the United States are under

way to compare the efficacy of Hypericum with that of
an SSRI.

Augmentation Strategies
The transition from one antidepressant to another is
time consuming, and patients sometimes feel worse in
the process (Thase & Rush, 1997). Many clinicians
bypass these problems by using a second medication to
augment an ineffective antidepressant. The best studied
strategies of this type are lithium augmentation, thyroid
augmentation, and TCA-SSRI combinations
(Nierenberg & White, 1990; Thase & Rush, 1997;
Crismon et al., 1999).
Increasingly, clinicians are adding a noradrenergic
TCA to an ineffective SSRI or vice versa. In an earlier
era, such polypharmacy (the prescription of multiple
drugs at the same time) was frowned upon. Thus far,
the evidence supporting TCA-SSRI combinations is not
conclusive (Thase & Rush, 1995). Caution is needed
when using these agents in combination because SSRIs
inhibit metabolism of several TCAs, resulting in a
substantial increase in blood levels and toxicity or other

adverse side effects from TCAs (Preskorn & Burke,
1992).

Psychotherapy and Counseling

Many people prefer psychotherapy or counseling over
medication for treatment of depression (Roper, 1986;
Seligman,1995). Research conducted in the past two
decades has helped to establish at least several newer
forms of time-limited psychotherapy as being as
effective as antidepressant pharmacotherapy in mild-to-

‘ psychotherapy (Klerman et al.,

Adults and Mental Health

moderate depressions (DiMascio et al., 1979; Elkin et
al., 1989; Hollon et al., 1992; Depression Guideline
Panel, 1993; Thase, 1995; Persons et al., 1996). The
newer depression-specific therapies include cognitive-
behavioral therapy (Becket al., 1979) and interpersonal
1984). These
approaches use a time-limited approach, a present tense
(“here-and-now”) focus, and emphasize patient
education and active collaboration. Interpersonal
psychotherapy centers around four common problem
areas: role disputes, role transitions, unresolved grief,
and social deficits. Cognitive-behavioral therapy takes
a more structured approach by emphasizing the
interactive nature of thoughts, emotions, and behavior.
It also helps the depressed patient to learn how to
improve coping and lessen symptom distress.

There is no evidence that cognitive-behavioral
therapy and interpersonal psychotherapy are
differentially effective (Elkin et al., 1989; Thase,
1995). As reported earlier, both therapies appear to
have some relapse prevention effects, although they are
much less studied than the pharmacotherapies. Other
more traditional forms of counseling and psycho-
therapy have not been extensively studied using a
randomized clinical trial design (Depression Guideline
Panel, 1993). It is important to determine if these more
traditional treatments, as commonly practiced, are as
effective as interpersonal psychotherapy or cognitive-
behavioral therapy.

The brevity of this section reflects the succinctness
of the findings on the effectiveness of these
interventions as well as the lack of differential
responses and “side effects.” It does not reflect a
preference or superiority of medication except in
conditions such as psychotic depression where
psychotherapies are not effective.

Bipolar Depression

Treatment of bipolar depression’? has received
surprisingly little study (Zornberg & Pope, 1993). Most
psychiatrists prescribe the same antidepressants for

 

2 Bipolar depression refers to episodes with symptoms
of depression in patients diagnosed with bipolar disorder.
Mental Health: A Report of the Surgeon General

treatment of bipolar depression as for major depressive
disorder, although evidence is lacking to support this
practice. It also is not certain that the same strategies
should be used for treatment of depression in bipolar IT
(i.e., major depression plus a history of hypomania) and
bipolar I (i.e., major depression with a history of at
least one prior manic episode) (DSM-IV).
Pharmacotherapy of bipolar depression typically
begins with lithium or an alternate mood stabilizer
(DSM-IV; Frances et al., 1996). Mood stabilizers
reduce the risk of cycling and have modest
antidepressant effects; response rates of 30 to 50
percent are typical (DSM-IV; Zornberg & Pope, 1993).
For bipolar depressions refractory to mood stabilizers,
an antidepressant is typically added. Bipolar depression
may be more responsive to nonsedating
antidepressants, including the MAOIs, SSRIs, and
bupropion (Cohn et al., 1989; Haykal & Akiskal, 1990;
Himmelhoch et al., 1991; Peet, 1994; Sachs et al.,
1994).The optimal length of continuation phase
pharmacotherapy of bipolar depression has not been
established empirically (DSM-IV). During the
continuation phase, the risk of depressive relapse must
be counterbalanced against the risk of inducing mania
or rapid cycling (Kukopulos et al., 1980; Wehr &
Goodwin, 1987; Solomon et al., 1995). Although not
all studies are in agreement, antidepressants may
increase mood cycling in a vulnerable subgroup, such
as women with bipolar II disorder (Coryell et al., 1992;
Bauer et al., 1994). Lithium is associated with
increased risk of congenital anomalies when taken
during the first trimester of pregnancy, and the
anticonvulsants are contraindicated (see Cohen et al.,
1994, for a review). This is problematic in view of the

high risk of recurrence in pregnant bipolar women
(Viguera & Cohen 1998).

Pharmacotherapy, Psychosocial Therapy, and
Multimodal Therapy

The relative efficacy of pharmacotherapy and the newer
forms of psychosocial treatment, such as interpersonal
psychotherapy and the cognitive-behavioral therapies,
is acontroversial topic (Meterissian & Bradwejn, 1989;

266

Klein & Ross, 1993; Munoz et al., 1994; Persons et al.,
1996). For major depressive episodes of mild to
moderate severity, meta-analyses of randomized
clinical trials document the relative equivalence of
these treatments (Dobson, 1989; Depression Guideline
Panel, 1993). Yet for patients with bipolar and
psychotic depression, who were excluded from these
studies, pharmacotherapy is required: there is no
evidence that these types of depressive episodes can be
effectively treated with psychotherapy alone
(Depression Guideline Panel, 1993; Thase, 1995).
Current standards of practice suggest that therapists
who withhold somatic treatments (i.e.,
pharmacotherapy or ECT) from such patients risk
malpractice (DSM-IV; Klerman, 1990; American
Psychiatric Association, 1993; Depression Guideline
Panel, 1993). .

For patients hospitalized with depression, somatic
therapies also are considered the standard of care
(American Psychiatric Association, 1993). Again, there
is little evidence for the efficacy of psychosocial
treatments alone when used instead of
pharmacotherapy, although several studies suggest that
carefully selected inpatients may respond to intensive
cognitive-behavioral therapy (DeJong et al., 1986;
Thase et al., 1991). However, in an era in which
inpatient stays are measured in days, rather than in
weeks, this option is seldom feasible. Combined
therapies emphasizing both pharmacologic and
intensive psychosocial treatments hold greater promise
to improve the outcome of hospitalized patients,
particularly if inpatient care is followed by ambulatory
treatment (Miller et al., 1990; Scott, 1992).

Combined therapies—also called multimodal
treatments—are especially valuable for outpatients with
severe forms of depression. According to a recent meta-
analysis of six studies, combined therapy (cognitive or
interpersonal psychotherapy plus pharmacotherapy)
was significantly more effective than psychotherapy
alone for more severe recurrent depression. In milder
depressions, psychotherapy alone was nearly as
effective as combined therapy (Thase et al., 1997b).
This meta-analysis was unable to compare combined
therapy with pharmacotherapy alone or placebo due to
an insufficient number of patients.
In summary, the DSM-IV definition of major

depressive disorder spans a heterogenous group of

conditions that benefit from psychosocial and/or
pharmacological therapies. People with mild to
moderate depression respond to psychotherapy or
pharmacotherapy alone. People with severe depression
require pharmacotherapy or ECT and they may also
benefit from the addition of psychosocial therapy.

Preventing Relapse of Major Depressive Episodes

Recurrent Depression. Maintenance pharmacotherapy
is the best-studied means to reduce the risk of recurrent
depression (Prien & Kocsis, 1995; Thase & Sullivan,
1995). The magnitude of effectiveness in prevention of
recurrent depressive episodes depends on the dose of
the active agent used, the inherent risk of the
population (i.e., chronicity, age, and number of prior
episodes), the length of time being considered, and the
patient’s adherence to the treatment regimen (Thase,
1993). Early studies, which tended to use lower
dosages of medications, generally documented a
twofold advantage relative to placebo (e.g., 60 vs. 30
percent) (Prien & Kocsis, 1995). In a more recent study
of recurrent unipolar depression, the drug-placebo
difference was nearly fivefold (Frank et al., 1990;
Kupfer et al., 1992). This trial, in contrast to earlier
randomized clinical trials, used a much higher dosage
of imipramine, suggesting that full-dose maintenance
pharmacotherapy may improve prophylaxis. Indeed,
this was subsequently confirmed in a randomized
clinical trial comparing full- and half-dose maintenance
strategies (Frank et al., 1993).

There are few published studies on the prophylactic
benefits of long-term pharmacotherapy with SSRIs,
bupropion, nefazodone, or venlafaxine. However,
available studies uniformly document 1 year efficacy
rates of 80 to 90 percent in preventing recurrence of
depression (Montgomery et al., 1988; Doogan &
Caillard, 1992; Claghorn & Feighner, 1993; Duboff,
1993; Shrivastava et al., 1994; Franchini et al., 1997;
Stewart et al., 1998). Thus, maintenance therapy with

~ Adults and Mental Health

the newer agents is likely to yield outcomes comparable
to the TCAs (Thase & Sullivan, 1995).

How does maintenance pharmacotherapy compare
with psychotherapy? In one study of recurrent depres-
sion, monthly sessions of maintenance interpersonal

_psychotherapy had a 3-year success rate of about 35

percent (i.e., a rate falling between those for active and
placebo pharmacotherapy) (Frank et al., 1990).
Subsequent studies found maintenance interpersonal
psychotherapy to be either a powerful or ineffective
prophylactic therapy, depending on the
patient/treatment match (Kupfer et al., 1990; Frank et

al., 1991a; Spanier et al., 1996).

Bipolar Depression. No recent randomized clinical
trials have examined prophylaxis against recurrent
depression in bipolar disorder. In one older, well-
controlled study, recurrence rates of more than 60
percent were observed despite maintenance treatment
with lithium, either alone or in combination with

~ imipramine (Shapiro et al., 1989).

Treatment of Mania

Acute Phase Efficacy

Success rates of 80 to 90 percent were once expected
with lithium for the acute phase treatment of mania
(e.g., Schou, 1989); however, lithium response rates of
only 40 to 50 percent are now commonplace (Frances
et al., 1996). Most recent studies thus underscore the
limitations of lithium in mania (e.g., Gelenberg et al.,
1989: Small et al., 1991; Freeman et al., 1992; Bowden
et al., 1994). The apparent decline in lithium
responsiveness may be partly due to sampling bias (i.e.,
university hospitals treat more refractory patients), but
could also be attributable to factors such as younger
age of onset, increased drug abuse comorbidity, or
shorter therapeutic trials necessitated by briefer
hospital stay (Solomon et al., 1995). The effectiveness
of acute phase lithium treatment also is partially
dependent on the clinical characteristics of the manic
episode: dysphoric/mixed, psychotic, and rapid cycling
episodes are less responsive to lithium alone (DSM-IV;
Solomon et al., 1995).
Mental Health: A Report of the Surgeon General

A number of other medications initially developed
for other indications are increasingly used for lithium-
refractory or lithium-intolerant mania. The efficacy of
two medications, the anticonvulsants carbamazepine
and divalproex sodium, has been documented in
randomized clinical trials (e.g., Small et al., 1991;
Freeman et al., 1992; Bowden et al., 1994; Keller et al.,
1992). Divalproex sodium has received FDA approval
for the treatment of mania. The specific mechanisms of
action for these agents have not been established,
although they may stabilize neuronal membrane
systems, including the cyclic adenosine monophosphate
second messenger system (Post, 1990).
anticonvulsant medications under investigation for their
effectiveness in mania include lamotrigine and
gabapentin.

Another newer treatment, verapamil, is a calcium
channel blocker initially approved by the FDA for
treatment of cardiac arrhythmias and hypertension.
Since the mid- 1980s, clinical reports and evidence from
small randomized clinical trials suggest that the
calcium channel blockers may have antimanic effects
(Dubovsky et al., 1986; Garza-Trevino et al., 1992;
Janicak et al., 1992, 1998). Like lithium and the
anticonvulsants, the mechanism of action of verapamil
has not been established. There is evidence of
abnormalities of intracellular calcium levels in bipolar
disorder (Dubovsky et al., 1992), and calcium’s role in
modulating second messenger systems (Wachtel, 1990)
has spurred continued interest in this class of
medication. If effective, verapamil does have the
additional advantage of having a lower potential for
causing birth defects than does lithium, divalproex, or
carbamazepine.

Adjunctive neuroleptics and high-potency benzo-
diazepines are used often in combination with mood
stabilizers to treat mania. The very real risk of tardive
dyskinesia has led to a shift in favor of adjunctive use
of benzodiazepines instead of neuroleptics for acute
stabilization of mania (Chouinard, 1988; Lenox et al.,
1992). The novel antipsychotic clozapine has shown
promise in otherwise refractory manic states (Suppes et
al., 1992), although such treatment requires careful
monitoring to help protect against development of

The |

agranulocytosis, a potentially lethal bone marrow
toxicity. Other newer antipsychotic medications,
including risperidone and olanzapine, have safer side
effect profiles than clozapine and are now being studied
in mania. For manic patients who are not responsive to
or tolerant of pharmacotherapy, ECT is a viable
alternative (Black et al., 1987; Mukherjee et al., 1994).
Further discussion of antipsychotic drugs and their side
effects is found in the section on schizophrenia.

Maintenance Treatment to Prevent Recurrences of
Mania

The efficacy of lithium for prevention of mania also
appears to be significantly lower now than in previous
decades; recurrence rates of 40 to 60 percent are now
typical despite ongoing lithium therapy (Prien et al.,
1984; Gelenberg et al., 1989; Winokur et al., 1993).
Still, more than 20 studies document the effectiveness
of lithium in preventing suicide (Goodwin & Jamison,
1990). Medication noncompliance almost certainly
plays a role in the failure of longer term lithium

_maintenance therapy (Aagaard et al., 1988). Indeed,

268

abrupt discontinuation of lithium has been shown to
accelerate the risk of relapse (Suppes et al., 1993).
Medication “holidays” may similarly induce a lithium-
refractory state (Post, 1992), although data are
conflicting (Coryell et al., 1998). As noted earlier,
antidepressant cotherapy also may accelerate cycle
frequency or induce lithium-resistant rapid cycling
(Kukopulos et al., 1980; Wehr & Goodwin, 1987).

With increasing recognition of the limitations of
lithium prophylaxis, the anticonvulsants are used
increasingly for maintenance therapy of bipolar
disorder. Several randomized clinical trials have
demonstrated the prophylactic efficacy of
carbamazepine (Placidi et al., 1986; Lerer et al., 1987;
Coxhead et al., 1992), whereas the value of divalproex
preventive therapy is only supported by uncontrolled
studies (Calabrese & Delucchi, 1990; McElroy et al.,
1992; Post, 1990). Because of increased teratogenic
risk associated with these agents, there is a need to
obtain and evaluate information on alternative
interventions for women with bipolar disorder of
childbearing age.
Service Delivery for Mood Disorders

The mood disorders are associated with significant
suffering and high social costs, as explained above
(Broadhead et al., 1990; Greenberg et al., 1993; Wells
et al., 1989; Wells et al., 1996). Many treatments are
efficacious, yet in the case of depression, significant
numbers of individuals either receive no care or
inappropriate care (Katon et al., 1992; Narrow et al.,
1993; Wells et al., 1994; Thase, 1996). Limitations in
insurance benefits or in the management strategies
employed in managed care arrangements may make it
impossible to deliver recommended treatments. In
addition, treatment outcome in real-world practice is
not as effective as that demonstrated in clinical trials,
a problem known. as the gap between efficacy and
effectiveness (see Chapter 2). The gap is greatest in the
primary care setting, although it also is observed in
specialty mental health practice. There is a need to
develop case identification approaches for women in
obstetrics/gynecology settings due to the high risk of
recurrence in childbearing women with bipolar
disorder. Little attention also has been paid to screening
and mental health services for women in
obstetrics/gynecology settings despite their high risk of
depression (Miranda et al., 1998).

Primary care practice has been studied extensively,
revealing low rates of both recognition and appropriate
treatment of depression. Approximately one-third to
one-half of patients with major depression go
unrecognized in primary care settings (Gerber et al.,
1989; Simon & Von Korff, 1995). Poor recognition
leads to unnecessary and expensive diagnostic
procedures, particularly in response to patients’ vague
somatic complaints (Callahan et al., 1996). Fewer than
one-half receive antidepressant medication according
to Agency for Health Care Policy Research
recommendations for dosage and duration (Simon et
al., 1993; Rost et al., 1994; Katon 1995, 1996;
Schulberg et al., 1995; Simon & Von Korff, 1995).
About 40 percent discontinue their medication on their
own during the first 4 to 6 weeks of treatment, and
fewer still continue their medication for the
recommended period of 6 months (Simon et al., 1993).
Although drug treatment is the most common strategy

269

Adults and Mental Health

for treating depression in primary care practice (Olfson
& Klerman, 1992; Williams et al., 1999), about one-
half of primary care physicians express a preference to
include counseling or therapy as a component of
treatment (Meredith et al., 1994, 1996). Few primary

-care practitioners, however, have formal training in

psychotherapy, nor do they have the time (Meredith et
al., 1994, 1996). A variety of strategies have been
developed to improve the management of depression in
primary care settings (cited in Katon et al., 1997).
These are discussed in more detail in Chapter 5 because
of the special problem of recognizing and treating
depression among older adults.

Another major service delivery issue focuses on the
substantial number of individuals with mood disorders
who go on to develop a chronic and disabling course.
Their needs for a wide array of services are similar to
those of individuals with schizophrenia. Many of the
service delivery issues relevant to individuals with
severe and persistent mood disorders are presented in
the final sections of this chapter.

Schizophrenia

Overview
Our understanding of schizophrenia has evolved since
its symptoms were first catalogued by German
psychiatrist Emil Kraepelin in the late 19th century
(Andreasen, 1997a). Even though the cause of this
disorder remains elusive, its frightening symptoms and
biological correlates have come to be quite well
defined. Yet misconceptions abound about symptoms:
schizophrenia is neither “split personality” nor
“multiple personality.” Furthermore, people with
schizophrenia are not perpetually incoherent or
psychotic (DSM-IV; Mason et al., 1997) (Table 4-6).
Schizophrenia is characterized by profound
disruption in cognition and emotion, affecting the most
fundamental human attributes: language, thought,
perception, affect, and sense of self. The array of
symptoms, while wide ranging, frequently includes
psychotic manifestations, such as hearing internal
voices or experiencing other sensations not connected
to an obvious source (hallucinations) and assigning
Mental Health: A Report of the Surgeon General

Table 4-6. DSM-IV diagnostic criteria for schizophrenia

 

A.
month period (or less if successfully treated):

(1) delusions

(2) hallucinations

(4) grossly disorganized or catatonic behavior

academic, or occupational achievement).

 

Characteristic symptoms: Two (or more) of the following, each present for a significant portion of time during a 1-

(3) disorganized speech (e.g., frequent derailment or incoherence)

(5) negative symptoms, i.e., affective flattening, alogia, or avolition

Note: Only one Criterion A symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up
a running commentary on the person's behavior or thoughts, or two or more voices conversing with each other.

Social/occupational dysfunction: For a significant portion of the time since the onset of the disturbance, one or more
major areas of functioning such as work, interpersonal relations, or self-care are markedly below the level achieved
prior to the onset (or when the onset is in childhood or adolescence, failure to achieve expected level of interpersonal,

Duration: Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least
4 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms) and may
include periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of the
disturbance may be manifested by only negative symptoms or two or more symptoms listed in Criterion A present in
an attenuated form (e.g., odd beliefs, unusual perceptual experiences).

Schizoaffective and mood disorder exclusion: Schizoaftective disorder and mood disorder with psychotic features
have been ruled out because either (1) no major depressive, manic, or mixed episodes have occurred concurrently
with the active-phase symptoms; or (2) if mood episodes have occurred during active-phase symptoms, their total
duration has been brief relative to the duration of the active and residual periods.

Substance/general medical condition exclusion: The disturbance is not due to the direct physiological effects of a
substance (e.g., a drug of abuse, a medication) or a general medical condition.

Relationship to a pervasive developmental disorder: \f there is a history of autistic disorder or another pervasive
developmental disorder, the additional diagnosis of schizophrenia is made only if prominent delusions or
hallucinations are also present for at least a month (or less if successfully treated).

 

 

unusual significance or meaning to normal events or
holding fixed false personal beliefs (delusions). No
single symptom is definitive for diagnosis; rather,
the diagnosis encompasses a pattern of signs and
symptoms, in conjunction with impaired occupational
or social functioning (DSM-IV).

Symptoms are typically divided into positive and
negative symptoms (see Table 4-7) because of their
impact on diagnosis and treatment (Crow, 1985;
Andreasen, 1995; Eaton et al., 1995; Klosterkotter et
- al., 1995; Maziade et al., 1996). Positive symptoms are

270

those that appear to reflect an excess or distortion of
normal functions (Peralta & Cuesta, 1998). The
diagnosis of schizophrenia, according to DSM-IV,
requires at least 1-month duration of two or more
positive symptoms, unless hallucinations or delusions
are especially bizarre, in which case.one alone suffices
for diagnosis. Negative symptoms are those that appear
to reflect a diminution or loss of normal functions (Roy
& DeVriendt, 1994; Crow, 1995; Blanchard et al.,
1998). These often persist in the lives of people
with schizophrenia during periods of low (or absent)
Adults and Mental Health

Table 4-7. Positive and negative symptoms of schizophrenia

Positive Symptoms of Schizophrenia

Delusions are firmly held erroneous beliefs due to distortions or exaggerations of reasoning and/or misinterpretations of
- perceptions or experiences. Delusions of being followed or watched are common, as are beliefs that comments, radio or
_ TV programs, etc., are directing special messages directly to him/her.

Hallucinations are distortions or exaggerations
- ("hearing voices" within, distinct from one’s own

: Disorganized speech/thinking,
schizophrenia. Disorganized thinking is

" indicator of thought disorder by the DSM-IV.

Catatonic behaviors are characterized by

of percepti

ion in any of the senses, although auditory hallucinations
thoughts) are the most common, followed by visual hallucinations.

also described as “thought disorder" or "loosening of associations," is a key aspect of

t
usually assessed primarily based on the person's speech. Therefore, tangential,

loosely associated, or incoherent speech severe enough to substantially impair effective communication is used as an |
|

Grossly disorganized behavior includes difficulty in goal-directed behavior (leading to difficuities in activities in daily
living), unpredictable agitation or silliness, social disinhibition, or behaviors that are bizarre to
purposelessness distinguishes them from unusual behavior prompted by delusional beliefs.

onlookers. Their

a marked decrease in reaction to the immediate surrounding environment,

sometimes taking the form of motionless and apparent unawareness, rigid or bizarre postures, Or aimless excess motor

activity.

somatic preoccupations.

Other symptoms sometimes present in schizophrenia but not often
inappropriate to the situation or stimuli, unusual motor behavior (pacing,

|

\

{

|
enough to be definitional alone include affect |
rocking), depersonalization, derealization, and |

Negative Symptoms of Schizophrenia

| Affective flattening is the reduction in the range and intensity of emotional expression, including facial expression, voice |

| tone, eye contact, and body language.
|

| Alogia,
, thoughts, and often

| apparent disinterest.

positive symptoms. Negative symptoms are difficult to
evaluate because they are not as grossly abnormal as
positives ones and may be caused by a variety of other
factors as well (e.g., as an adaptation to a persecutory
delusion). However, advancements in diagnostic
assessment tools are being made.

Diagnosis is complicated by early treatment of
schizophrenia’s positive symptoms. Antipsychotic
medications, particularly the traditional ones, often
produce side effects that closely resemble the negative
symptoms of affective flattening and avolition. In
addition, other negative symptoms are sometimes
present in schizophrenia but not often enough to satisfy
diagnostic criteria (DSM-IV): loss of usual interests or
pleasures (anhedonia), disturbances of sleep and

or poverty of speech, is the lessening of speech fluency and productivity,

271

thought to reflect slowing or blocked

manifested as laconic, empty replies to questions. |

i
Avolition is the reduction, difficulty, or inability to initiate and persist in goal-directed behavior, it is often mistaken for
|

eating; dysphoric mood (depressed, anxious, irritable,
or angry mood); and difficulty concentrating or
focusing attention.

Currently, discussion is ongoing within the field
regarding the need for a third category of symptoms for
diagnosis: disorganized symptoms (Brekke et al., 1995;
Cuesta & Peralta, 1995). Disorganized symptoms
include thought disorder, confusion, disorientation, and
memory problems. While they are listed by DSM-IV as
common in schizophrenia—especially during
exacerbations of positive or negative symptoms
(DSM-IV)—they do not yet constitute a formal new
category of symptoms. Some researchers think that a
new category is not warranted because disorganized

symptoms may instead reflect an underlying
Mental Health: A Report of the Surgeon General

dysfunction common to several psychotic disorders,

rather than being unique to schizophrenia (Toomey et
al., 1998).

Cognitive Dysfunction

Recently there has also been more clinical and research
attention on cognitive difficulties that many people
with schizophrenia experience (Levin et al., 1989;
Harvey et al., 1996). Cognitive problems include
information processing (Cadenhead et al., 1997),
abstract categorization (Keri et al., 1998), planning and

regulating goal-directed behavior (“executive

functions”), cognitive flexibility, attention, memory,

and visual processing (Cornblatt & Keilp, 1994;
Mahurin et al., 1998). These cognitive problems are
especially associated with negative and disorganized
symptoms but seem to be distinct (Basso et al., 1998;
Brekke et al., 1995; Cuesta & Peralta, 1995; Voruganti
et al., 1997), although others disagree (Roy &
DeVriendt, 1994).

These cognitive problems vary from person to
person and can change over time. In some situations it
is unclear whether such deficits are due to the illness or
to the side effects of certain neuroleptic medications
(Zalewski et al. 1998). As research on brain
functioning grows more sophisticated, some models
posit dysfunction of fundamental cognitive processes at
the center of schizophrenia, rather than as one of
numerous symptoms (Andreasen, 1997a, 1997b;
Andreasen et al., 1996). On the basis of neuro-
psychological and neuroanatomical data, for example,
some researchers posit that schizophrenia is a disorder
of the prefrontal cortex and its ability to perform the
essential cognitive function of working memory
(Goldman-Rakic & Selemon, 1997). Problems in such
fundamental areas as paying selective attention,
problem-solving, and remembering can cause serious
difficulties in learning new skills (social interaction,
treatment and rehabilitation) and performing daily tasks
(Medalia et al., 1998); treatment of such deficits is
discussed in later sections of the chapter.

272

Functional Impairment

The criteria for a diagnosis of schizophrenia include
functional impairment in addition to the constellation
of symptoms outlined above. For formal diagnosis, a
person must be experiencing significant dysfunction in
one or more major areas of life activities such as
interpersonal relations, work or education, family life,
communication, or self-care (Docherty et al., 1996;
Patterson et al., 1997, 1998). These problems result
from the complex of symptoms and their sequelae, but
have been linked more to negative than to positive
symptoms (Ho et al., 1998). “They have serious
economic, social, and psychological effects:
unemployment, disrupted education, limited social
relationships, isolation, legal involvement, family
stress, and substance abuse. Such sequelae form the
most distressing aspects of the illness for many people
and contribute to the increased risk of suicide among
people diagnosed with schizophrenia.

Cultural Variation

On first consideration, symptoms like hallucinations,
delusions, and bizarre behavior seem easily defined and
clearly pathological. However, increased attention to
cultural variation has made it very clear that what is
considered delusional in one culture may be accepted
as normal in another (Lu et al., 1995). For example,
among members of some cultural groups, “visions” or
“voices” of religious figures are part of normal
religious experience. In many communities, “seeing” or
being “visited” by a recently deceased person are not
unusual among family members. Therefore, labeling an
experience as pathological or a psychiatric symptom
can be a subtle process for the clinician with a different
cultural or ethnic background from the patient, indeed,
cultural variations and nuances may occur within the
diverse subpopulations of a single racial, ethnic, or
cultural group. Often, however, clinicians’ training,
skills, and views tend to reflect their own social and
cultural influences.

Clinicians can misinterpret and misdiagnose
patients whose cognitive style, norms of emotional
expression, and social behavior are from a different
culture, unless clinicians become culturally competent
(see Chapter 2 and Center for Mental Health Services
[CMHS], 1997). For example, clinicians may
misinterpret a client’s deferential avoidance of direct
eye contact as a sign of withdrawal or paranoia, or a
normal emotional reserve as flattened affect if they are
unaware of the norms of cultural groups other than
their own. There is some empirical evidence that such
misinterpretations happen widely. One finding is that
African-American patients are more likely than white
patients to be diagnosed with severe psychotic
disorders in clinical settings (Snowden & Cheung,
1990; Hu et al., 1991; Lawson et al., 1994, Strakowski
et al., 1995). The overdiagnosis of psychotic disorders
among African Americans is interpreted by some as
evidence of clinician bias.

People with differing cultural backgrounds also
may experience and exhibit true schizophrenia
symptoms differently (Brekke & Barrio, 1997; Thakker
& Ward, 1998). Culture shapes the content and form of
positive and negative symptoms (Maslowski et al.,
1998). For example, people in non-Western countries
report catatonic behavior among psychiatric patients
much more commonly than in the United States. How
culture, societal conditions, and diagnosing tendencies
among clinicians in various countries interact to create
these differences is being studied but is not yet well
understood.

No description of symptoms can adequately convey
a person’s experience of schizophrenia or other serious
mental illness. Two individuals with very different
internal experiences and outward presentations may be
diagnosed with schizophrenia, if both meet the
diagnostic criteria (Brazo & Dollfus, 1997; Kirkpatrick
et al., 1998). Additionally, their symptoms and
presentation may vary considerably over time (Ribeyre
& Dollfus, 1996). This considerable variation (Basso et
al., 1997; Sperling et al., 1997) has led to the naming of
several subtypes of schizophrenia, depending on what
symptoms are most prominent. Currently these are seen
as variations within a single disorder. Similarly, the
diagnosis is often difficult because other mental
disorders share some common features. Diagnosis
depends on the details of how people behave and what
they report during an evaluation, the diagnostician, and

273

Adults and Mental Health

variations in the illness over time. Therefore, many
people receive more than one diagnostic label over the
course of their involvement with mental health
services. Refining the definition of schizophrenia and
other serious mental illnesses to account for these

individual and cultural variations remains a challenge

to researchers and clinicians.

Prevalence

Studies of schizophrenia’s prevalence in the general
population vary depending on the way diagnostic
criteria are applied and the population, setting, and
method of study (Hafner & an der Heiden, 1997). In
general, 1-year prevalence in adults ages 18 to 54 is
estimated to be 1.3 percent (Table 4-1). Onset generally
occurs during young adulthood (mid-20s for men, late-
20s for women), although earlier and later onset do
occur. It may be abrupt or gradual, but most people
experience some early signs, such as increasing social
withdrawal, loss of interests, unusual behavior, or
decreases in functioning prior to the beginning of active
positive symptoms. These are often the first behaviors
to worry family members and friends.

Prevalence of Comorbid Medical Illness

The mortality rate in persons with schizophrenia is
significantly higher than that of the general population.
While elevated suicide accounts for some of the excess
mortality—and is a serious problem in its own
right—comorbid somatic illnesses also contribute to
excess mortality. Until recently, there was little
information on the prevalence of comorbid medical
illnesses in people with schizophrenia (Jeste et al.,
1996). A recent study was among the first to document
systematically that people with schizophrenia are beset
by vision and dental problems, as well as by high blood
pressure, diabetes, and sexually transmitted diseases.
Their self-reported lifetime rates of high blood pressure
(34.1 percent), diabetes (14.9 percent), and sexually
transmitted diseases (10.0 percent) are higher than
those for people of similar age in the general
population (Dixon et al., 1999; Dixon et al., in press-a).
The reasons for excess medical comorbidity are
unclear, yet medical comorbidity is independently
Mental Health: A Report of the Surgeon General

associated with lower perceived physical health status,
more severe psychosis and depression, and greater
likelihood of a history of a suicide attempt (Dixon et
al., 1999). These findings have important implications
for improving patient management (Dixon et al., in
press-b).

Course and Recovery

It is difficult to study the course of schizophrenia
and other serious mental illnesses because of the
changing nature of diagnosis, treatment, and social
norms (Schultz et al., 1997). Overall, research indicates
that schizophrenia’s course over time varies

considerably from person to person (DSM-IV; Wiersma

et al., 1998) and varies for any one person (Moller &
von Zerssen, 1995). The variability may emanate from
the underlying heterogeneity of the disease process
itself, as well as from biological and genetic
vulnerability, neurocognitive impairments, socio-
cultural stressors, and personal and social factors that
confer protection against stress and vulnerability
(Liberman et al., 1980; Nuechterlein et al., 1994). Most
individuals experience periods of symptom
exacerbation and remission, while others maintain a
steady level of symptoms and disability which can
range from moderate to severe (Wiersma et al., 1998).
Most people experience at least one, often more,
relapse after their first actively psychotic episode (Herz
& Melville, 1980; Falloon, 1984; Gaebel et al., 1993;
Wiersma et al., 1998). Often these are periods of more
intense positive symptoms, yet the person continues to
struggle with negative symptoms in between episodes
(Gupta et al., 1997; Schultz et al., 1997). However,
whether such exacerbations have the same degree of
disabling and distressing effects each time depends
greatly on the person’s coping skills and support
system. Over time, many people learn successful ways
of managing even severe symptoms to moderate their
disruptiveness to daily life (e.g., Hamera et al., 1992).
Therefore, earlier years with the illness are often more
difficult than later ones. Additionally, gradual onset
and delays in obtaining treatment seem to raise the risk
of longer episodes of acute illness over time (Wiersma
-et al., 1998). Early treatment with antipsychotic

274

medications has been found to predict better long-term
outcomes for people experiencing their first psychotic
episode, as compared with a variety of control groups,
including those in more advanced stages (Lieberman et
al., 1996; Wyatt et al., 1997, 1998; Wyatt & Henter,
1998).
The course of schizophrenia is also influenced by
personal orientation and motivation, and by supports in
the form of skill-building assistance and rehabilitation
(Lieberman et al., 1996; Awad et al., 1997; Hafner &
an der Heiden, 1997). These, in turn, are heavily
influenced by regional, cultural, and socioeconomic
factors in addition to individual factors (Dassori et al.,
1995).

Family factors also are related to the course of
illness. Following hospitalization, patients who return
home are more likely to relapse if their family is
identified as critical, hostile, or emotionally
overinvolved than if their family is not so identified
(Jenkins & Karno, 1992; Bebbington & Kuipers, 1994).
This is a controversial finding because it appears to
blame -family members (Hatfield et al., 1987).
However, recent studies suggest an interaction between
families and the patient (Goldstein, 1995b), suggesting
that the negative emotions of some family members
may be a reaction to, more than a cause of relapse in,
the family member. Blaming either the family or the
patient overlooks important ways both parties interact
and how such interactions are associated with the
course of schizophrenia. In addition, there is a need to
examine what part the role of families’ prosocial
functioning (family warmth and family support) plays
in the course of schizophrenia to identify how family
factors can serve as protective factors (Lopez et al., in
press).

Despite the variability, some generalizations about
the long-term course of schizophrenia are possible
largely on the basis of longitudinal research. A small
percentage (10 percent. or so) of patients seem to
remain severely ill over long periods of time (Jablensky
et al., 1992; Gerbaldo et al., 1995). Most do not return
to their prior state of mental function. Yet several long-
term studies reveal that about one-half to two-thirds of
people with schizophrenia significantly improve or
recover, some completely (for a review see Harding et
al., 1992). These studies were important because they
began to dispel the traditional view, dating back to the
19th century, that schizophrenia had a uniformly
downhill course (Harding et al., 1992). Several other
longitudinal studies, however, found less favorable
patient outcomes with other cohorts of patients
(Harrow et al., 1997). The differences in outcomes
between the studies are thought to be explained on the
basis of differences in patient age, length of followup,
expectations about prognosis, and types of services
received (Harrow et al., 1997).

The importance of a rehabilitation focus in shaping
patient outcome was supported by one of the only
direct comparisons between patient cohorts. The
Vermont cohort consisted of the most severely affected
patients from the “back wards” of the state hospital
(Harding et al., 1987). As part of a statewide program
of deinstitutionalization, the cohort was released in the
1950s to a hospital-based rehabilitation program and
then to what was at the time an innovative, broad-based
community rehabilitation program, which incorporated
social, residential, and vocational components.’
Patients’ degree of recovery at followup after three
decades was measured by global functional
improvement and other functional measures. One-half
to two-thirds of the Vermont cohort significantly
improved or recovered (Harding et al., 1987). The
receipt of community-based rehabilitation was
considered key to their recovery on the basis of a study
comparing their progress with that of a matched cohort
of deinstitutionalized patients from Maine. The Maine
cohort did not function as well after receiving more
traditional aftercare services without a rehabilitation
emphasis (DeSisto et al., 1995a, 1995b). Although the
findings from the Vermont cohort, as well as those
from a cohort in Switzerland (Ciompi, 1980), are
widely cited by consumers as evidence of recovery
from mental illness, a topic discussed in detail in
Chapter 2, it bears noting that patients in the Vermont
cohort represented a less rigorously defined

 

13 . :
These are the vital components of most contemporary rehabil-
itation programs (see section on service delivery).

275

Adults and Mental Health

conceptualization of schizophrenia than is common
today, which may account, in part, for the more
favorable outcomes.

In summary, schizophrenia does not follow a single
pathway. Rather, like other mental and somatic
disorders, course and recovery are determined by a
constellation of biological, psychological, and
sociocultural factors. That different degrees of recovery
are attainable has offered hope to consumers and
families.

Gender and Age at Onset

There appear to be gender differences in the course and
prognosis of schizophrenia. Women are more likely
than men to experience later onset, more pronounced
mood symptoms, and better prognosis (DSM-IV),
although the prognosis difference recently has come
under question.

Current research (e.g., Hafner & an der Heiden,
1997; Hafner et al., 1998) suggests that some of the
apparent gender differences in course and outcome
occur because for some women schizophrenia does not
develop until after menopause. This delay is thought to
be related to the protective effects of estrogen, the
levels of which diminish at menopause. According to
this line of reasoning, men have no such delay because
they lack the protective estrogen levels. Therefore, a
higher proportion of men develop schizophrenia earlier.

Generally, early onset (younger than age 25 in most
studies) is associated with more gradual development
of symptoms, more prominent negative symptoms
across the course (DSM-IV), and more neuro-
psychological problems (Basso et al., 1997; Symonds
et al., 1997), regardless of gender. Early onset also
usually involves more disruption of adult milestones,
such as education, employment achievements, and
long-term social relationships (Nowotny et al., 1996).
People with later onset often have reached these
milestones, cushioning them from disruptive sequelae
and enabling better coping with symptoms (Hafner et
al., 1998). Therefore, early onset (more men than
women) often yields a more difficult first several years,
although not necessarily a worse long-term outcome.