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Psychother Psychosom 1998;67:125–132
Michael A. Weitzner
H. Lee Moffitt Cancer Center,
Tampa, Fla., USA
Neuropsychiatry and Pituitary
Disease: An Overview
................................................... ...........................................................................................................
Key Words
It has been recognized for some time that psychiatric symptoms, such as
depression, anxiety, and behavioral alterations, may occur in patients who
have pituitary disease. From other research focused on endocrine abnormalities seen in patients with psychiatric illness, it is understood that there is a
significant interrelationship between the endocrine system and mental health.
More recent research focusing on neural circuits in the brain and the impact
of alterations in neurotransmission and neurohormonal modulation has
shown that the prefrontal cortex can be affected by perturbations in functioning occurring in distant sites. Such is the situation with the hypothalamicpituitary axis. Through its rich connections with other limbic structures, the
hypothalamic-pituitary axis may affect the behavioral control exerted by the
prefrontal cortex, causing mood and personality alterations. In the more
severe cases, an apathy syndrome may develop which must be carefully differentiated from depression and other cognitive disorders. This report will review:
(1) the neuroanatomical components that cause the behavioral changes observed in many patients with pituitary disease; (2) the current concept of
apathy syndrome; (3) the differentiation of apathy syndrome from major
depression; (4) the underlying neurobiology of apathy, and (5) potential treatments.
Ó1998 S. Karger AG, Basel
E-Mail [email protected]
Fax+41 61 306 12 34
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Psychoneuroendocrinological research pertaining to
the hypothalamic-pituitary-adrenocortical axis (HPA)
has shed much light on the association of psychiatric
illness with endocrine abnormalities [7]. Research in major depression has documented abnormalities in the HPA
[7]. It has also been shown that the majority of patients
with depression will not recover from their depression
unless the HPA disturbance is corrected. They also remain at risk for relapse of their depression [8–12]. Research suggests that, in addition to major depression,
senescence and stressful life events cause an increase in
endogenous corticosteroids. This elevation in endogenous
corticosteroids may account for the down-regulation of
hippocampal glucocorticoid receptors. The hippocampus
Michael A. Weitzner, MD
Psychosocial Oncology Program
H. Lee Moffitt Cancer Center
12902 Magnolia Drive
Tampa, FL 33612 (USA)
Tel. +1 (813) 972 8483, Fax +1 (813) 979 3906, E-Mail [email protected]
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Psychiatric symptomatology in endocrine disorders
and pituitary disease has long been recognized [1–3].
Cushing himself had an appreciation for the association
between psychosomatic illness and endocrine disorders.
He was very interested in whether stress caused the pituitary dysfunction, or whether the pituitary disease induced the stress he observed in many of his patients.
Similarly, he wondered whether other psychiatric symptoms he observed, such as depression and anxiety, were
due to the hormonal alterations caused by the pituitary
disease [4]. As a result of these early ponderings, much
work has been done recently on the relationship of endocrine disease to psychiatric disease [5, 6] and on the limbichypothalamic control of hormonal function [7].
The Frontal Lobes and the Limbic System
In any discussion of apathy, one must first begin with
a review of the involved neuroanatomical components;
the frontal lobes and the limbic system. The frontal lobes
are our ‘governing bodies’ for behavior and they may be
affected not only by direct insults such as trauma or
space-occupying lesions, but also by problems that arise
in other, more distant parts of the brain, such as the
hypothalamus and pituitary gland [19]. Diaschisis refers
to this effect of dysfunction of distant areas of the brain
Psychother Psychosom 1998;67:125–132
on the frontal lobes and is related to the disruption in
normal neurotransmission between different areas of the
brain caused by destructive lesions, trauma, or neurochemical alterations [20]. Behavior, then, is comprised of
two components: (1) environmental influences (i.e., family,
work, stress, etc.) and (2) biological influences (i.e., frontal
lobe and limbic system) [21]. The frontal lobe has three
major anatomical aspects: (1) dorsolateral; (2) medial,
and (3) orbital. Pyramidal and extrapyramidal disorders
are the result of dysfunction of the motor and premotor
areas of the frontal lobe and are not the focus of this
discussion. Rather, this discussion will focus on the disorders resulting from dysfunction of the associative cortex
of the frontal lobe (i.e., the prefrontal cortex) and the
impact they have on hypothalamic-pituitary function and
vice versa [22].
The prefrontal cortex is comprised of the cortical
projections from the mediodorsal nucleus of the thalamus
[19]. The function of the dorsolateral prefrontal cortex
is primarily cognitive, while the orbital and medial prefrontal areas are mainly responsible for attentional,
affective, and emotional function [22]. The prefrontal cortex has major afferent input from the limbic system. The
limbic system was a construct developed to reemphasize
the neuroanatomical correlates of emotion, as espoused
by Papez [23, 24]. Papez’s circuit describes the simplistic
anatomical notion of how the cerebral cortex influences
the hypothalamus (the building up of the ‘emotive process’) and how the latter influences the cerebral cortex
(‘psychic coloring’) [25]. Newer experimental neuroanatomical techniques developed over the past 40 years have
led to an expanded conception of the limbic system both
in neuroanatomical and functional terms [25].
The limbic system represents a functional complex of
the prefrontal cortex, diencephalon, and brainstem that
are structurally and functionally interrelated. On a functional level, this complex is thought to be directly involved
in processes important to survival, including the following: (1) homeostasis (i.e., modulation of hormone release,
initiation of feeding and drinking behavior, activation
of visceral effector mechanisms); (2) defense and attack
behavior, and (3) sexual and reproductive behavior [26].
On a structural level, the limbic system is comprised of
the prefrontal cortex, septal and preoptic regions, hippocampus, amygdala, the bed nucleus of the stria terminalis,
epithalamus, hypothalamus, anterior and medial thalamus, the ventral tegmental area, and the interpeduncular
nucleus (fig. 1) [19, 26].
The hypothalamic-pituitary axis plays an important
role in the limbic system. It is well understood that the
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is an important regulatory site for limbic-hypothalamicpituitary-adrenal feedback and may play a very important
role in the emotional and cognitive impact of pituitary
disease [13, 14].
Much of the research conducted on the role of endocrine dysfunction in psychiatric illness has bearing on our
understanding of the psychiatric symptoms that result
from pituitary disease. There is much anecdotal evidence
suggesting that psychological or mental symptoms may
herald the onset of endocrine disorders [15]. These may
represent the first signs of hormonal instability, due to
the sensitivity of the brain to small changes in hormonal
levels, or they may reflect a predisposition for hypothalamic-pituitary activation [16]. For example, patients with
Cushing’s disease often demonstrate pronounced psychopathology, including mental changes with depression,
lethargy, cyclic mood instability, impaired cognitive function, deficits in concentration and memory and vegetative
signs such as sleeplessness [17]. These mental symptoms
may predate the physical changes that are more obviously
diagnostic of the patient with Cushing’s disease.
Patients with pituitary disease may have many different
psychiatric presentations, including depression, anxiety, behavioral disturbances, and personality alterations. Another,
more recently described condition, which may be seen in
patients with pituitary disease is apathy syndrome. Apathy
syndrome is a neuropsychiatric condition that is commonly
seen in patients who have brain disease, including those with
hypothalamic-pituitary dysfunction [18]. It is thought that
disruption of normal brain functioning, either on a structural or neurohormonal level, may lead to an apathy syndrome. This report will review: (1) the neuroanatomical
components that cause the behavioral changes observed in
many patients with pituitary disease; (2) the current concept
of apathy syndrome; (3) the differentiation of apathy syndrome from major depression; (4) the underlying neurobiology of apathy, and (5) potential treatments.
Fig. 1. Summary of the limbohypothalamic complex. Subdivision of the area into
central units and limbic rings. H>hypothalamus; LMA>limbic midbrain area; PO>
preoptic region; S>septum. Reprinted with
permission from Nieuwenhuys et al. [26].
Copyright Springer, Heidelberg.
The role of the prefrontal cortex and the limbic structures in the regulation of behavior cannot be overempha-
sized. These areas have primary responsibility for motivation and drive. Apathy may occur throughout the lifespan
and has been described as a symptom, as a specific clinical
syndrome, and as a dimension of behavior [18, 30, 31].
Certainly, apathy has been described as an important
symptom in psychiatric illness, particularly schizophrenia
and depression. Apathy has been used to describe the
lack of interest, lack of feeling, lack of concern, indifference, flat affect, and emotional unresponsiveness characteristic of depression [32, 33]. It is evident, however, that
lack of emotion or interest is not a coherent definition
of apathy. Defining apathy in this way creates ambiguity
since the emotional state of a person and the motivation
that person has to do things are not the same. Neuropeptide and neurotransmitter research has allowed apathy to
emerge as a clinical syndrome [34–36]. From a neuropsychiatric perspective, apathy reflects the absence of motivation and drive seen in frontal lobe dysfunction but which
can also be present in other neurological disorders [37].
This syndrome of apathy has direct bearing on pituitary
disease given the important role the hypothalamus has
on motivation.
Apathy has three components: (1) observable behavior,
such as decreased goal-directed behavior; (2) emotional
content, such as decreased emotional reactivity and dis-
Neuropsychiatry and Pituitary Disease
Psychother Psychosom 1998;67:125–132
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major responsibility of the hypothalamus and pituitary
gland is the maintenance of the internal milieu. They are
responsible for coordinating electrolyte balance, blood
glucose levels, basal temperature, metabolic rate, autonomic tone, sexual phase, circadian oscillations, immunoregulation, and certain aspects of emotional functioning
and attention [27, 28]. Structurally, the HPA has close
connections with certain limbic structures, including the
mediodorsal nucleus of the thalamus [26]. Consequently,
the HPA may have indirect effects on the prefrontal cortex, thereby playing an important role in the regulation
of four types of behavior: (1) memory and learning;
(2) modulation of drive; (3) affective coloring of experience, and (4) higher control of hormonal and autonomic
tone [29]. As mentioned previously, there is a relationship
between endocrine function and stress. Thus, the impact
that the HPA has on the four behavioral functions mentioned above is also determined by the degree of acute
or chronic psychological stress that is present [16].
Apathy: Motivation versus Depression
The biggest challenge for the clinician is the differentiation of the symptom of apathy related to emotional,
cognitive, or medical problems from the syndrome of
apathy that is due to amotivation. As mentioned previously, associating apathy with amotivation implies a decrease in goal-directed behavior [33] with the problem
resulting from a disruption in the motivational functions
of the neural circuits linking the prefrontal cortex, amygdala, and subcortical nuclei, including the nucleus accumbens, globus pallidus, medial dorsal nucleus of the thalamus, and ventral tegmental area [41–43].
Perhaps the most difficult differentiation is between
apathy syndrome and major depression. A primary difference between the two is the decreased motivation that
defines apathy syndrome. Major depression is characterized primarily as a disturbance in mood. Thus, the emotional and cognitive domains are most useful in this
differentiation. From an emotional perspective, patients
with apathy syndrome do not admit to feeling down or
depressed. In addition, they will show similar blunted
emotional responses to both positive and negative rewards. Patients with major depression admit to feeling
Psychother Psychosom 1998;67:125–132
depressed and tend to perceive and respond selectively
to negative events. From a cognitive domain perspective,
the patient with depression has pervasive negative cognition [44]. For patients with apathy syndrome, however,
there is lack of concern, with diminution of goals, interests, and curiosity [39]. For those patients with depression
who describe a lack of interest, it is most often reflective
of despair, hopelessness, and pessimism. Therefore, the
lack of interest seen in patients with major depression
is reflective of their cognitive distortions of failure in
achieving goals, whereas patients with apathy syndrome
actually devalued their goals and so are truly unconcerned
The Neurobiology of Apathy Syndrome
We know that neurological diseases affecting the
frontal lobes, such as dementia, traumatic brain injuries,
strokes, and tumors, produce changes in personality and
behavior leading to amotivation and apathy syndromes
[37]. Symptoms of frontal lobe disease include problems
initiating behavior, repetitive or perseverative behavior,
decreased social involvement, and lack of empathy [33].
These symptoms may also be seen in patients with pituitary disease.
Each frontal region is part of a specific corticalsubcortical circuit involving the thalamus, basal ganglia,
and forebrain nuclei and damage to a specific frontal
region or its subcortical components produces the same
syndrome [41, 45, 46]. Three of the syndromes produced
by frontal lobe damage involve apathy: (1) mesiofrontal
damage involving the cingulate gyrus produces apathy;
(2) dorsolateral frontal damage produces apathy associated with impairment in executive cognitive capacities
necessary for planning and monitoring goal-directed behavior, and (3) orbitofrontal damage causes changes in
personality marked by irritability, angry outbursts, disinhibited sexual behavior, with an underlying background
of abulia and apathy [33, 47]. These frontal regions are
connected to specific regions of the caudate nucleus, nucleus accumbens, globus pallidus, and medial dorsal nucleus of the thalamus. Injury to or any alteration of any
component of these three circuits produces the behavioral
and cognitive symptoms characteristic of that circuit
(fig. 2) [45].
In addition to the classic prefrontal cortex syndromes,
perturbations in the thalamus may also cause behavioral
problems. Damage or disruption to the mediodorsal nuclei of the thalamus produce neuropsychological deficits
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tress, and (3) thought content, as evidenced by decreased
goal-directed cognition, future goals, interests, and curiosity [38, 39]. It is not simply the lack of emotion that
defines apathy; it is the presence of diminished emotional
responsiveness to goal-related events and decreased emotional distress. It is, therefore, the ‘not caring’ that defines
apathy. This problem is particularly difficult to assess and
manage [33]. The primary reason for this difficulty relates
to the fact that the patient suffering from apathy rarely
self-refers for an evaluation of apathy and it is seldom
recognized by clinicians. The patient with more severe
apathy may not recognize it for what it is, while the patient
with a milder form of apathy may not comment about
the apathy. In either situation, it is not taken seriously
by the family or the health care professional. Many times
it is discounted by families, patients, and health care
professionals as depression or ‘s(he) is just feeling sorry
for her(him)self’. However, apathy may add further stress
to a family that is already heavily stressed by the illness
[33, 40]. It can also place a tremendous burden on the
spouse or significant other who must take on additional
responsibilities of the household, personal and family
relationship that would have been done by the person
with apathy.
Fig. 2. Organization of the three frontalsubcortical circuits in which lesions produce
apathy as a symptom associated with other
changes in cognition and personality (dorsolateral and lateral orbital cortex) or as the
defining feature of the clinical syndrome (anterior cingulate cortex). VA>ventral anterior. MD>medial dorsal. Reprinted from
Cummings [45]. Used with permission. Copyright 1993, American Medical Association.
and behavioral disturbances. Reactions from dysphoria
and irritability to silly cheerfulness and disinhibition have
been observed [48]. Memory impairment, apathy, and
distractibility have also been shown to occur with disruption to the thalamus [49, 50]. Since the HPA provides
significant afferent input to the mediodorsal nucleus of
the thalamus, any perturbation in hypothalamic-pituitary
function will affect the frontal-subcortical circuits and
cause apathy syndrome. Dysfunction of the diencephalon
and amygdala may also produce apathy syndromes since
they are critical structures for the organization of motivational processes. The amygdala activates broad areas of
the hypothalamus and brain stem in response to motivationally significant events [33].
Mesocortical and mesolimbic dopaminergic tracts are
thought to be important in the development of apathy,
presumably due to dopamine hypoactivity, and increasing
dopaminergic activity is the primary strategy for treatment of apathy syndrome [42, 51]. It is thought that
the mesocortical tract hypoactivity causes the impaired
executive functioning while the mesolimbic tract hypoactivity is responsible for the affective component to apathy
[51]. The ventral tegmental area, from where both the
mesocortical and mesolimbic tracts originate, innervates
not only the prefrontal cortex but also the nucleus accumbens, amygdala, hippocampus, ventral pallidum, mediodorsal nucleus of the thalamus, pedunculopontine region
of the brain stem, and the hypothalamus. These interrelated structures represent the motivational state of the
organism and serve to translate motivation into action
(fig. 3) [33, 52].
As already mentioned, there is a significant association
between pituitary disease and psychiatric illness. Major
depression, significant anxiety, and behavioral and personality changes have been documented [16, 53, 54]. It is
also understood that many of the psychiatric disturbances
seen in pituitary disease are directly related to the effect
of the tumor, both direct and indirect, or hormonal alterations occurring as a result of the tumor [55]. The neural
network and the neuroanatomy of the apathy syndrome
have been discussed. Disruption to these pathways leading to the observed psychiatric disturbances in pituitary
disease are the result of extensions of the tumor beyond
the sella turcica or neuroendocrine effects of the tumor
itself. Upward extension of the tumor occurs in the direction of the third ventricle, causing mental symptoms typical of diencephalic tumors: (1) complex disorders of
movement and behavior; (2) memory disturbances [55].
Forward extension may involve the frontal lobes causing
compression of normal brain tissue. This scenario would
cause involvement of areas responsible for higher level
executive and cognitive functions, resulting in impaired
problem-solving behavior, less regulation of attention,
problems with temporal organization of behavior, and
decreased modulation of affective states. People tend to
be more irritable and are depressed-appearing. Forward
extension may occur laterally to the temporal lobes. Problems tend to be more personality-focused, with increased
irritability, intensification of previous dominant personality traits, coping mechanisms, and adaptive styles.
Neuropsychiatry and Pituitary Disease
Psychother Psychosom 1998;67:125–132
Pituitary Disease and Psychiatric Symptoms
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Fig. 3. The motive circuit responsible for
translating motivationally relevant environmental stimuli into adaptive motor responses.
The circuit lies partly in classic limbic structures, such as the amygdala and hippocampus, and transmits to classic motor output
systems, such as the motor cortex, basal ganglia, and reticulospinal tract. MD>mediodorsal thalamus. NA>nucleus accumbens.
PFC>prefrontal cortex. PPN>pedunculopontine motor region. VP>ventral pallidum.
VTA>ventral tegmental area. Reprinted
with permission from Kalivas and Barnes
[42]. Copyright CRC Press, Boca Raton, Fla.
The first element in treatment of apathy syndrome is
education of the patient and family. It is important that
patients and families know the difference between the
symptom of apathy as it pertains to depression and the
syndrome of apathy. This knowledge is helpful in putting
the patient’s dysfunction in perspective and allaying their
concern that the patient is depressed and is not aware of
it. Patients’ and families’ understanding of the patient’s
behavioral limitations from a neurological perspective is
also important so that they are not blamed, by themselves
or their families, for their inactivity or lack of concern
for others. A neuropsychological evaluation is important
Psychother Psychosom 1998;67:125–132
to document any cognitive impairment and functional
limitations need to be interpreted in light of the neurocognitive deficits present. When neurocognitive deficits are
present, cognitive rehabilitation becomes an important
component of the treatment of apathy syndrome [57].
Cognitive rehabilitation entails combining adaptive environmental interventions and prosthetic devices with rehabilitative counseling. Rehabilitative counseling seeks to
make optimal use of residual capacities and at the same
time to foster development of new skills and sources of
gratification [38, 58].
The next step in treatment is to optimize management
of the primary medical or neurological disease. Endocrine
abnormalities require direct treatment. To be effective, apathy must be a specific target of treatment. Apathy and related symptoms may be side effects of selective serotonin
reuptake inhibitors or neuroleptics. Fluoxetine, fluvoxamine [59] and paroxetine [60] have been shown to cause amotivation and disinterest, which is oftentimes alleviated by
dose reduction. Sertraline, venlafaxine, and buproprion
may be preferable alternatives since they have not been
shown to cause amotivation [61]. Apathy that is associated
with depression should be treated with an antidepressant,
preferably one that targets norepinephrine and dopamine,
such as buproprion. If apathy continues even after the depressive symptoms have resolved, then stimulant therapy
should be considered. However, this residual apathy may
also be related to preexisting frontal-subcortical disease
which warrants further diagnostic evaluation and treatment [62, 63]. Dopamine agonist drugs and/or stimulants
are oftentimes very helpful in the improvement of the ap-
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Neuropsychological impairment occurs in patients
with pituitary tumors. Studies have documented problems
with executive functioning, verbal memory, and visual
memory. These deficits have been shown to occur even
in the absence of cranial irradiation. Causative factors
are thought to be: (1) damage to the hypothalamus by the
tumor; (2) surgical trauma to the frontal lobes; (3) postoperative infection or hemorrhage; (4) hydrocephalus;
(5) irradiation; (6) endocrine abnormalities causing myxedema, hypoglycemia, sleep apnea, or psychosis, and
(7) depression associated with chronic ill-health and multiple hospital admissions. There also appears to be an
association between neuropsychological impairment and
tumor size and type, surgical procedure, and previous
irradiation [56].
athy seen in these patients [40]. Stimulants have also been
found to have a significant role in the treatment of the apathy experienced by patients with primary brain tumors
[Meyers et al., unpub. data] [64].
Apathy, then, is more than merely a symptom; it is a
syndrome. A unifying explanation for the presence of
apathy syndrome in patients with pituitary disease is that
apathy is caused by a disturbance of neurotransmission
or neuromodulation at the level of the hypothalamic
microenvironment. This disturbance in the HPA has indirect effects on prefrontal lobe function by virtue of its
more direct disruption in neurotransmission in the medial
dorsal nucleus of the thalamus. The hypothalamus is strategically placed between neural systems associated with
the amnesia syndromes (i.e., hippocampus, amygdala,
mammillary bodies, medial dorsal thalamus, and basal
forebrain). It is the center of neuroendocrine, autonomic,
and homeostatic regulation and has a major role in the
expression of emotional behavior. It also has major input
to and receives output from other components of the
limbic system. Finally, many hypothalamic peptides are
thought to serve as neuromodulators as well as having a
role in anterior pituitary function. Normal patterns of
secretion are likely to be easily disrupted by pituitary
tumors and/or their treatment. Treatment for these emotional and behavioral problems is available but is rather
intricate, oftentimes involving the use of multiple medications which affect different neurotransmitters. Medications are also only part of the treatment. Individual and
family counseling is often necessary to help the person
and the family system adapt to this major disruption.
Families are often emotionally exhausted by the emotional roller-coaster rides the person with pituitary disease experiences. Without professional help, previously
well-adapted and functioning families are destroyed not
by the tumor itself, but the emotional havoc wrought in
its wake. This is preventable; it only takes a mind willing
to see ‘the forest through the trees.’
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