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 Abstract Pituitary Neuropsychiatry Psychosomatics Behavior 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 0033–3190/98/0673–0125$15.00/0 E-Mail email@example.com Fax+41 61 306 12 34 http://www.karger.com This article is also accessible online at: http://BioMedNet.com/karger Psychoneuroendocrinological research pertaining to the hypothalamic-pituitary-adrenocortical axis (HPA) has shed much light on the association of psychiatric illness with endocrine abnormalities . Research in major depression has documented abnormalities in the HPA . 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 firstname.lastname@example.org Downloaded by: Tufts University 22.214.171.124 - 10/27/2017 12:28:32 PM 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 . 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 . 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 . Diaschisis refers to this effect of dysfunction of distant areas of the brain 126 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 . 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) . 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 . The prefrontal cortex is comprised of the cortical projections from the mediodorsal nucleus of the thalamus . 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 . 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’) . 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 . 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 . 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 Weitzner Downloaded by: Tufts University 126.96.36.199 - 10/27/2017 12:28:32 PM 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 . 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 . 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 . 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 . 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. . 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 . 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 Apathy 127 Downloaded by: Tufts University 188.8.131.52 - 10/27/2017 12:28:32 PM 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 . 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 . 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 . 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  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 128 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 . For patients with apathy syndrome, however, there is lack of concern, with diminution of goals, interests, and curiosity . 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 . Symptoms of frontal lobe disease include problems initiating behavior, repetitive or perseverative behavior, decreased social involvement, and lack of empathy . 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) . 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 Weitzner Downloaded by: Tufts University 184.108.40.206 - 10/27/2017 12:28:32 PM 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 . 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 . Used with permission. Copyright 1993, American Medical Association. and behavioral disturbances. Reactions from dysphoria and irritability to silly cheerfulness and disinhibition have been observed . 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 . 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 . 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 . 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 . 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 Downloaded by: Tufts University 220.127.116.11 - 10/27/2017 12:28:32 PM 129 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 . Copyright CRC Press, Boca Raton, Fla. Treatment 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 130 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 . 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  and paroxetine  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 . 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- Weitzner Downloaded by: Tufts University 18.104.22.168 - 10/27/2017 12:28:32 PM 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 . athy seen in these patients . 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] . Conclusions 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.’ ................................................................................................................................................................. References Neuropsychiatry and Pituitary Disease 9 Greden JF, Gardner R, King D, Grunhaus L, Carroll BJ, Kronfol Z: Dexamethasone suppression tests in antidepressant treatment of melancholia: The process of normalization and testretest reproducibility. 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