There is a need to increase clinicians’ awareness of major depression, because it is one of the most common diseases found in primary care settings and its treatment can be both highly successful and cost-effective (1). At the same time, general medical conditions should always be considered in the differential diagnosis of depression, especially in elderly patients; delays in making the proper diagnosis may lead to a worsening prognosis of underlying medical conditions (2). These complementary approaches are indispensable to the appropriate recognition and management of both psychiatric and general medical conditions in older individuals (3). We present the case of an elderly man who was seen with depressive symptoms. His disease course and clinical evaluations illustrate the importance of an open-minded and balanced approach to diagnosis.
Mr. A was an 86-year-old retired pharmacist who was brought by his son to a geriatric psychiatry inpatient unit after 1 year of noticeable depressive symptoms. He had no history of psychiatric symptoms until age 79. At that time, after a failed business venture, he had several months of depressed mood and social isolation but no major somatic complaints. This episode passed without specific treatment, and Mr. A returned to his normal baseline functioning. He was described as an "outgoing" person. At age 81, Mr. A moved from his retirement home to another state to be closer to his son, a mental health professional. At age 85, Mr. A again developed depressive symptoms, including a depressed mood, anergia, anhedonia, social isolation, poor appetite, decreased concentration, and irritability. Mr. A himself also noted some impairments in short-term and long-term memory, concomitant with the depressive symptoms. Mr. A had adult-onset diabetes mellitus, which was managed with insulin. Four months after the onset of his depressive symptoms, he was taken to a local hospital for a hypoglycemic episode. He was stabilized in the emergency room without complications. After Mr. A’s discharge home, his son noted that his anergia, anhedonia, social withdrawal, and irritability worsened. Diminished sexual function as well as reduced ability to carry out daily routines were reported by Mr. A’s son to be associated with his depressive symptoms.
Mr. A was the oldest of three children. He graduated with a pharmacy degree. He spent 2 years in military service, saw no combat, and received an honorable discharge. Subsequently, Mr. A worked as a pharmacist in a large city for many years and had considerable financial success with his own business. He was married twice. His first wife died of cancer, and he had separated amicably from his second wife at age 84. His only child, a son from his first marriage, was a mental health professional. At age 81 he moved into a detached single apartment on his son’s property. Mr. A used alcohol only socially, had a history of smoking 50 packs per year (he quit at about age 60), and never used street drugs. There was no known family history of major depression.
Formerly at a high level of functioning, Mr. A had failed his written driver’s test three times in the 3 months before his admission; he reported feeling distressed over these failures. Mr. A also began having erectile dysfunction, which, his son noted, might have had an impact on his self-esteem. At that time, Mr. A received a prescription for methylphenidate (5 mg/day) for a diagnosis of major depression. No therapeutic response was noted. Several weeks later Mr. A began to express hopelessness. At about this time his medication was switched to sertraline (25 mg/day and then 50 mg/day). One month before his admission, it was noted that Mr. A had lost nearly 30 lb over the previous several months. He was seen by a gastroenterologist for an outpatient evaluation of his weight loss, which was reportedly negative. The thoroughness of his examination was unclear to us, but it was presumed to have included endoscopy. Mr. A continued generally to deteriorate, although his cognition seemed to have improved after switching to treatment with sertraline. He developed new somatic complaints 3 weeks before admission. Mr. A began complaining of intermittent diffuse cramping pain in his abdomen. The pain varied in duration and intensity and was not notably related to meals or bowel movements, although there was some alleviation with positional change. Two weeks before admission, Mr. A also began complaining of lower back pain that he did not characterize but that he did not associate with his abdominal pain. One week later, he began refusing to leave his bed because of both lack of motivation and pain.
Initial Mental Status Examination
At admission, Mr. A appeared to be his stated age and was well groomed, but he appeared cachectic and was holding his abdomen and rocking. He was, however, cooperative with the examination and extremely polite. He was alert, and his orientation was intact. Mr. A reported that his mood was depressed; his affect was noted to be constricted. His speech was goal-directed with a normal rate, rhythm, and volume. He expressed vague suicidal ideation but neither intent nor plan. He did not report any homicidal ideation, hallucinations, or delusions. On the Mini-Mental State examination (4), he scored 27 out of a possible 30. His score was less than perfect because he was unable to name the state and county he was in and was unable to recall one of the three words he was asked to commit to memory for 5 minutes. Mr. A’s insight and judgment were recorded as being intact.
Medical History and Examination
Mr. A had adult-onset diabetes mellitus, which had been diagnosed years earlier, and benign prostatic hyperplasia. He also had peripheral vascular disease with intermittent claudication; 1 year before admission, he had been diagnosed with bilateral iliac artery thromboses. His surgical history included a cholecystectomy at age 65. He did not report experiencing any recent fever, nausea, vomiting, or bowel changes. He was taking the following medications: docusate sodium (500 mg/day orally) for chronic constipation, sertraline (50 mg/day) for depression, pentoxifylline (400 mg t.i.d. orally) for claudication, terazosin (10 mg orally at bedtime) for benign prostatic hyperplasia, and isophane insulin (25 U subcutaneously every morning) for type II diabetes mellitus. He weighed 119 lb; the ideal weight for a man of his height was estimated to be 148 lb. His systolic blood pressure was elevated, 162 mm Hg, but he had normal diastolic pressure (79 mm Hg) and a normal heart rate (79 bpm). His respiratory rate and oral temperature were normal. The results of his general physical examination were notable for abdominal tenderness to palpation without palpable mass in the right upper quadrant, an absence of lymphadenopathy, a loud bruit over his aorta and bilateral iliac arteries, generalized weakness, and a symmetrically enlarged prostate. The results of his head, heart, lung, abdomen, back, integument, and musculoskeletal examinations were otherwise benign, and his rectal examination was negative for occult bleeding. A neurologic examination revealed only an unsteady gait.
Mr. A was admitted to a geriatric psychiatry inpatient unit to assess fully his depressive symptoms, cognitive decline, and weight loss. He continued to receive sertraline, and he was given a combination of acetaminophen and hydrocodone bitartrate as needed for pain. The results of blood chemistry, coagulation, and liver panels and a CBC were abnormal only for an elevated blood glucose level of 220 mg/dl. Mr. A’s hemoglobin A1c level was 11.9%, indicating poor diabetes control. His thyroid stimulating hormone (TSH) level was 4.85 mU/liter, which was within normal limits, and his prostate-specific antigen level was 6.9 ng/ml, which was consistent with his benign prostatic hyperplasia. His vitamin B12 and folate levels were normal. The results of a urinalysis revealed abnormally high glucose and protein levels and large amounts of blood. An ECG revealed a right bundle branch block. A computerized tomography (CT) scan of his head without contrast showed scattered involutional changes that were greater than expected for Mr. A’s age and foci of low density in the right cerebellum and left frontal deep white matter. These were thought to represent old infarcts.
Mr. A was socially isolative, lying alone in bed and resisting interaction with other patients. While he continued complaining of abdominal pain, he ate close to 100% of all his meals. He consistently refused help with dressing and grooming and was able to accomplish both adequately. He did have occasional bouts of confusion; he was unable to keep track of which grooming activities he had completed. On neuropsychological testing, Mr. A scored 123 out of 144 on the Mattis Dementia Rating Scale (5), indicating mild to moderate global cognitive impairment.
Mr. A underwent a general ultrasound survey of his abdomen in order to investigate his abdominal pain. A 6-cm heterogeneous mass was visualized adjacent to the pancreatic head, and the left hepatic lobe was prominent and diffusely heterogeneous. An abdominal CT scan without contrast was then performed for better characterization of the lesion, confirming that the mass was heterogeneous, was centered on the pancreatic head, and appeared to encase the gastric antrum. The mass was thought to be either a pancreatic pseudocyst or a pancreatic cancer. Also noted was a single 1.5-cm, low-density lesion in the left hepatic lobe, which was possibly a metastasis.
Mr. A showed appropriate concern over these findings and consented to an ultrasound-guided biopsy of the pancreatic mass, which was then performed by the interventional radiology service. A pathologic examination of the biopsy revealed a poorly differentiated pancreatic adenocarcinoma. The prognosis, given the advanced stage of disease and the histopathology, was poor. There was a significant risk of gastric outlet obstruction. Radiation treatment and chemotherapy were offered for palliation.
Over the next 10 days, Mr. A remained in the hospital with increasing depressive symptoms and delirium, including delusions and disorientation. His symptoms were noted to vary directly with his dose of intravenous narcotics for the control of abdominal pain. The delirium was considered multifactorial in etiology; it was secondary to the primary disease, his intermittent constipation, and the narcotics taken for pain control. Aggressive bowel care and reductions in the pain-control drug regimen offered some improvement. After a 16-day stay, Mr. A was discharged for home with a 24-hour caregiver; his care was to be managed by a home hospice. He received adequate pain control, although his delirium and depression persisted. For these symptoms, he continued taking sertraline (50 mg/day), methylphenidate (5 mg/day), and clonazepam (0.5 mg at bedtime). Mr. A reportedly died from complications of his pancreatic cancer several months after his discharge.
In summary, Mr. A had had one episode of depression at age 79. He was seen at age 86 with 1 year of increasing depressive symptoms, subsequently developed weight loss, and finally suffered cramping abdominal and back pain. He did not respond to trials of low doses of methylphenidate or to sertraline treatment. A medical evaluation after admission to a geriatric psychiatry inpatient unit revealed a poorly differentiated adenocarcinoma of the pancreatic head, with a possible liver metastasis and impending gastroduodenal obstruction.
Mr. A likely experienced several neuropsychiatric pathologic processes, including forms of depression, dementia, and delirium. Although his most important diagnosis was ultimately pancreatic adenocarcinoma, throughout the course of his illness, various neuropsychiatric conditions were manifested. We will discuss the differential diagnosis for Mr. A at different stages of his clinical course. For each diagnosis discussed, we will note the corresponding codes from DSM-IV.
First Episode of Depression
At age 79, with no prior psychiatric history, Mr. A had experienced several months of depressed mood and social isolation after a failed business venture. He did not seek treatment, and the episode was self-limited. When this history was elicited (7 years later), it was unclear whether other manifestations might have been present, although Mr. A did not report somatic symptoms. Depending on the other symptoms present, this episode might have represented a major depressive disorder, single episode, mild (DSM 296.21). If the criteria for major depression had not been met, this episode would have been diagnosed as minor depressive disorder (DSM 311). Alternatively, since the episode occurred within 3 months of the failure of Mr. A’s business venture, if the symptoms were thought to be in response to that failure, adjustment disorder with depressed mood (DSM 309.0) would have been the appropriate diagnosis. Given Mr. A’s history of diabetes and vascular disease, an underlying general medical etiology might have been considered. It is unlikely, however, that the episode was related to these general medical conditions in view of his complete recovery and certainly not to his subsequent pancreatic cancer, given the time separation.
Second Episode of Depression
At age 85, Mr. A began experiencing depressive symptoms that met the criteria for major depressive disorder. He had no manic or psychotic symptoms. Depending on the classification of his prior depressive episode, he could have been given a diagnosis of major depressive disorder, severe, without psychotic features—either recurrent (DSM 296.33) or single episode (DSM 296.23). In the latter case, the presence of infarcts on a CT scan might have been viewed as "vascular depression" (6). General medical causes, as previously mentioned, should have been considered, although a general workup might not have been productive at the early stage of Mr. A’s disease.
At about the same time, Mr. A began having memory changes, causing mild impairment. Had this been regarded as part of the normal aging process, the diagnosis of exclusion, i.e., age-related, cognitive decline (DSM 780.9) could have been considered after ruling out other etiologies. Nine months after the noted onset of memory loss, Mr. A demonstrated some decline in executive functioning by failing his driver’s license test three times. He met the criteria for dementia at that time, which could have also accounted for depressive symptoms of any severity. The most common etiology of dementia is Alzheimer’s disease, suggesting a possible diagnosis of dementia of the Alzheimer’s type, late onset, with depressed mood (DSM 290.21). Given Mr. A’s medical history, a diagnosis of vascular dementia with depressed mood (DSM 290.43) could have been considered; at Mr. A’s admission, a CT scan of the head revealed multiple infarctions, although there was no clinical history of a stroke. Mr. A’s cognitive symptoms could also have been attributed to major depressive disorder, although neuropsychological testing suggested an underlying dementia.
General Medical Conditions
Mr. A’s subsequent weight loss of 30 lb over several months was clearly an indication for extensive medical evaluation. Common causes of unwanted weight loss that could have been considered included diabetes, hyperthyroidism, malabsorption syndromes, cancers, infections, gastrointestinal obstruction, hypercalcemia, and adrenal insufficiency. Alzheimer’s disease and depression also cause weight loss and might have been considered diagnoses of exclusion (7). Mr. A received gastrointestinal endoscopic examinations, which were reportedly negative, indicating no gross obstruction. At his admission to the psychiatric inpatient unit, the results of laboratory studies revealed that Mr. A’s diabetes was poorly controlled. Other common causes of weight loss could have been tentatively excluded, because he had a normal TSH level, no steatorrhea or other malabsorption symptoms, no fever, and normal results for blood chemistries and blood counts. Mr. A’s midepigastric and back pains were further indications for abdominal imaging to assess for an abdominal process. His smoking history put him at an increased risk for cancers of the lung, esophagus, stomach, kidney, bladder, and pancreas (7). His aortic and iliac bruits also hinted at possible thromboses secondary to the hypercoagulable state seen in malignancies, superimposed on his history of peripheral vascular disease (8).
After imaging studies and a subsequent biopsy were completed, which provided a definitive diagnosis, pancreatic cancer could have been regarded as the underlying cause of Mr. A’s depressive symptoms over the previous year: mood disorder due to pancreatic cancer, with a major depressive-like episode (DSM 293.83). We will discuss later the link between pancreatic cancer and depression.
At admission, Mr. A was noted to have intermittent acute episodes of confusion. These could have been considered manifestations of delirium secondary to a general medical cause, superimposed on dementia: coded as vascular dementia with delirium (DSM 290.42). During his hospital stay, his symptoms appeared to be exacerbated, at least in part because of iatrogenic factors. While the anticholinergic effects of antidepressant medications have been implicated in delirium, the frequency and severity of Mr. A’s episodes were observed to vary directly with the use of opioids for control of his abdominal pain (9). His main diagnosis was most likely opioid-induced delirium (DSM 292.81), although pain and constipation (attributable in part to both opioid use and his tumor) likely exacerbated it. His reaction to his diagnosis and poor prognosis might also have contributed to a decline in his emotional and cognitive status, further complicating his symptom complex.
Pancreatic Cancer and Depression
Depression is common among patients with cancer (10). In particular, mood symptoms, especially depression, have long been reported as manifestations of pancreatic cancer (11–13). There may be a greater incidence of depression before the diagnosis of pancreatic cancer compared to the diagnosis of other abdominal neoplasms (14).
Pancreatic cancer is a relatively common and deadly tumor, with an age-adjusted incidence of 13 and 8 per 100,000 American men and 100,000 American women, respectively, which ranks it among the top five cancers for each gender (15). Onset of the disease is generally in late life, with 80% of the cases diagnosed between the sixth and eighth decades. African Americans and Japanese Americans are at higher risk for pancreatic cancer than are Caucasian Americans (15, 16). In almost all populations, the incidence has been rising over the past 50 years. One proposed explanation for this increase is the growing rate of tobacco use. Smoking has been observed to be a strong risk factor for pancreatic cancer (17). Other risk factors include a high-calorie, high-fat diet and chronic pancreatitis. Alcohol use is a noted risk factor for chronic pancreatitis and pancreatic cancer (16). Specific inherited factors have been implicated in pancreatic cancer and several gene loci have been identified; all are believed to have autosomal dominant inheritance patterns (18). Individuals with a first-degree family member with pancreatic cancer have a five to 10-fold higher risk of developing that disorder than do individuals with first-degree relatives without pancreatic cancer (19). Several psychotropic medications, including methylphenidate, have been associated with acute pancreatitis or pancreatic dysfunction, but none has any known association with pancreatic cancers (20).
Five-year survival rates for pancreatic cancer are low (1%–3%), as patients tend to be seen late in the course of the disease because of the typically insidious onset (15, 21). The only curative therapy for pancreatic cancer, to our knowledge, has been surgical resection. Unfortunately, of the 60%–70% patients who are surgically explored, only 10%–20% have their tumors detected early enough to be resectable (22).
The biologic cause of depression in patients with early-stage pancreatic cancer is unclear. Green and Austin discussed several hypotheses (23). Endocrine explanations have focused on the production of depressogenic substances by pancreatic tumors, including adrenocorticotropic hormone, parathormone, thyrotropin-releasing hormone, glucagon, serotonin, and insulin. Acid-base disruptions have also been proposed, with neoplastic blockage of pancreatic exocrine ducts causing shunting of bicarbonate into the systemic circulation, putatively leading to anxiety and subsequent depression. Although these explanations are speculative, a possible biologic link between pancreatic cancers and depression is supported by clinical studies (23).
Mr. A had only one reported risk factor for pancreatic cancer: his history of smoking 50 packs per year. He had no reported history of pancreatitis, familial pancreatic disease, or recent-onset type II diabetes mellitus. His symptom profile was suspicious for a carcinoma only after his severe weight loss. Mr. A’s diabetes had been diagnosed 10–15 years earlier, although it is possible that his diabetes control over the previous year had been worsened by his pancreatic cancer. His peripheral thromboses 1 year before admission might also have been interpreted as a nonspecific sign of an underlying malignant process.
It is true that the onset of depression in an elderly person warrants a consideration of underlying medical disorders, including cancer. Yet a question remains: when should a clinician consider a workup for a specific disorder such as pancreatic cancer when faced with a differential diagnosis for the reappearance of depression in an elderly man? There is a need for a comprehensive diagnostic evaluation in elderly persons that has to be balanced against good clinical judgment as well as the economics of health care. Since depression has been shown to be an early symptom of pancreatic cancer, an early workup based on this symptom might advance the detection of pancreatic cancer by 6 months or more in some cases. At the same time, given the high prevalence of depression in the elderly and the relatively low incidence of pancreatic cancer, routine workups for pancreatic cancer in depressed patients in whom specific suspicions are not raised would be of low yield. Furthermore, early investigations may be negative and thereby lead to a false sense of security. Even after a medical workup with negative results, therefore, it is important for physicians to keep their differential diagnostic options open. Mr. A’s negative gastroenterologic evaluation might have eased concern about a possible general medical cause for his symptoms and further delayed a prompt and thorough assessment. A general medical evaluation may lack the sensitivity for detecting an underlying cause, either because the evaluation was not comprehensive enough or because it was undertaken too early, before manifestations of the disease were noted. This may lead to the conclusion that the diagnosis is psychogenic and may prejudice clinicians against undertaking later medical evaluations to assess new symptoms. Thus, even where the etiology is presumed to be psychogenic, clinicians should take seriously the possibility that new psychiatric or somatic symptoms in an elderly person may be manifestations of an underlying medical disease. Where suspicion of malignancy is raised, an internal medicine or surgical consultation should be obtained.
In conclusion, this case illustrates the necessity for an open-minded approach to continued investigation for general medical causes of psychopathologic symptoms in elderly persons.
Received May 9, 2000; revision received Aug. 8, 2000; accepted Sept. 22, 2000. From the Department of Psychiatry, University of California at San Diego; and the VA San Diego Healthcare System.Supported in part by NIMH grants MH-43695, MH-49671, and MH-19934, and by the U.S. Department of Veterans Affairs. Address reprint requests to Dr. Jeste, Geriatric Psychiatry Division, University of California, San Diego, VA San Diego Healthcare System (116A-1), 3350 La Jolla Village Dr., San Diego, CA 92161; email@example.com (e-mail).