After ruling out a substance/medication-induced etiology, the clinician next determines whether the psychiatric symptoms are due to the direct effects of a nonpsychiatric medical condition. This and the previous step of the differential diagnosis make up what was traditionally considered the “organic rule-outs” in psychiatry, in which the clinician is asked to first consider and rule out “physical” causes of the psychiatric symptomatology. Although DSM no longer uses words such as organic or physical, to avoid the anachronistic mind-body dualism implicit in such terms, the need to first rule out substances and nonpsychiatric medical conditions as specific causes of the psychiatric symptomatology remains crucial. For similar reasons, the phrase “due to a medical condition” is avoided in DSM because of the potential implication that psychiatric symptomatology and mental disorders are separate and distinct from the concept of “medical conditions.” In fact, from a disease classification perspective, psychiatric disorders are but one chapter of the International Classification of Diseases (ICD), as are infectious diseases, neurological conditions, and so forth. Thus, when the phrase “due to another medical condition” is used in DSM-5-TR disorder names, what is really meant is that the symptoms are due to a medical condition that is classified outside the ICD mental disorders chapter—that is, a nonpsychiatric medical condition. In DSM-5-TR text, the phrase “medical condition” is modified with adjectives such as another, other, or general to clarify that the etiological condition, like a mental disorder, is a medical condition—but is differentiated from psychiatric medical conditions by virtue of being nonpsychiatric.

From a differential diagnostic perspective, ruling out a nonpsychiatric medical etiology is one of the most important and difficult distinctions in psychiatric diagnosis. It is important because many individuals with nonpsychiatric medical conditions have resulting psychiatric symptoms as a complication of the medical condition and because many individuals with psychiatric symptoms have an underlying medical condition. The treatment implications of this differential diagnostic step are also profound. Appropriate identification and treatment of the underlying nonpsychiatric medical condition can be crucial in both avoiding medical complications and reducing the psychiatric symptomatology.

This differential diagnosis can be difficult for four reasons: 1) symptoms of some psychiatric disorders and of many nonpsychiatric medical conditions can be identical (e.g., symptoms of weight loss and fatigue can be attributable to a Depressive or Anxiety Disorder or to a nonpsychiatric medical condition); 2) sometimes the first presenting symptoms of a medical condition are psychiatric (e.g., depression preceding other symptoms in pancreatic cancer or a brain tumor); 3) the relationship between the nonpsychiatric medical condition and the psychiatric symptoms may be complicated (e.g., depression or anxiety as a psychological reaction to having the nonpsychiatric medical condition vs. the medical condition being a cause of the depression or anxiety via its direct physiological effect on the CNS); and 4) psychiatric patients are often seen in settings primarily geared toward the identification and treatment of mental disorders in which there may be a lower expectation for, and familiarity with, the diagnosis of medical conditions.

Virtually any psychiatric presentation can be caused by the direct physiological effects of a nonpsychiatric medical condition, and these presentations are diagnosed in DSM-5-TR as one of the Mental Disorders Due to Another Medical Condition (e.g., Depressive Disorder Due to Hypothyroidism). It is no great trick to suspect the possible etiological role of a nonpsychiatric medical condition if the patient is encountered in a general hospital or primary care outpatient setting. The real diagnostic challenge occurs in mental health settings in which the base rate of nonpsychiatric medical conditions is much lower but nonetheless consequential. While it is not feasible (nor cost-effective) to order every conceivable screening test on every patient, it is important to direct the history, physical examination, and laboratory tests toward the diagnosis of those nonpsychiatric medical conditions that are most commonly encountered and most likely to account for the presenting psychiatric symptoms (e.g., thyroid function tests for depression, brain imaging for late-onset psychotic symptoms).

Once a nonpsychiatric medical condition is established, the next task is to determine its etiological relationship, if any, to the psychiatric symptoms. There are five possible relationships: 1) the nonpsychiatric medical condition causes the psychiatric symptoms through a direct physiological effect on the brain; 2) the nonpsychiatric medical condition causes the psychiatric symptoms through a psychological mechanism (e.g., depressive symptoms in response to being diagnosed with cancer—diagnosed as Major Depressive Disorder or Adjustment Disorder); 3) medication taken for the nonpsychiatric medical condition causes the psychiatric symptoms, in which case the diagnosis is a Medication-Induced Mental Disorder (see “Step 2: Rule Out Substance Etiology” in this chapter); 4) the psychiatric symptoms cause or adversely affect the nonpsychiatric medical condition (e.g., in which case Psychological Factors Affecting Other Medical Conditions may be indicated); and 5) the psychiatric symptoms and the nonpsychiatric medical condition are coincidental (e.g., hypertension and Schizophrenia). In the real clinical world, however, several of these relationships may occur simultaneously with a multifactorial etiology (e.g., a patient treated with an antihypertensive medication who has a stroke may develop depression due to a combination of the direct effects of the stroke on the brain, the psychological reaction to the resultant paralysis, and a side effect of the antihypertensive medication).

There are two clues suggesting that psychopathology is caused by the direct physiological effect of a nonpsychiatric medical condition. Unfortunately, neither of these is infallible, and clinical judgment is always necessary.

• The first clue involves the nature of the temporal relationship and requires consideration of whether the psychiatric symptoms a) begin following the onset of the nonpsychiatric medical condition, b) vary in severity with the severity of the medical condition, and c) remit when the medical condition resolves. When all of these relationships can be demonstrated, a fairly compelling case can be made that the nonpsychiatric medical condition has caused the psychiatric symptoms; however, such a clue does not establish that the relationship is physiological (the temporal covariation could also be due to a psychological reaction to the nonpsychiatric medical condition). Also, sometimes the temporal relationship is not a good indicator of underlying etiology. For instance, psychiatric symptoms may be the first harbinger of the nonpsychiatric medical condition and may precede by months or years any other manifestations. Conversely, psychiatric symptoms may be a relatively late manifestation occurring months or years after the nonpsychiatric medical condition has been well established (e.g., depression in Parkinson’s disease).

• The second clue that a nonpsychiatric medical condition should be considered in the differential diagnosis is whether the psychiatric presentation is atypical in symptom pattern, age at onset, or course. For example, the presentation cries out for a medical workup when severe memory or weight loss accompanies a relatively mild depression or when severe disorientation accompanies psychotic symptoms. Similarly, the first onset of a manic episode in an elderly patient may suggest that a nonpsychiatric medical condition is involved in its etiology. However, atypicality does not in and of itself indicate a nonpsychiatric medical etiology because the heterogeneity of independent psychiatric disorders leads to many “atypical” presentations.

Nonetheless, the most important bottom line with regard to this task in the differential diagnosis is not to miss possibly important underlying nonpsychiatric medical conditions. Establishing the nature of the causal relationship often requires careful evaluation, longitudinal follow-up, and trials of treatment.