Evidence-Based Reviews

Treating ‘depression’ in patients with schizophrenia

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A thorough differential diagnosis determines the best treatment approach



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Approximately 25% of schizophrenia patients experience course-related depression.1-4 Depression in patients with schizophrenia is linked to reduced social and vocational functioning, increased likelihood of psychotic relapse and rehospitalization, and other problems.2-4 Depression in patients with schizophrenia also has been linked to undesirable life events, especially “exit events” such as losing people in their lives, as well as suicidal ideation, suicide attempts, and completed suicides. Overall, it has been noted that approximately 10% of patients with schizophrenia commit suicide.5 Depressed schizophrenia patients are at particularly high risk for suicide the first few months after diagnosis and after hospital discharge.

Confirm the diagnosis

The best approach to treating depressive symptoms in schizophrenia patients is to formulate a thorough differential diagnosis (Table 1).

Table 1

Differential diagnosis of ‘depression’ in schizophrenia

Organic factors
Antipsychotic-induced dysphoria
Negative symptoms
Acute disappointment reactions
Chronic disappointment reactions
Prodrome of psychotic relapse
Organic etiologies such as medical illnesses—including anemia, cancer, endocrinopathies, infections, and autoimmune, metabolic, cardiovascular, and neurologic disorders—may contribute to a patient’s depressive symptoms. “Depression” also can be a side effect of medications used to treat medical conditions, such as antihypertensive and antineoplastic agents, steroidal and nonsteroidal anti-inflammatory agents, and sedative hypnotics, or could be secondary to dose reduction or discontinuation of other agents, such as corticosteroids or psychostimulants. Substance abuse also can play a role in depressive symptoms, either through acute or chronic use or discontinuation. In particular, chronic cannabis abuse can lead to an anergic state that resembles depression, and cocaine withdrawal typically features depression-like symptoms. Additionally, withdrawal from caffeine or nicotine—substances patients with schizophrenia often use heavily—can lead to dysphoric states that are difficult to distinguish from depression.

Antipsychotic-induced dysphoria. Blockade of dopamine receptors is an important feature of all antipsychotics; however, dopamine neurotransmission also is involved in the brain’s “pleasure” pathways. Individuals who take antipsychotics may experience reduced joy from once-pleasurable activities. Results of studies on the link between depression and antipsychotics have been mixed.2,4 Although some researchers have found depressed mood common among patients receiving antipsychotics, others have failed to show differences between patients treated with antipsychotics and those randomized to placebo.

Akinesia, a parkinsonian side effect of antipsychotics, can be blatant or subtle. The blatant form involves large muscle groups; these patients present with diminished arm swing, stooped posture, and parkinsonian gait. Easily spotted, such patients are unlikely to be considered depressed.

The more subtle form of akinesia is easier to confuse with depression. It can affect small muscle groups, such as in the face or vocal cords. Lack of responsiveness of facial expression is easily confused with blunted affect, low mood, lack of interest, or emotional unresponsiveness. Subtle akinesia also can impair a patient’s ability to initiate or sustain motor behavior. Many activities, from striking up a conversation to changing television channels, involve initiating and sustaining motor behavior, which these patients’ basal ganglia are underequipped to do. Life becomes boring and patients criticize themselves for “being lazy.” Patients with akinesia also are prone to dysphoria.6,7 When the lack of spontaneous motor behavior found in subtle akinesia is combined with diminished experience of pleasure due to antipsychotic blockade of dopamine, a patient may feel that “nothing is worth the effort.”

Akathisia is another movement disorder of the basal ganglia that can be triggered by antipsychotics. Whereas a patient with akinesia experiences having a “broken starter motor,” the akathisia patient experiences “a starter motor that won’t turn off.” Akathisia can be blatant or subtle. A patient with blatant akathisia has difficulty remaining seated and often paces. In subtle akathisia, increased motor activity is less dramatic, and patients may simply wander or talk excessively. Akathisia also has a dysphoric component that, when the movement is interpreted as restlessness or agitation, may look like depression.8

Negative symptoms. Primary negative symptoms in schizophrenia have several features in common with depression, which can create diagnostic challenges.9 These include anhedonia, social withdrawal, lack of initiative, lowered energy, diminished expectations and/or self confidence, and reduced speech or activity. The main feature that distinguishes the primary negative symptom syndrome from depression is prominent blue mood, which is present in depression but not in negative symptoms. Cognitive features—such as guilt, pessimism, and suicidal thoughts—are common in depression, but usually are absent in negative symptoms.

Acute disappointment reactions. Short-term reactions to negative life events can include depressed mood, pessimism, self-blame, impaired concentration, and sleep and appetite disturbances. With acute disappointment reactions, there is an identifiable proximal loss or disappointment, and the duration of the reaction is relatively brief, from a couple of hours to a few weeks.

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