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Exploring the Psychosis-Depression Interface: Clinical Implications

Exploring the Psychosis-Depression Interface: Clinical Implications


Patients often present with both depressive and psychotic symptoms, which can complicate diagnosis and treatment. While there are obvious differences between feelings of depression and associated neurovegetative symptoms, and the hallucinations and delusions of psychosis, there is accumulating evidence of shared causes. There is also increasing overlap in the medications used to treat these symptoms.

This article reviews the distinction between depressive and psychotic symptom domains, current knowledge about the etiology and neurobiology of depression and psychosis, and how this knowledge can inform the treatment of patients with features of both.


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The comorbidity between mood and psychotic symptoms has been known since at least the second century, when Galen noted that patients with depression could also have delusional beliefs.1 However, there has been ongoing debate in psychiatry about the diagnostic classification of psychotic and mood disorders.2 During the 19th century, Emil Kraepelin and others favored a separate category for schizophrenia and psychotic disorders with a mood component, such as bipolar disorder.3 This approach has largely been maintained in DSM-5. As a result, depressed and psychotic symptoms are usually thought of as being separate entities with different causes.

Differential diagnosis

Clinically, the differential diagnosis rests primarily on the timing, progression, and overlap of psychotic versus depressive symptoms. Patients with schizoaffective disorder have psychotic symptoms that persist with and without mood disorder symptoms. In depression with psychotic features, patients generally have a history of previous depressive episodes, and the current episode begins with classic depression that worsens over time, at which point psychotic symptoms emerge. Conversely, patients with primary psychotic illnesses such as schizophrenia can become depressed when they realize the poor prognosis, loss of function, and dependence on caregivers—much as with any chronic medical illness. A reactive depression of this sort in schizophrenia is more likely when a psychotic episode has resolved and the patient has insight into his or her condition.

Patients who initially present with classic depression can develop psychotic symptoms, typically when the depression is severe. These psychotic symptoms are often an extreme extension of their negative thoughts and low mood, but sometimes there can be more bizarre delusions and hallucinations that seem disconnected with their mood state. Common mood congruent delusions include unrealistically hopeless perspectives about concrete stressors, such as divorce, job loss, or death of a loved one. Patients may feel as if they will never be able to attract another mate, find another job, or overcome grief. Other patients develop somatic delusions or hallucinations that there is a bad smell emanating from their body due to a terminal illness or that there is some other severe medical problem that remains undiagnosed. Patients may also experience irrational fears or persecutory paranoia, to the point where they feel the need to arm themselves or take measures to avoid being followed.

Psychotic symptoms in schizophrenia or other primary psychotic disorders such as delusional disorder can be subjectively different from those in psychotic depression. The classic description of delusions in schizophrenia by Schneider4 captures the themes of external control through thought control, insertion, and withdrawal. Modern manifestations of these same themes can include delusions about microchips implanted into the teeth or skull that are used by the government or scientists to control the patient. Patients may also have delusional fears about electronic tracking devices in their car or home and may feel that their body movements are also being controlled by an external agent. Auditory hallucinations in schizophrenia are almost always of human voices that recapitulate the delusional beliefs, often making comments about the patient that indicate constant surveillance.5

Diagnosing the cause of depressive symptoms in schizophrenia is complicated by several factors. The first is that depression can mimic negative symptoms of schizophrenia: anhedonia, low motivation, social withdrawal, and flat affect. In addition, antipsychotic medications, through blocking dopamine D2 receptors, strongly inhibit dopamine signaling to the nucleus accumbens, one of the main structures in the reward pathway. Antipsychotic medications can thereby sap motivation and reduce responses to rewarding stimuli and generate behaviors that are clinically indistinguishable from a primary depressive disorder.


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