Exploring the Psychosis-Depression Interface: Clinical Implications

October 31, 2016

A review of 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.

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.


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.


Treatment decisions

The question of what causes depressed and psychotic symptoms is clinically relevant to the choice of treatment. The cause of symptoms is generally not a diagnostic criterion in the DSM, and this approach has inadvertently obscured thinking about psychiatric disease etiology. The traditional view is that there are different causes for psychotic and depressive symptoms, which is consistent with the idea that they exist on the opposite ends of a spectrum. In this spectrum model, depression or bipolar disorder with psychotic features could be seen as being in the middle, where the 2 symptom domains overlap. Patients with both psychotic and depressive symptoms therefore have the unfortunate co-occurrence of 2 different disease processes, and thus there must be individual treatments directed at each symptom cluster.

An alternative view is that psychosis is a manifestation of a more severe form of illness, with depression at the milder end of a spectrum of severity rather than etiology. In this second framework, the causes of depressive and psychotic symptoms are shared, and the clinical presentation depends on the disease severity in a given patient. Postpartum depression and psychosis are a good example of this paradigm, since the origin or at least trigger for the psychiatric symptoms is clearly related to childbirth and the attendant changes in hormonal milieu. Thus, the treatments for both symptom clusters should be similar, differing only in more aggressive treatment when psychosis is present.

Clinical manifestations

Although the clinical manifestations of depression and psychosis appear quite different, there is evidence of substantial overlap in etiology. The heritability of schizophrenia is estimated to be between 70% and 80%, making it one of the most genetically influenced psychiatric disorders-and indeed of any type of illness. The relative contribution of genetic factors to depression is quite low compared with schizophrenia, with heritability in the 30% range.6 Despite large differences in heritability, there is considerable overlap in genetic susceptibility for major mental disorders, including depression, schizophrenia, bipolar disorder, ADHD, and autism spectrum disorders.7

In addition to genetic epidemiological evidence for overlapping origins of both mood and psychotic disorders, there are also examples in which rare genetic variants cause both types of symptoms. The DISC1 (disrupted-in-schizophrenia 1) gene was originally discovered in a unique Scottish family with high rates of mental illness caused by a chromosomal translocation that severs the DISC1 gene.8 Family members with the mutation have a variety of diagnoses ranging from schizophrenia to bipolar disorder and depression. Animal models with DISC1 and other mutations suggest that gene-environment interactions and genetic background can modulate behavioral phenotype, which may be the case in humans as well.9-11 These examples demonstrate that a single genetic cause can result in a variety of clinical presentations that have different diagnostic labels.

Receptor systems traditionally associated primarily with psychosis or cognition, such as the dopamine and glutamate systems, respectively, also play a role in regulating mood. The antidepressant bupropion inhibits the synaptic reuptake of both norepinephrine (like classic tricyclic antidepressants) and dopamine. Protein interactions with the dopamine D2 receptor can regulate depression-related behavior in animal models and are a promising target for new antidepressant drug development.10,12 The role of glutamate in regulating mood is clearly shown by the discovery of the rapid antidepressant effects of ketamine, a veterinary and pediatric anesthetic also used recreationally as a hallucinogenic and dance party drug. Although the anesthetic and hallucinogenic effects of ketamine have been attributed to the blockade of NMDA glutamate receptors, recent research suggests that the antidepressant effects are NMDA-independent and may be mediated instead by metabotropic glutamate receptors.13

Recognizing that current antidepressants and antipsychotics are symptomatic treatments and that there is overlap in the causes of depression and schizophrenia, a specific diagnostic label is not crucial for optimal treatment. Instead, a more pragmatic focus is to select the simplest medication regimen that will maximize therapeutic effects and minimize adverse effects. As always, minimizing the number of medications prescribed concurrently is likely to be optimal because the number and complexity of drug interactions increase exponentially with additional medications.


Treatment strategies

Both antidepressant and antipsychotic medications can be used to treat comorbid depressive and psychotic symptoms; however, monotherapy with a drug with dual efficacy for both types of symptoms can also be tried. Several medications originally developed and marketed as antipsychotics are now approved by the FDA as augmentation treatments for refractory depression. This trend began with quetiapine and now includes other atypical antipsychotics, such as aripiprazole, and a combined olanzapine/fluoxetine formulation. Although the use of antipsychotics to augment antidepressant treatment is relatively new, the pharmacological overlap in efficacy is not new. Amoxapine is an old heterocyclic compound that has both antidepressant and antipsychotic properties.

The antipsychotics currently approved for augmentation treatment of depression are an obvious choice in psychotic depression. However, quetiapine has quite low affinity for the D2 receptor, and aripiprazole is not a D2 antagonist like other antipsychotics but a partial agonist.14 Thus, a more potent D2-antagonist antipsychotic (eg, haloperidol, risperidone, paliperidone, fluphenazine, pimozide) may be preferable to achieve sufficient D2 occupancy for antipsychotic effects while minimizing off-target adverse effects when combined with antidepressant medication. Severe depression with prominent psychotic symptoms may also present with strong suicidal ideation or with drastic psychomotor retardation and catatonia, at which point patients may stop eating and drinking. Such scenarios usually require intervention with ECT, which typically has a rapid effect on both psychotic and depressive symptoms.

To minimize adverse effects, it is vital to consider the off-target effects of medications that are to be combined. The most commonly used antidepressants primarily inhibit monoamine reuptake, including norepinephrine, serotonin and, in the case of bupropion, dopamine. Conversely, all antipsychotics bind to dopamine D2 receptor, which is a member of the G-protein coupled receptor family. Therefore, lower-affinity antipsychotics (eg, clozapine, quetiapine, chlorpromazine, ziprasidone, loxapine) tend to cross-react with other G-protein coupled receptors, such as a- adrenergic (causing orthostatic hypotension), histamine (sedation), serotonin (sexual dysfunction, appetite), and muscarinic acetylcholine (constipation, dry mouth, tachycardia, confusion). These receptors, particularly muscarinic acetylcholine receptors, are also blocked by the tricyclic antidepressants (eg, desipramine, imipramine, nortriptyline, amitriptyline); thus, combined treatment with a low-potency antipsychotic may exacerbate anticholinergic adverse effects.


The co-occurrence of psychosis and depression in a variety of contexts, combined with recent genetic discoveries, weakens the diagnostic distinction between these symptoms. There is also increasing overlap in the medications used to treat these symptoms, and a judicious selection of combination therapy can minimize adverse effects and enhance compliance. Further research into the causes of these symptoms may generate better treatment targets that could eventually be more specific and more effective.


Dr. Wong is Psychiatrist and Scientist, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario; and Professor of Psychiatry, University of Toronto. He reports no conflicts of interest concerning the subject matter of this article.


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