Psychotic depression

Psychotic major depression (PMD) is a type of depression that can include symptoms and treatments that are different from those of non-psychotic major depressive disorder (NPMD). PMD is estimated to affect about 0.4% of the population (or one in every 250 people). Many people with psychotic depression experience delusions, which are beliefs or feelings that are untrue or unsupported.

PMD is sometimes mistaken for NPMD, schizoaffective disorder, schizophrenia or other psychotic disorders. Bipolar patients may experience PMD during depressed states. PMD is usually episodic, lasting for a defined amount of time, but in some cases can be chronic. PMD has unique biological features, which have led to innovative treatments. While PMD is often treated with a combination of antidepressants and antipsychotics, researchers have been developing new treatments that address the pathophysiology of PMD more directly.

Symptoms
Currently, PMD is considered a severe form of major depression, but patients with mild or moderate depression may still have psychotic features. Many people with PMD experience delusions, which are beliefs or feelings that are untrue or unsupported. Paranoid delusions or delusions of guilt may be the most common psychotic symptoms in PMD. Patients with PMD often have concerns that people are paying special attention to them or are trying to persecute them. Patients who experience delusional guilt may believe that they are being punished for past misdeeds or are responsible for problems they couldn’t possibly be responsible for.

Other common delusions include those in which people are concerned that something is terribly wrong with their bodies and physical health, when actually there isn’t anything wrong. Unlike other psychotic disorders, the delusions in PMD may not be very obvious. Delusions appear to be more common than hallucinations in PMD, but some people with PMD do hallucinate, or see or hear things that others do not. Auditory hallucinations (sounds) are perhaps the most common hallucinations seen in PMD. While other patients may report seeing, touching or smelling things that are not there, it is less common.

Other symptoms that are common in PMD are agitation, difficulty falling asleep, and frequent waking during the night. In addition, patients with PMD may have a greater suicide risk than patients with NPMD. Finally, those with PMD may have greater cognitive deficits (e.g., memory problems) than those with NPMD.

Course
The course of PMD may be helpful in distinguishing it from other disorders. Most PMD patients report having an initial episode between the ages of 20 and 40. Over a lifetime, it appears that PMD patients experience an average of 4 to 9 episodes. As with NPMD, the episodes of PMD tend to last for a certain amount of time and subside. While PMD can be chronic (lasting more than 2 years), most PMD episodes last less than 24 months. Unlike psychotic disorders such as schizophrenia and schizoaffective disorder, patients with PMD generally function well between episodes, both socially and professionally.

Diagnostic criteria
According to the Diagnostic and Statistical Manual of Mental Disorders (DSM), a widely used manual for diagnosing mental disorders, patients who show at least six of the following symptoms in a period of two weeks may be diagnosed with PMD. In order to qualify for a PMD diagnosis, patients need to report either (1) or (3), and (10), along with three or four other symptoms (for a total of six). These symptoms also must be different from how patients felt or behaved at a previous time.


 * 1) depressed mood most of the day nearly every day
 * 2) noticeably increased or decreased sex drive
 * 3) loss of interest or pleasure in all, or almost all, activities most of the day nearly every day
 * 4) significant weight loss or weight gain, OR decrease or increase in appetite nearly every day
 * 5) insomnia OR hypersomnia (sleeping excessively) nearly everyday
 * 6) psychomotor agitation (moving more quickly) OR retardation (moving more slowly) nearly every day, so much that other people notice
 * 7) fatigue OR loss of energy nearly every day
 * 8) feelings of worthlessness OR excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)
 * 9) diminished ability to think or concentrate, OR indecisiveness, nearly every day
 * 10) recurrent thoughts of death (not just fear of dying), recurrent ideas about suicide without a specific plan, or a suicide attempt or specific plan for committing suicide
 * 11) delusions or hallucinations
 * 12) increased and intense daydreaming

The symptoms cannot meet criteria for a Mixed Episode (diagnosed by a clinician) or be due to the effects of a substance or illness. The symptoms also must cause distress or impairment in functioning.

Differential diagnosis
PMD is most frequently confused with NPMD, but it may also be mistaken for the schizophrenia spectrum disorders, including schizoaffective disorder. These are differentiated from PMD by the presence of psychotic symptoms outside of a major depressive episode. In a schizoaffective patient, hallucinations and delusions will occur in the absence of major depressive episodes.

Schizophrenia generally has more disordered thinking and delusional symptoms than PMD. It is unusual for PMD patients to show flight of ideas, loose association, echolalia (repeating what others say), word salad (meaningless speech), and other elements of thought disorders that characterize schizophrenia. Likewise, the presence of bizarre delusions ("Aliens have planted a receiver in my head") appears to be less common in PMD than schizophrenia. However, neither bizarre delusions, nor marked thought disorder necessarily eliminate a diagnosis of PMD. Bipolar disorder can sometimes present with PMD. It is estimated that as many as 42% of patients with PMD in adolescence or young adulthood are likely to develop some type of manic episode later. It is important to take a history of manic symptoms in any younger patient who presents with PMD.

Other psychotic disorders with which PMD is sometimes confused include delusional disorder, substance induced psychotic disorder (with MDD), post-psychotic depressive disorder of schizophrenia, and brief psychotic disorder. The primary way of distinguishing between PMD and any of these disorders lies more in evaluating the course of the illness rather than simply identifying specific symptoms.

Pathophysiology
There are a number of biological features that may distinguish PMD from NPMD. The most significant difference may be the presence of an abnormality in the hypothalamic pituitary adrenal (HPA) axis. The HPA axis, which is sometimes referred to as the stress hormone axis, appears to be chronically over-activated in PMD. Other abnormalities found in PMD include sleep abnormalities and changes in other areas of brain function.

History of treatments
Before electroconvulsive therapy (ECT) was invented in the 1930s, it was frequently observed that patients experiencing delusions with depression had poorer response to medication treatment. ECT seemed to have similar effects for depressed patients both with and without psychotic symptoms. The interest in psychotic depression increased after tricyclic antidepressants (TCAs) became available, because while NPMD responded to TCAs, PMD did not. In the past 40 years there has been a renewed interest in PMD. The FDA is considering a special class of drugs for the treatment of PMD as researchers learn more about the biology of the disease.

Many studies have suggested that PMD differs from MDD in treatment response. PMD is less likely than MDD to respond to placebo and to the use of only an antidepressant or an antipsychotic. The combination of an antidepressant and an antipsychotic appears to be necessary for the treatment of PMD. Early studies suggest an 80-90% response rate in PMD with combination treatment.

Established treatment strategies
While there is some evidence that anti-depressant pharmacotherapy with selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) may be effective in treating PMD, patients with PMD often do not respond to monotherapy and require a combination of anti-depressant and anti-psychotic medication.

Electroconvulsive therapy (ECT), along with combination antidepressant-antipsychotic treatment, is the other established treatment of PMD. ECT may have a more reliable track record in improving symptoms than pharmacological treatments. However, the stigma, cost, and cognitive side effects often make it a second or third line treatment except in special circumstances. For example, if a patient's PMD is imminently life threatening as a result of suicide risk or cachexia, ECT may be considered first line treatment. In addition, a patient who cannot tolerate medications, or has responded more favorably to ECT in the past, may be considered for ECT first.

Experimental treatment strategies
The current treatments of PMD are reasonably effective but tend to carry a high side effect burden and may take a long time to work. Combination treatment with atypical antipsychotics and SSRIs tend to be associated with significant weight gain and sexual dysfunction. TCAs are lethal in overdose and some are associated with extra-pyramidal side effects including tardive dyskinesia. Finally, ECT has side effects of temporary cognitive deficits (e.g., confusion, memory problems), in addition to the burden of repeated exposures to general anesthesia.

Among the newer experimental treatments is the study of glucocorticoid antagonists, including mifepristone. These strategies may treat the underlying pathophysiology of PMD by correcting an overactive HPA axis. By competitively blocking certain neuro-receptors, these medications render cortisol less able to directly act on the brain. Transcranial magnetic stimulation (TMS) is being investigated as an alternative to ECT in the treatment of depression. TMS involves the administration of a focused electromagnetic field to the cortex to stimulate specific nerve pathways. A number of early studies have shown promise of TMS in MDD with few side effects. TMS does not require anesthesia and has not been associated with significant cognitive deficits.