Psychosis is preceded by a 3–4-year prodromal phase characterized by non-specific symptoms and deficits in approximately 75% of patients with a first episode of psychosis (FEP), said Michael First, Professor of Clinical Psychiatry at Columbia University, NY and Editorial and Coding Consultant for the Diagnostic and Statistical Manual (DSM-5). Terminologies that have been used to describe different prodromal states are:

• Early psychosis risk syndrome or early prodromal state
• Later psychosis risk syndrome, also known as later prodromal, ultra-high risk (UHR), clinical high-risk (CHR), or at-risk mental state (ARMS)
• Schizophrenia prodrome – which can only be identified retrospectively

Psychosis is preceded by a 3–4 year prodromal phase in 75% of patients, but only 25% of clinical high-risk (CHR) individuals develop psychosis within 2 years

Risk of psychosis for individuals with CHR psychosis

Among individuals with CHR psychosis, 15% develop psychosis within 1 year and 25% within 2 years, said Tyrone Cannon, Professor of Psychology and Psychiatry, University of Southern California, CA.

The goals of treatment for these individuals are to reduce the symptoms of CHR, depression and anxiety and the risk of conversion to full psychosis; and to support educational opportunities and continued social engagement.

Treatment is generally provided using a stepped-care approach with cognitive behavioral therapy, family psychoeducation, and encouraging social skills. Medication is often prescribed for depression and anxiety, but there is no evidence that antipsychotic medications prevent the onset of psychosis, Professor Cannon said.  

APS is a condition for further study

The term APS was introduced in 2011 to remove the stigma and confusion associated with the prodromal “risk” terminology, explained Professor First.

The criteria for APS are:

• Symptoms: attenuated delusions, hallucinations or disorganized speech severe enough to seek clinical intervention – with relatively intact reality and no apparent mental, physical or substance abuse cause
• Frequency: at least once a week over the past month
• Progression: starting or worsening over the past year

APS fulfills many of the criteria for an officially recognized mental disorder diagnosis in the Diagnostic Criteria and Codes section II of DSM-5, but is currently placed in section III – Emerging Measures and Models – as a condition for further study.

Professor First said that the limited and inconclusive diagnostic reliability data for APS in clinical practice had led to its placement in section III. Issues of concern were the potential for a high false-positive rate in the community and the associated stigma.

A risk calculator to improve diagnostic reliability

The North American Prodrome Longitudinal Study (NAPLS) was set up to build an individualized risk calculator to determine the probability of conversion of CHR to psychosis in an individual patient,¹ and to determine whether hormonal, electrophysiological and anatomical abnormalities associated with schizophrenia are stable or progress from the pre-onset phase to the full psychosis phase, explained Professor Cannon.

NAPLS was set up to determine whether hormonal, electrophysiological and anatomical abnormalities associated with schizophrenia are stable or progress from the pre-onset phase to the full psychosis phase

The risk calculator has proved useful for recruiting individuals and encouraging adherence to treatment programs. Integrating biomarker data may improve prediction for the future development of psychosis, he said.

Unravelling the pathophysiology – markers, synaptic pruning and hippocampal atrophy

Professor Cannon described the application of a “greedy” regression algorithm to the NAPLS to select analytes that discriminates HR symptoms in those who developed psychosis from those who did not develop psychosis and healthy controls during a two-year follow-up.² The selection of 15 analytes included markers of inflammation, oxidative stress and hypothalamic-pituitary dysfunction.

Synaptic pruning may be related to excessive C4 activity

Meanwhile, neuropathology studies have demonstrated reduced spine density in layer 3 pyramidal cells, Professor Cannon said, and it has been suggested that synaptic pruning may play a role in the development of psychosis.³ In addition, research also indicates that those who convert to psychosis show a steeper rate of cortical thinning in the superior and medial prefrontal cortex.⁴

Professor Cannon also highlighted that genes for schizophrenia impact the innate immune system and synaptic plasticity.⁵ Excessive activity in the complement (especially at the C4 level) resulting in a decrease in the number of synapses has been implicated in the development of schizophrenia.^6,7

Hippocampal CA1 atrophy best predicts conversion to psychosis

Scott Small, Professor of Neurology, Columbia University, NY, outlined a progressive pathophysiological process for psychosis starting with hypermetabolism in the CA1 region of the hippocampus in prodromal schizophrenia followed by atrophy. CA1 atrophy best predicts conversion to psychosis, he said.

Hypermetabolism is a measure of increased blood flow, suggesting an underlying inefficiency, explained Professor Small, and hippocampal glutamate – high levels may be neurotoxic – is the predominant pathophysiology. More work is now needed to determine the pathophysiological time course, he concluded.