A 19-year-old college sophomore is brought to the clinic by her mother, who is concerned about her anxiety. Her grades have dropped, and she is “suspicious” of her roommates and has a strong feeling that “reality is not what it seems.”

When a patient presents with soft signs of psychosis or bipolar disorder, how can we tell if they will go on to develop the full syndrome? Screening instruments are time consuming, require advanced training, and largely have not been validated to detect early “prodromal” symptoms. In this article, we will discuss how to identify and treat prodromal symptoms to reduce the likelihood of progression to the full disorder. 

The schizophrenia prodrome

About 75% of patients with schizophrenia show early prodromal symptoms, including changes in sleep, avolition, and erratic behavior. Cannabis use is a strong predictor of progression to schizophrenia. Other risk factors include family history of psychosis, cognitive deficits, history of suicidality, adverse childhood experiences, and lower socioeconomic status (Conroy S et al, Curr Treat Options Psychiatry 2018;5(1):113–128; Althwanay A et al, Cureus 2020;12(6):e86392020).

The bipolar prodrome

Prodromal symptoms can also precede the full onset of bipolar disorder. These symptoms run the gamut of the DSM, including symptoms of ADHD, anxiety, conduct, and substance use disorder, as well as subthreshold symptoms of mania and depression. For those who convert to the full disorder, the prodromal phase lasts about two years on average. A family history of bipolar disorder is the most potent predictor of conversion to bipolar disorder, particularly in the parents or grandparents (Post RM et al, J Affect Disord 2020;272:508–520). Most studies define the bipolar prodrome as youth with active psychiatric symptoms and a first-degree relative with the disorder.

In one study that followed the offspring of parents with bipolar disorder for five years, it was the severity of the symptoms rather than their particular nature that predicted conversion (Diler RS et al, Bipolar Disord 2017;19(5):344–352). Worsening of psychiatric symptoms on an antidepressant is also a strong predictor (Conroy et al, 2018). Childhood trauma is also predictive, and patients with a history of childhood trauma also have an early onset of bipolar disorder (Post et al, 2020; Conroy et al, 2018). 

Prevention

Medications, psychotherapy, and natural treatments have all been tried to prevent conversion to major psychiatric disorders, with some surprising results. Antipsychotics did not prevent conversion to schizophrenia in three trials that tested olanzapine, risperidone, and ziprasidone in patients with prodromal psychotic symptoms. Since young people are more susceptible to the metabolic side effects of these medications, most clinical guidelines do not recommend antipsychotics for prodromal psychotic symptoms (Mei C et al, Clin Psychol Rev 2021;86:102005).

For prodromal bipolar disorder, pharmacotherapy is poorly studied, and the evidence is not strong enough to recommend it. However, there is evidence to suggest caution with antidepressants. A small trial of paroxetine in children with depression whose parents had bipolar disorder was halted early because over half of participants developed mania on the antidepressant, regardless of whether it was used as monotherapy or in combination with valproate (Findling RL et al, J Child Adolesc Psychopharmcol 2008;18:615–621). Schneck and colleagues developed and tested an algorithm for children and teens who have a parent with bipolar disorder. They recommend avoiding antidepressants in patients with subthreshold mixed or manic symptoms and those with a history of mood worsening on antidepressants (Schneck CD et al, J Child Adolesc Psychopharmacol 2017;27(9):796–805).

Omega-3s

There is some evidence that omega-3 fatty acids prevent conversion to schizophrenia. One study randomized 81 adolescents with prodromal psychotic symptoms to a three-month course of placebo or omega-3s (700 mg EPA + 480 mg DHA daily) (Amminger GP et al, Nat Commun 2015;6:7934). At seven-year follow-up, those who took the brief course of omega-3s were four times less likely to develop schizophrenia (10% vs 40%). 

Omega-3s also have evidence in pediatric bipolar depression, and a small randomized trial found efficacy in youth with prodromal symptoms of bipolarity (1400 mg EPA + 200 mg DHA daily). In that study, omega-3s reduced depressive but not manic symptoms after three months, as well as two to five years later in an open-label extension (Fristad MA et al, J Affect Disord 2021;281:24–32). However, not all studies of omega-3s for prevention of schizophrenia and bipolar have been positive.

Putting it into practice

Psychotherapy, supported by numerous trials, is more effective than medication in preventing full disorder conversion. For our 19-year-old patient with prodromal psychosis and a family history of schizophrenia, omega-3 fatty acids, family therapy, and skill-focused psychotherapy with cannabis cessation are recommended (Saraf G et al, Lancet Psychiatry 2021;8(1):64–75; Zheng Y et al, Schizophr Bull 2022;48(1):8–19).

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