Differential Diagnosis of Schizophrenia and Bipolar Disorder

Stanford University Schizophrenia and Bipolar Education Day, July 30 2005

Lecture Outline:

Editor's Note: the following is a summary of a lecture given by Dr. Terence Ketter, Associate Professor of Psychiatry & Behavioral Sciences and Chief of the Bipolar Disorders Clinic at the Stanford University School of Medicine. Direct quotes will be indicated with quotation marks; any other text is paraphrase based on Dr. Ketter's words.

According to one study surveying members of the National Depression and Bipolar Support Alliance, there is an average delay of 10 years from the first onset of symptoms to correct diagnosis and treatment of psychiatric disorders. This is an immense and potentially dangerous delay - schizophrenia and bipolar disorder can easily become degenerative diseases, with more and more brain damage occuring as psychotic or mood episodes continue unabated. Dr. Ketter cited some of the major reasons for this delay between symptoms and treatment, including:

  • People do not realize that their experiences are out of the spectrum of normal behaviors.
  • Frequent midsiagnoses (for example, misdiagnosis of bipolar as unipolar depression, or misdiagnosis of childhood-onset bipolar disorder as ADHD) delays correct treatment for the true condition.

These misdiagnoses can cause years of delay to proper treatment, with potentially destructive results. Imagine, for example, treating a child who actually has pediatric bipolar disorder with ritalin for a supposed case of ADHD. Giving such a child a stimulant can lead to mood destabilization. Similarly, giving a patient in a depressive episode antidepressants (the standard treatment for unipolar depression) without a mood stabilizer will potentially destabilize someone with bipolar disorder.

Schizophrenia and bipolar disorder are are often misdiagnosed as one another, and this is not so surprising when we consider how much the two disorders have in common. For example:

  • Schizophrenia and bipolar disorder share medications. Five of the current atypical antipsychotics originally approved to treat schizophrenia are now also approved as treatment for acute mania. Two of them are even approved as maintenance treatments for bipolar disorder. The fact that these two diseases are helped by some of the same pharmacological treatments indicates that they may have similar pathophysiology causing the symptoms.
  • The positive symptoms of schizophrenia can look like the symptoms in about 50% of manic episodes, epecially those with psychotic features. (These can include delusions of grandeur, hallucinations, disorganized speech, paranoia, etc).
  • The negative symptoms of schizophrenia can closely resemble the symptoms of a depressive episode (these include apathy, extreme emotional withdrawal, lack of affect, low energy, social isolation, etc).
  • The two disorders share abnormalities in some of the same neurotransmitter systems. For example, both depressive episode symptoms and the negative symptoms of schizophrenia are at least partially mediated by serotonin. Likewise, the positive symptoms of schizphophrenia and the symptoms of mania are mediated in some way by excesses of dopamine signalling. The atypical antipsychotics approved for both these disorders work on both the serotonin and the dopamine systems.

However, despite a significant overlap in symptoms, treatment, and pathophysiology, the current system for diagnosing psychiatric disorders in Western medicine (in the U.S., the DSM-IV contains all the guidelines for psychiatric diagnosis) emphasizes a categorical separation between diseases. In other words, it emphasizes differences, not similarities. In the past this differential diagnosis separation was more important; before the advent of the atypical antipsychotics, first-generation neuroleptics used for schizophrenia actually made bipolar disorder worse.

"[The DSM-IV] really is a categorical system, and people just fall through the gaps, folks who have intermediate difficulties," Dr. Ketter said.

He suggested that perhaps we should now consider a more dimensional approach to diagnosis, one that would focus on treating the common symptoms and pathophysiology.

We can use an analogy from physics to examine the categorical vs. dimensional approach question. When asked whether light is a wave or a particle, a physicist will correctly answer: "it is both". However, depending on what question we are trying to answer, it can be more helpful to emphasize one model (wave or particle characteristics) over the other. If we can hold on to two different ways of looking at the same thing, we may be able to get more information. Similarly with psychiatric diagnoses, depending on what we are trying to do, it can be more helpful at times to approach diagnoses categorically (as separate entities) and at other times dimensionally (as a spectrum).

Some of the most compelling evidence for how to look at these disorders, said Dr. Ketter, is coming out of the field of genetics. The data suggest that "these disorders are complex, that they have a robust genetic component, but [they are] built on a number of small-effect genes." Some of these genes may be related to both bipolar disorder and schizophrenia. "This is the kind of data," Dr. Ketter continued, "that would support this kind of dimensional spectrum.

A categorical approach does not only break down when we compare major disorders such as schizophrenia and bipolar disorder. For example, the DSM-IV also groups diagnoses into large "class categories" called axes; it classifies disorders into five different Axes (I - V).

"The Axis-I disorders [i.e. schizophrenia, bipolar, and unipolar depression, among others] are thought to be certain biological disorders, related to a genetic vulnerability, that are triggered by something in the environment. We also have these so-called "axis-II disorders"...that [historically] had to do with Freudian psychology, and personality. As it turns out, as we learn more and more about these disorders, these Axis-II or 'personality-trait' type disorders are being vaccuummed back up into the Axis-I disorders."

"The impact of this is very important," Dr. Ketter continued, "because there is a biology to these disorders." Not just individual diagnoses, but also broader categories of disorders, are being approached from a more dimensional perspective as we learn more about their underlying causes.

Acknowledging commonalities through a dimensional spectrum approach has allowed us to broaden the clinical power of the atypical antipsychotics, which work on both the serotonin and the dopamine system to address some of the common symptoms that appear in both schizophrenia and bipolar disorder. Having medicines that can work for both disorders "can be very, very, valuable" said Dr. Ketter. However, he continued "one of the dangers is that we'll let down our guard, and think that diagnosis doesn't matter...but there are important differences between schizophrenia and bipolar disorder that we need to pay attention to."

Some key differences are visible at the initial onset of symptoms. According to a Depression and Bipolar Support Alliance survey (formally the National Manic-Depression Association), 33% of people diagnosed with bipolar disorder remember depression as being their initial symptom experiences, and 32% recall mania at their first onset. Only 9% of survey respondants experienced psychotic symptoms first. This shows that even though these symptoms can appear in people with either disorder, certain types of symptoms may be more likely to appear at the onset of one disease than the other. Similarly, the classic onset of schizophrenia symptoms will be more likely to include delusions that are odd or bizarre, not so much delusions of religious grandiosity, which are more often seen in bipolar disorder.

"The symptoms that come first are usually the symptoms that will indicate what's going on, but not always," Dr. Ketter cautioned. "There are always some people with bipolar disorder that have odd delusions."

The following table, based off of one of Dr. Ketter's presentation slides, shows some of the differences most often noted between schizophrenia and bipolar disorder at the onset of the illness:

Clues to determine an initial diagnosis of schizophrenia or bipolar


Premorbid behavior:
History of depression?

Family History:

Affective disorders


Dr. Ketter also emphasized that environmental input may influence which of the disease paths eventually manifests in certain individuals. The risk for developing bipolar disorder for someone who's identical twin already has bipolar disorder is about 70% - it's not 100%, he indicated. This shows a significant role for environment interaction with genes.

"Genetics confer some kind of a vulnerability, and there may be protective factors and triggering factors. It could be that someone that someone had a disposition to bipolar disorder or schizophrenia, and they took a hallucinogen, had a psychotic experience from it, and then they ended up developing the symptoms of schizophrenia."

(Editor's note: Scienctists has identified several possible "triggers" such as Dr. Ketter mentions above, correlations between people who tend to develop schizophrenia or bipolar disorder and certain environmental factors in their lives or backgrounds. See some possible environmental contributors to schizophrenia, and what you can do to maybe reduce your risk. See also possible environmental contributors to bipolar disorder.)

So what can we conclude about the debate between categorical vs. dimensional models for psychiatric disorders? "About three-quarters of the data suggests that [the disorders] are dimensional, and about one quarter suggests that they are different categories," says Dr. Ketter. Moreover, data has definitely shown some utility for adjunct mood stabilizer therapy for treating schizophrenia, and definite utility for the second-generation antipsychotics for treating bipolar disorder.

However, Dr. Ketter closed by saying reminding us that we should be shooting for a combined categorical and dimensional approach. "There will be times when a very categorical approach will be more useful, and other times when a dimensional-spectrum approach will be more useful."



   Copyright 1996-2004. Schizophrenia.com. All Rights Reserved.