References

1. Stahl SM, Mood Disorders, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 453–5102. Stahl SM, Antidepressants, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 511–6663. Stahl SM, Mood stabilizers, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 667–7204. Stahl SM, Selegilene, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 489–965. Stahl SM and Felker A. Monoamine oxidase inhibitors: a modern guide to an unrequited class of antidepressants. CNS Spectrums 13: 10, 855–706. Stahl SM, Lithium, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 277–827. Stahl SM, Ziprasidone, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 589–948. Schwartz TL and Stahl, SM, Ziprasidone in the Treatment of Bipolar Disorder, in Akiskal H and Tohen M, Bipolar Psychopharmacotherapy: Caring for the Patient, 2nd edition, Wiley Press, in press

Patient FileThe Case: The young woman whose doctors could not decide whether she has schizophrenia, bipolar disorder or both

The Question: Is there a such thing as schizoaffective disorder?

The Dilemma: Does treatment depend upon whether the diagnosis is schizophrenia, bipolar disorder or schizoaffective disorder?

Pretest Self Assessment Question(answer at the end of the case) In recent studies, the classical discontinuity hypothesis for schizophrenia and affective disorders has been consistently:

A. Corroborated

B. Rejected

C. None of the above

Patient Intake 26-year-old female arrives with both her parents

Chief complaint: “I’m here because of my parents; I’m completely normal and I do not need medications”

The patient has a four-year history of psychotic illness; and according to her parents has had a progressive downhill course following the onset of her illness

She has delusions and hallucinations, which seem not to be treatable in a robust way with usual doses of antipsychotics

Psychiatric History Prior to onset of psychotic symptoms, thought to have an anxiety disorder at age 20, and given diazepam (Valium), but a few months later clearly had a psychotic break

Psychiatric History of First Psychotic Break: Schizophrenia Onset of psychotic illness characterized by delusions and hallucinations without prominent affective symptoms at age 21, when she was a junior in college, diagnosed as schizophrenic

She was hospitalized and given haloperidol initially, followed by risperidone (Risperdal)

Risperidone seemed not to work, so she was switched to olanzapine (Zyprexa) plus escitalopram (Lexapro) and clonazepam (Klonopin), which she received as an outpatient after leaving the hospital

She was well enough after this to start as a teacher’s aide, but was not well enough to go back to college

Psychiatric History of Second Psychotic Break: Mania After a brief time she stopped her medications and relapsed into what was diagnosed as a manic episode, but with clear psychotic symptoms as well

She had ideas of reference, particularly about God controlling her and that she was a prophet, and had themes of religiosity

She reinstituted olanzapine and added lamotrigine (Lamictal), and then moved away from home

Psychiatric History of Third Psychotic Break: Mania Because of weight gain she switched to ziprasidone (Geodon, Zeldox) while maintaining lamotrigine, but then stopped ziprasidone and developed recurrent manic/psychotic symptoms diagnosed as bipolar disorder

Psychiatric History of Unremitting Psychosis: Schizoaffective Disorder She was hospitalized for six months at a residential treatment center and diagnosed as schizoaffective disorder

She refused medications until forced to take them by legal proceedings

She was then given ziprasidone, lamotrigine, haloperidol (Haldol), lorazepam (Ativan), and lithium

Brief trials with aripiprazole (Abilify) and lithium were unimpressive

She was then switched to olanzapine plus lamotrigine

She was doing poorly, apparently unresponsive to her medications despite several months of treatment, so her parents took her out of the long term residential treatment facility and brought her home

Psychiatric History: Treatment Resistant Schizoaffective Disorder The patient comes in for her initial psychiatric evaluation 6 months after leaving the residential treatment facility. She is still living at her parents’ home and continues to take olanzapine 30 mg/day and lamotrigine 400 mg/day

Her response has been poor

She is not experiencing weight gain; her only significant side effect is gastrointestinal (GI) discomfort

Social and Personal History Non smoker

Some girlfriends, some dating in high school but little dating in college

Denies use of drugs, alcohol, marijuana

Medical History Normal BMI and BP

Routine blood tests including fasting glucose and triglycerides are normal

Family history Paternal uncle: “mentally unstable”

Maternal uncle: posttraumatic stress disorder (PTSD) and paranoid state

Paternal grandmother: hospitalized long ago for some sort of psychotic break

Patient Intake During evaluation she seems a bit hebephrenic

She is somewhat tangential and incoherent and is quite disruptive

She exhibits inappropriate laughter and constant interruptions as well as occasional affective irritability

She states, “My fiancé is a beautiful butterfly; there are caterpillars in the world. I don’t want you talking to my parents. God is talking to me.”

She is not able to track direct questions; she sits silently for 30 seconds or longer after direct questioning and then goes on talking with psychotic content

By the end of the interview she is leaning forward, her head on her hands and knees, unresponsive to attempts to explain things to her

She is not currently suicidal but is also not extremely responsive to direct questioning

Do you find the designation of schizoaffective disorder useful in your practice?

Yes

No

Based on the information provided, how would you diagnose this patient?

Bipolar I disorder

Schizoaffective disorder

Schizophrenia

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation Current evaluation confirms psychotic disorder, with lack of insight, probably more schizophrenic than schizoaffective, with bipolar disorder doubtful

By history she seems to have had some affective episodes, so at this time her best working diagnosis may be schizoaffective disorder

Seems to have had psychotic episodes not only when manic, but also when depressed and even when mood apparently normal

Do you treat schizoaffective disorder differently than you do schizophrenia?

Yes

No

Of the following options, which antipsychotic would you choose for this patient?

Increase dose of olanzapine (currently at 30 mg/day)

Switch to quetiapine (Seroquel)

Switch to clozapine (Clozaril)

Switch to an intramuscular formulation of one of the antipsychotics

Get plasma drug levels of her current olanzapine and lamotrigine to see if she is absorbing them and/or is compliant

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation, Continued She has affective and psychotic symptoms over the past 5 years, often at the same time, episodically, and clearly disabling and at times requiring hospitalization

The history is not clear in terms of what symptoms she had at what times, and the parents, patient and medical records are conflicting as to whether this is more consistent with schizophrenia, mania or schizoaffective disorder during various episodes

Regardless of her actual diagnosis, the most striking thing is that she has an apparent lack of response to antipsychotics, with waxing and waning of psychotic symptoms not clearly changing when medications given, but also not clear how compliant she has been

The patient is not currently out of control, and her parents believe that hospitalization is not necessary

Decided to keep medication treatment unchanged and find out what her plasma drug levels are

Case Outcome: First Interim Followup, Week 4 Her lamotrigine level is high normal and her olanzapine level is within the therapeutic range; thus, she is compliant and absorbing her medications at the present time despite stating she does not need to take medications

Her lamotrigine dose is decreased from 400 mg/day to 200 mg/day– There is not much evidence to suggest that 400 mg is more effective than 200 mg for bipolar disorder and the patient believes her GI upset is due to the higher dose of lamotrigine

Her olanzapine dose is increased to 40 mg/day

Case Outcome: Second Interim Followup, Week 8 No improvement in psychosis or affect, but patient believes her GI symptoms are better

Instructed to increase her olanzapine dose to 50 mg/day

Case Outcome: Third Interim Followup, Week 12 No improvement, so instructed to increase her olanzapine to 60 mg/day

Case Outcome: Fourth Interim Followup, Week 16 No improvement, but sedated; no notable weight gain

Switched to clozapine

Case Outcome: Fifth Interim Followup, Week 20 Still no improvement, but continues on clozapine plus lamotrigine

Case Debrief There is current debate surrounding the clinical utility of schizoaffective disorder as a diagnosis

An unequivocal definition of schizoaffective disorder does not exist, with differences between ICD-10 and DSM-IV. Diagnostic reliability is also relatively low, with many patients changing their diagnosis over time to bipolar disorder or schizophrenia

At the neurobiological level there is evidence both in favor of and against separation of psychotic and affective disorders, depending on the dimension studied

Whatever the diagnosis, there is apparent treatment resistance to antipsychotics so far

Take-Home Points Schizoaffective disorder may be a way for a clinician to avoid making a decision as to whether the patient has either schizophrenia or bipolar disorder

Few hints from neuroimaging or genetics studies exist to help differentiate schizophrenia from bipolar disorder, let alone from schizoaffective disorder

Kraepelin proposed a classical dichotomy, of two separate diseases to explain severe mental illness, one with a poorer outcome (schizophrenia or dementia praecox) and one with a better outcome (manic depressive illness or bipolar disorder)

What about cases in between? Even Kraepelin recognized numerous such cases

It can be very difficult in practice to determine whether a patient is schizophrenic, bipolar or schizoaffective, particularly at the beginning of the illness, and particularly if the same examiner has not observed the patient over time and in different clinical states

The diagnostic debate may be more of an academic exercise than a clinically useful designation

Empirically, it is important to search for mood symptoms in psychotic patients, and to treat these with mood stabilizers as well as antipsychotics

Performance in Practice: Confessions of a Psychopharmacologist What could have been done better here?– More active efforts to retrieve old medical records or to speak directly with clinicians who managed her case over the past 5 years may have thrown light on the diagnosis– Such information may also help clarify if the patient really has failed to respond to medications or if some medications were more effective than others, or indeed whether she was noncompliant at times– In fact, times when she knowingly discontinued medications were associated with recurrent psychosis and rehospitalization, so even though medication did not restore her to full asymptomatic function, her medications may have been useful in preventing acute relapses

Possible action item for improvement in practice– Focus on treatment rather than diagnosis– Search more carefully for mood symptoms over her past course of illness– Emphasize mood stabilizers such as valproate or lithium rather than antipsychotics, since antipsychotics are not robustly restoring her function– Look into vocational rehabilitation now that the patient is in a stable living situation at home

Tips and Pearls Chaos is chaos no matter what you call it

There is no such thing as schizoaffective disorder. Long live schizoaffective disorder (see references to this debate at the end of this case)

The question of diagnosis can distract the clinician and family from efforts to restore function and even attain a symptomatic and functional recovery from a psychotic illness of any kind

Two-Minute Tute: A brief lesson and psychopharmacology tutorial (tute) with relevant background material for this case – Schizophrenia vs bipolar vs schizoaffective

The dichotomous disease model and schizoaffective disorder The dichotomous disease model in the tradition of Kraepelin proposes that schizophrenia and bipolar disorder are separate and distinct diseases

In the Kraepelinean model, schizophrenia is a chronic unremitting illness with a poor outcome and a decline in function (non restitutio ad integrum) whereas bipolar disorder is a cyclical illness with a better outcome and good restoration of function between episodes (restitution ad integrum)

However, there is great debate as to how to define the borders between these two illnesses

One notion is that cases with overlapping symptoms and intermediate disease courses can be seen as a third illness, schizoaffective disorder

Today, many define this border with the idea that “even a trace of schizophrenia is schizophrenia”

From this “schizophrenia centered perspective,” many overlapping cases of psychotic mania and psychotic depression might be considered to be either forms of schizophrenia, or to be schizo-affective disorder with schizoaffective disorder seen as a form of schizophrenia with affective symptoms

A competing point of view within the dichotomous model is that “even a trace of mood disturbance is a mood disorder”

From this “mood/affective-centered perspective,” many overlapping cases of psychotic mania and psychotic depression might be considered to be either forms of a mood/affective/bipolar disorder or to be schizo-affective disorder with schizoaffective disorder seen as a form of mood/affective/bipolar disorder with psychotic symptoms

Where patients have a mixture of mood symptoms and psychosis, it can be difficult to tell whether they have a psychotic disorder like schizophrenia, a mood disorder like bipolar or a schizoaffective disorder, or even whether these are distinctions without a difference

Proponents of the dichotomous model point out that treatments for schizophrenia differ from those for bipolar disorder, since lithium is rarely helpful in schizophrenia, and anticonvulsant mood stabilizers have limited efficacy for psychotic symptoms in schizophrenia, and perhaps only as augmenting agents

Treatments for schizoaffective disorder can include both treatments for schizophrenia and treatments for bipolar disorder

The current debates within the dichotomotous model are: If you have bipolar disorder do you have a good outcome and if you have schizophrenia do you have a poor outcome? What genetic and biological markers rather than clinical symptoms can distinguish one from another?

The single disease continuum model and schizoaffective disorder The single disease model proposes that schizophrenia and bipolar disorder are opposite ends of the spectrum of the same disease, with schizoaffective disorder in the middle of this spectrum

Today, it is not clear whether psychotic mood disorders, either mania or depression, are phenotypically or genotypically distinguishable from the traditional conceptualization of schizophrenia

The current debate within the continuum model is whether this is a multifaceted expression of a single disease or whether the spectrum consists of many different diseases, with overlapping genetic, epigenetic and biomarkers as well as overlapping clinical symptoms and functional outcomes

Basic science may be telling us there is only one highly complex disease

Proponents of the continuum model point out that treatments for schizophrenia overlap greatly now with those for bipolar disorder, since second generation atypical antipsychotics are effective in the positive symptoms of schizophrenia and in psychotic mania and psychotic depression, and are also effective in nonpsychotic mania and in bipolar depression and unipolar depression

These same second generation atypical antipsychotics are effective for the spectrum of symptoms in schizoaffective disorder

From the single disease perspective, failure to give mood stabilizing medications may lead to suboptimal symptom relief in patients with psychosis, even those whose prominent psychotic symptoms mask or distract clinicians from seeing underlying and perhaps more subtle mood symptoms

In the one disease model, schizophrenia can be seen as the extreme end of a spectrum of severity of mood disorders and not a different disease

Schizophrenia and schizoaffective disorder can both therefore have severe psychotic symptoms that obscure mood symptoms and a chronic course that eliminates cycling, shows resistance to antipsychotic treatments, and prominent negative symptoms, yet be just a severe form of the same illness

In this one disease model, schizoaffective disorder would be a milder form of the illness with less severe psychotic features and more severe mood features

The debate rages on …

Posttest Self Assessment Question: Answer In recent studies, the classical discontinuity hypothesis for schizophrenia and affective disorders has been consistently:

A. Corroborated

B. Rejected

C. None of the above

Answer: C