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, Lamotrigine in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 259–665. Stahl SM, Lithium, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 277–826. Stahl SM, Ziprasidone, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 589–947. Stahl SM, Aripiprazole, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 45–508. 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

Patient FileThe Case: The son whose parents were desperate to have him avoid Kraepelin

The Question: Can you forecast whether an adolescent will become bipolar, schizophrenic or recover?

The Dilemma: Should you treat symptoms empirically when the diagnosis changes every time the patient comes for a visit?

Pretest Self Assessment Question(answer at the end of the case) Which symptom would better fit a mood disorder spectrum rather than a psychotic disorder spectrum?

A. Affective symptom

B. Cognitive symptom

C. Social symptom

Patient Intake 18-year-old male adolescent

Chief complaint: Depressive mood, with deterioration of social and cognitive performance at school

Psychiatric History: Childhood By age 7, patient developed symptoms consistent with attention deficit disorder, and was treated with stimulants from age 7 to 13

He did very well on stimulants, had good performance in school and adequate peer relationships, although he was somewhat more isolative and less social than his peers

Psychiatric History: Adolescence By age 13, he had a decided step off in his function, and became progressively unable to interact with peers at school; his school performance also deteriorated

This coincided with a series of several surgeries on his sinuses for a chronic fungal infection

He was evaluated to determine if there was a central nervous system involvement, but that was mostly, although not entirely, ruled out

From age 13 to age 18, the patient has been evaluated at three different major medical centers and was given numerous diagnoses in that period of time– attention deficit hyperactivity disorder– schizoaffective disorder– major depressive disorder– Asperger’s syndrome– bipolar disorder– possible neurologic celiac sprue– possible complications of sinus infections and surgery– most recently, he has been diagnosed as either prodrome of schizophrenia or an autism spectrum disorder, and has begun clozapine (Clozaril) titration, with some day time sedation

He has had symptoms of depression, suicidal ideation, alternating with rage and problems of control

He has not had any overt hallucinations, but has had inappropriate ideas such as being able to move a lock by telekinesis

He has tried many different antipsychotics, anticonvulsants, lithium, and antidepressants– Antidepressants have activated him, similarly to when he used to take stimulants, causing him to be more provokable

Medical History Patient’s past medical history is significant for sinus infections, which are now resolved

Possible sprue, although laboratory testing appears to have ruled this out

Family History Father: panic attacks

Sister: attention deficit hyperactivity disorder

Maternal grandfather: mood swings

Paternal grandmother: depression

Uncle: alcoholism

Cousin: bipolar disorder

Patient Intake Patient arrived on time for his appointment, and was accompanied by his mother for the interview

He was casually dressed in a black T-shirt and appeared to be his stated age

When engaging in conversations, he had appropriate eye contact, however when the examiner was speaking with his mother, he sat with downcast eyes and appeared to be in some distress

He seemed to be forlorn, and even depressed

He seemed to be feeling hopeless in the sense that it was not worth trying and that life no longer had any joy, that he was unable to be happy with the worry that he would never be able to become happy

He was not suicidal although he had had these thoughts in the past and said he just wished someone would kill him

His memory and judgment appeared to be intact

His insight appeared to be limited and the patient appeared to have given up hope

Current medications– Clozapine (Clozaril): 100 mg in the morning and 100 mg at night– Escitalopram (Lexapro, Ciprilex): 5 mg per day

Of the following choices, what would be your differential diagnosis?

Anxiety Disorder

Asperger like syndrome/autistic spectrum disorder

Bipolar disorder

Major depressive disorder

Prodrome of schizophrenia

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation No clear diagnosis, and all the diagnoses in the list above could be considered although an anxiety disorder seems the least likely diagnosis

The patient is clearly a complicated case; but the differential diagnosis should probably be between a prodrome of schizophrenia carrying over from Asperger-like syndrome earlier in development versus a bipolar spectrum disorder with current depressive features

Diagnosis is perhaps not the issue here, and symptoms may be more important to document, track and treat empirically

Despite the history and some of the diagnoses given by previous examiners, this case has more of an affective feel than a psychotic one, based on the history gathered here and according to his current clinical state

This brings up the question of why clozapine is being given

On the other hand, cases like this can morph between appointments and over time, and although he presents with a more affective spectrum appearance today, perhaps diagnostic judgment should be withheld while monitoring for more psychosis spectrum symptoms over the next few appointments and over the next few months

What factors might help you to make a diagnosis or prognosis that the patients are anxious to have and pressing you to deliver?

No clear family history of schizophrenia or psychotic illness

Positive family history of bipolar disorder

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation, Continued Unfortunately, there are no genetic tests or biological markers to distinguish between a schizophrenic versus a bipolar illness; in fact, many research tests overlap between these two diagnoses, rather than distinguish one from another

The previous activation by an antidepressant is of interest, and could suggest a bipolar disorder, but antidepressants can often worsen active psychosis

However, this patient is not actively psychotic and antidepressants can treat prodromal symptoms of schizophrenia

Seems like the best option here is to keep an open mind about diagnosis and reassure the parents that the best action plan may be to reduce symptom burden empirically while not causing unacceptable side effects

The immediate therapeutic goal is to improve social and academic performance, and to reduce the patient’s and family’s current chief complaint, namely depression

How would you treat him now?

Continue treatment as is

Decrease or discontinue clozapine

Increase the dose of clozapine

Discontinue escitalopram

Increase the dose of escitalopram

Add lithium or an anticonvulsant mood stabilizer

Switch to another atypical antipsychotic

Further Investigation: Is there anything else you would especially like to know about this patient?

What about his school placement, vocational placement, how he spends his day, and whether he is participating in psychotherapy or interacting with peers?

– The patient is living at home, not going to school or working, and spends most of his time in bed or watching TV– Denies substance abuse, including alcohol and marijuana– Has not had significant psychotherapy– Parents are intelligent, well read, and well connected to the elite medical community, proactive, supportive and yet anxious about his outcome and feeling a bit guilty– Parents are worried he will develop schizophrenia and want him to avoid this “Kraepelinian” outcome

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation, Continued The dose of clozapine was reduced to 75 mg in the morning and increased to 125 mg in the evening to determine if the patient tolerated the daytime sedation better

as the patient had never had his lipids monitored or his body mass index recorded, this procedure was initiated

The dose of escitalopram was cautiously increased to 10 mg per day to try treating his depressive symptoms

Suggested referral to a psychotherapist, but this suggestion was not enthusiastically received by either the patient or parents

The risks, benefits, and alternatives were explained to the patient and his mother and they consented to the treatment plan

Attending Physician’s Mental Notes: First Interim Followup, Week 4 Unfortunately, the patient became activated on the increased dose of escitalopram

What would you do now to address his depressive symptoms?

Decrease the dose of escitalopram and initiate valproate

Keep the increased dose of escitalopram and initiate valproate

Stop escitalopram and initiate valproate

Attending Physician’s Mental Notes: First Interim Followup, Week 4, Continued The dose of escitalopram was decreased to 5 mg per day

Valproate (Depakote) was added, and once its titration was complete, the dose of escitalopram was again increased to 10 mg per day

Attending Physician’s Mental Notes: Second Interim Followup, Week 8 The patient’s depressive symptoms seemed to resolve over time

Blood counts normal, no weight gain, some sedation

What would you do now about his clozapine treatment?

Continue clozapine

Reduce clozapine dose or discontinue clozapine

Attending Physician’s Mental Notes: Second Interim Followup, Week 8, Continued Seems like this case is responding as if it is a bipolar disorder, with worsening now for the second time on an antidepressant, this time even in the presence of clozapine, and also responding to valproate even though this medication is better documented to treat mania than depression in bipolar disorder

On the one hand, “if it ain’t broke, don’t fix it” and leave well enough alone

On the other hand, he may be “overtreated” with clozapine and a switch to another antipsychotic could be considered but not a discontinuation of all antipsychotics at the present time

The parents are quite reluctant to discontinue clozapine, and since the patient is tolerating it reasonably well, that seems prudent for now

However, if sedation does not improve over time, he may require a dose reduction of clozapine or valproate

In the long run, depending upon clinical response and whether the patient develops any metabolic problems, clozapine may be switched to another antipsychotic

Patient is sent for fasting triglycerides to monitor his insulin resistance, as well as a full lipid panel, and glucose

Now that the patient is in a better space, with more motivation, mother and patient were pressed to pursue weekly psychotherapy at least for support, information, explanation of the treatments, and exploration of how he feels about having this illness and how it is impacting his life and his future

Case Debrief When treating complicated child and adolescent cases, with multiple possible diagnoses, it can be challenging to find the appropriate treatment plan.

In this case, it appeared most useful to treat this patient as an evolving bipolar disorder patient with an antipsychotic, with an anticonvulsant mood stabilizer, and with an antidepressant, although any medication treatment is controversial

This patient’s case is clearly unstable and evolving, with a strong affective nature to the illness and poor social interactions rather than profound current cognitive symptoms

Over the past few months since his initial evaluation, his condition fits the mood disorder spectrum better than the schizophrenia/autism/psychotic disorder spectrum

The cognitive and social symptoms are consistent either with a schizophrenia prodrome or with reversible symptoms of an affective disorder, but it is too soon to tell or to pass long term diagnostic judgment or to make accurate prognostic statements

For now, it seems logical to first stabilize this patient’s mood and see what happens, at least offering short term relief of that symptom

Although it makes examiners, parents and patients uneasy, the fact remains that only time will tell.

Take-Home Points Childhood onset psychiatric disorders are wild cards, and the current state of the art unfortunately is that it is not yet possible to predict with great accuracy the natural history of psychiatric illness in a given individual

In general, however, the earlier the onset of symptoms, and the more severe, the worse the outcome, especially if poor school performance and peer interactions damage the development of a healthy self esteem

Genetic and neuroimaging tests of high risk individuals seek to predict who will get schizophrenia, but these remain research tools and not yet very helpful in clinical practice

No drug is approved for the social withdrawal and cognitive decline of the schizophrenia prodrome, but these same symptoms can be due to an affective disorder for which there are a number of treatments available even in children and adolescents

It is often best to make an optimistic diagnosis and an optimistic prognosis in cases like this to keep hope alive and to justify attempts at symptomatic therapeutic interventions if risks are outweighed by the potential benefits

However, there is no documented disease modification by any medication to alter the natural history of whatever illness underlies the symptoms in such cases

Performance in Practice: Confessions of a Psychopharmacologist What could have been done better here?

– Parents may be interested in research evaluation with neuroimaging, neuropsychological testing, and genetic testing, given that they pursue medical evaluations and second opinions at a number of top medical centers– The pursuit of a diagnosis may be a distraction from empiric focus on reducing current symptoms and dealing with the anxiety that is caused by so many unknowns– On the other hand, inheriting a patient already on clozapine can seem very aggressive treatment given the state of the evidence supporting that approach

Possible action item for improvement in practice– Supporting the family in getting the best available diagnostic and therapeutic information while helping them work through the crisis of having an uncertain diagnosis with uncertain treatments and uncertain long term outcomes, due to the nature of the state of the art and not due to going to the wrong doctors or medical centers– Reassure with distribution of the latest information and cutting edge findings without avoiding the need for here and now treatments of symptoms, for which not only medications but also potentially psychotherapy may be useful. Going to school and working outside the home can also be therapeutic while the ambiguities of the ultimate diagnosis and outcome are still in limbo

Tips and Pearls For cases like this, be skeptical of the apparent diagnosis on any given visit

Track symptoms and their severity, and empirically treat while being careful to monitor side effects

Affective symptoms may be a better prognostic sign than psychotic or negative or cognitive symptoms, and in this case were apparently responsive to treatment in a family with first degree relatives who have bipolar disorder but no schizophrenia

Children and adolescents with ever changing psychiatric symptoms and diagnoses without robust treatment responses should be monitored carefully for progression of symptoms

To treat or not to treat, that is the question– Clinicians must decide whether to err on the side of undertreatment (error of omission)– or on the side of overtreatment (error of commission) since prodromal cases have unpredictable outcomes

Genetic testing and biological markers are poised to enter clinical practice but are not understood well enough for routine clinical use

Ad hoc, ergo propter hoc: just because the patient improves after a given medication does not mean that he improves because of a given medication. That is, symptoms wax and wane spontaneously, and even though the patient was on powerful medications, he may have improved because of a fluctuating illness and not because of treatment response, so keep an open mind as to how to treat him in the future if his symptoms recur or new ones develop, especially on stable medication treatment

Two-Minute Tute: A brief lesson and psychopharmacology tutorial (tute) with relevant background material for this case – Ultra high risk of psychosis

– Schizophrenia prodromes

Criteria for ultra high risk of psychosis: one or more of the following1. Attenuated psychotic symptoms, having experienced sub-threshhold attenuated psychotic symptoms during the past year2. Brief limited intermittent psychotic symptoms, having experienced episodes of frank psychotic symptoms that have not lasted longer than a week and have been spontaneously abated3. State and trait risk factors, having schizotypal personality disorder or a first-degree relative with a psychotic disorder and have experienced a significant decrease in functioning during the previous yearNeuropsychological functioning in ultra high risk of psychosis Global neuropsychological functioning is significantly lower in ultra high risk individuals who progress to psychosis than in those who do not, and is worst in those with a family history of psychosis

Processing speed is reduced in ultra high risk individuals compared to normal controls

Verbal learning and memory are reduced in ultra high risk individuals compared to normal controls

Visuospatial functioning may be relatively spared

Verbal memory deficits may indicate a prefrontal-hippocampal neurodevelopmental abnormality

Generalized neurocognitive impairment may be a nonspecific vulnerability marker

Neurocognitive deficits in schizophrenia are largely uncorrelated with positive symptoms

Neurocognitive deficits in schizophrenia only modestly improved if at all by antipsychotic treatment

Prodromes: are making a diagnosis and prescribing treatment merciful or ahead of the data? Dopamine overactivity may predate the onset of schizophrenia in those with prodromal psychotic symptoms

Dopamine overactivity may correlate with severity of prodromal symptoms and neurocognitive dysfunction

Reduced cortical connectivity in schizophrenia is likely to be present from birth

Hypothetically, if this progresses beyond a critical threshold, psychotic symptoms erupt as a function of normal neuromaturational events such as synaptic pruning during adolescence, and/or environmental insults

Frequent diagnoses in patients who saw psychiatrists before the diagnosis of schizophrenia– Impulse disorder not otherwise specified– ADHD– Bipolar disorder not otherwise specified

Posttest Self Assessment Question: Answer Which symptom would better fit a mood disorder spectrum rather than a psychotic disorder spectrum?

A. Affective symptom

B. Cognitive symptom

C. Social symptom

Answer: A