References

1. Kaplan GB, Vasterling JJ, and Vedak PC. Brain-derived neurotrophic factor in traumatic brain injury, post-traumatic stress disorder and their comorbid conditions: role in pathogenesis and treatment. Behav Pharmacol 2010; 21(506): 427–372. Sayer NA, Rettmann NA, Carlson KF et al. Veterans with history of mild traumatic brain injury and posttraumatic stress disorder: challenges from provider perspective. J Rehabil Res Dev 2009; 46(6): 703–163. Vanderploeg RD, Belanger HG, and Curtiss G. Mild traumatic brain injury and posttraumatic stress disorder and their associations with health symptoms. Arch Phys Med Rehabil 2009; 90(7): 1084–934. Hill JJ 3rd, Mobo BH Jr, and Cullen MR. Separating deployment-related traumatic brain injury and posttraumatic stress disorder in veterans: preliminary findings from the Veterans Affairs traumatic brain injury screening program. Am J Phys Med Rehabil 2009; 88(8): 605–145. Pietrzak RH, Johnson DC, Goldstein MB et al. Posttraumatic stress disorder mediates the relationship between mild traumatic brain injury and health and psychosocial functioning in veterans of Operations Enduring Freedom and Iraqi Freedom. J Nerve Ment Dis 2009; 197(10): 748–536. Hoge CW, Wilk JE, and Herrell R. Methodological issues in mild traumatic brain injury research. Arch Phys Med Rehabil 2010; 91(6): 9637. Hoge CW, McGurk D, Thomas JL et al. Mild traumatic brain injury in U.S. soldiers returning from Iraq. N Engl J Med 2008; 358(5): 453–638. Hoge CW, Goldberg HM, Castro CA, Care of war veterans with mild traumatic brain injury – flawed perspectives, New Eng J Med 2009 360: 1588–919. Stahl SM, Anxiety Disorders and Anxiolytics, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 721–7210. Stahl SM, Duloxetine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 165–7011. Stahl SM, Lorazepam, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 295–912. Stahl SM, Stahl’s Illustrated Anxiety, Stress and PTSD, Cambridge University Press, New York, 2010

Patient FileThe Case: The young man who is failing to launch

The Question: What is the underlying illness and when can you make a long term diagnosis?

The Dilemma: What can you do for a young adult on a tragic downhill course of social and cognitive decline?

Pretest Self Assessment Question(answer at the end of the case) Individuals who ultimately develop schizophrenia typically exhibit what pattern of cognitive functioning prior to disorder onset?

A. Normal cognitive functioning during premorbid and prodromal phases

B. Impaired cognitive functioning that is stable across premorbid and prodromal phases

C. Impaired cognitive functioning premorbidly with further decline during the prodromal phase

D. Progressive decline of cognitive functioning across premorbid and prodromal phases

Patient Intake 21-year-old man who states he has no chief complaint but is here because his parents made him come

The chief complaint of the parents is that their son is not transitioning successfully into independent adult life (i.e., failure to launch)

Early Psychiatric History: Childhood and Adolescence Obtained from the parents and from medical and school records

The patient has been aloof and a loner with strange ideas and behaviors since childhood

Somewhat rigid and obsessive; needs to follow a strict order when doing things

Language development in grade school appeared normal, but had difficulty reading and was considered learning disabled by third grade

Was considered to have possibly a form of ADHD and thus given methylphenidate (Ritalin) as a child without clear therapeutic effects

Was then considered to have possibly a form of OCD and thus given trials of fluvoxamine (Luvox, Faverin) and venlafaxine (Effexor XR) as an adolescent to treat some obsessive compulsive tendencies but without clear therapeutic effects

Recent Psychiatric HistoryLate Adolescence and Early Adulthood After graduation from high school, went on a two year mission for his church

On his mission, he was picked on, as his peers considered him slow and dumb

Upon his return, his family immediately noted a dramatic change in function and behavior

He seemed disorganized and confused, had strange behavioral changes and displayed noticeable deterioration in his handwriting, reading, and communicating including using simple language

Did not complete sentences, had long delays in conversation in order to organize his thoughts, was not engaging in conversations, and let his conversations trail off

There was a noticeable change in his voice quality and he had inappropriate facial grimaces

He has been losing things, including pay checks; doesn’t seem to know how to use an ATM (Automated Teller Machine at the bank) or fill out deposit slips

Does not groom or change his clothes unless prompted by his mother

Appears immature and childlike and seems to have difficulty understanding nuances and complex language, both written and spoken

Some are wondering whether he had exposure to meningitis while on his mission, but no accurate diagnosis appears in his mission chart

Patient was recently prescribed atomoxetine (Strattera) with no clear response

Social and Personal History Non smoker

No past or current history of drug abuse, including alcohol and marijuana

Few friends, no dating

Has not attended college since graduating high school

Has been living at home for a year since returning from his mission

Family History Father: history of learning disabilities, but is a successful small businessman now

Sister: ADHD and learning disabilities

Two maternal uncles: depression

Paternal cousin: diagnosed with Landau Kleffner syndrome (a rare disorder of childhood with aphasia and an abnormal EEG, sometimes confused with or misdiagnosed as autism, Aspberger’s Syndrome, pervasive developmental disorder, hearing impairment, learning disability, auditory/verbal processing disorder, ADHD, mental retardation, childhood schizophrenia or emotional/behavioral problems)

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation This started out looking like a case of ADHD or some sort of minor learning disability, possibly morphing into OCD in adolescence, but then something horrible seems to have happened during his mission

Does he have a condition related to what his cousin has (Landau Kleffner syndrome)?

Although this could be a schizophrenic prodrome, could it also be an organic brain disorder from infection, chronic subdural hematoma, brain tumor, or seizure disorder?

Medical History Normal BMI, BP

Routine blood tests normal

Normal physical and neurological exams

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

– What about a detailed neurological evaluation and neuropsychological testing?Neurological Evaluation– Possible diagnosis of previous developmental learning difficulties in grade school– In retrospect, had a period of severe somnolence during a bad respiratory infection while on his mission, so considered the possiblility of a missed diagnosis of previous meningitis– MRI several months after this episode of somnolence and respiratory infection is negative except for a few non-specific bilateral frontal lobe white matter high-signal foci– EEG is within normal limitsNeuropsychological Testing– Neuropsychological testing shows problems with executive functioning, organization, and suggestion of schizoid personality disorder or schizophrenia– Has a documented decline in IQScore in 9th grade:– Verbal IQ of 107– Performance IQ of 113– Full Scale IQ of 111Score now:– Verbal IQ of 89– Performance IQ of 85– Full Scale IQ of 87

Patient Intake First time patient is seen, he is accompanied by his father and mother

Patient is awkward, detached, aloof, and seems anxious and withdrawn

He is able to relate tentatively to physician and to speak with a reserved and simple language processing style

He is able to understand and relate to simple questions, but seems to get lost when the pace of the conversation between physician and parents accelerates and becomes more complex and subtle

Second time patient is seen, he is accompanied by his mother only

He is more socially engaged and relaxed, has better eye contact and shows humor

At times, he is even poignant in his relationship with his mother: when she discusses his qualities of having empathy and tenderness his mother becomes tearful and the patient is able to connect with her in way that shows he is clearly able to track the nature of the conversation

His memory appears to be intact

Has good judgment

Uses only simple language but is not bizarre and has no delusions or hallucinations

There is evidence of slow cognition and executive dysfunction but no actual problems with short term memory

Has some insights into his condition

Wishes to have a job where he could work by himself, i.e., as a truck driver, and live in the mountains

Is willing to go to school and live at home for a while, but would like to live independently

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation It appears as though organic causes of this patient’s symptoms have been ruled out

However, prodromal symptoms of schizophrenia overlap with normal behaviors and also with behaviors of numerous other more benign psychiatric disorders and cannot be considered diagnostic: superstitiousness, irritability, distractibitiliy, anxiety, social withdrawal

The parents want to know if there are genetic tests or biological markers yet available to help make the diagnosis of eventual schizophrenia or if they must simply wait for the next shoe to drop, namely a first break episode of psychosis

What would you do?

Tell them that there are no genetic tests for schizophrenia

Tell them that there is no way to prevent schizophrenia

Refer them to an academic medical center for research

Refer them to the internet

Case Outcome: First Interim Followup At this point, the family was informed that genetic or biological predictors of schizophrenia remain research tools, although many lines of evidence converge upon abnormalities of the NMDA (N-methyl-d-aspartate) glutamate receptor and glutamate synapses in schizophrenia

A potential referral was discussed with the family to a schizophrenia genetics research center, for potential genotyping of affected and unaffected family members, particularly on the father’s side, including the cousin with Landau Kleffner syndrome

However, the family was cautioned that this information would not have immediate value in informing the family about the diagnosis of this patient, but might help future family members or others with similar symptoms

Besides glutamate genes, the research center could evaluate genetic variants of both the dopamine metabolizing enzyme COMT (catechol-O-methyl transferase) and the L-methyl folate forming enzyme MTHFR (methylene tetrahydrofolate reductase), since variants of these enzymes interact to enhance the chances of cognitive dysfunction in schizophrenia

However, these studies are “ahead of the curve” for clinical practice and would not be covered by insurance and it is not yet possible to use this strategy to predict the outcome of this patient, even though such a possibility may be introduced into clinical practice soon

From the information given, what do you think is his most likely diagnosis?

Asperger’s Syndrome

Prodrome of schizophrenia

Schizophrenia

Schizoid personality disorder

Severe form of social anxiety with underlying developmental delays

Attending Physician’s Mental Notes: First Interim Followup Patient possibly meets diagnostic criteria for Asperger’s Syndrome at the present time, although the disorder and its symptoms are not stable and continue to evolve:– Pervasive developmental disorder characterized predominantly by impairment in social interaction without profound delay in language

Recent step off in his function may be categorized as prodrome of schizophrenia– Diagnosis of schizophrenia is not currently possible, but social oddities and cognitive disturbances, predominantly of an executive dysfunctioning, is quite typical of a schizophrenic prodrome

Severe form of social anxiety superimposed upon developmental delays and/or schizoid personality may be considered but is less probable

The patient is provisionally diagnosed as pervasive developmental disorder of the Asperger’s type, but is monitored for the possible progression of further symptoms of schizophrenia

No diagnosis of schizophrenia made at this point

One new concept that could fit this patient is “ultra high risk for developing psychosis,” as he meets the criteria of state and trait risk factors (i.e., has a first degree relative with a psychotic disorder plus he has experienced a significant decrease in functioning)

Now the family wants to know if there is any treatment for their son, to reduce his symptoms or to prevent the onset of schizophrenia

What would you do?

Tell the patient and his family that there is no approved treatment for the schizophrenia prodrome

Tell them that there is no known treatment that can prevent progression of a prodrome to schizophrenia and that not all patients with a prodrome progress to schizophrenia anyway

Tell them that treatments for schizophrenia have considerable expense and risks, including diabetes, weight gain, dyslipidemia, sedation, and tardive dyskinesia and that the risk:benefit calculation is in favor of observation without treatment

Tell them that symptomatic treatments with anxiolytics, antidepressants, omega-3 fatty acids, or antipsychotics may be justified but are “off label” and unapproved

Attending Physician’s Mental Notes: First Interim Followup, Continued No approved treatment for schizophrenia prodrome

Many studies of atypical second generation antipsychotics, antidepressants, omega-3 fatty acids and anxiolytics in patients at high risk for developing psychosis have some encouraging results in reducing current symptoms but not necessarily delaying onset of first episode psychosis

Should one err on the side of overtreatment or undertreatment?

On balance, it was decided to treat the patient psychopharmacologically

Of the following choices, how would you treat this patient?

Continue atomoxetine

Stop atomoxetine and start an anxiolytic drug

Stop atomoxetine and start an antidepressant

Stop atomoxetine and start an atypical antipsychotic

Attending Physician’s Mental Notes: First Interim Followup, Continued Discontinued atomoxetine

A trial of an atypical antipsychotic may be indicated, at least to treat current symptoms, as some studies have shown symptomatic relief but not convincing prophylactic measures against progression to psychosis, nor improvement in current functional disability– Might be beneficial to help the patient interact socially and reduce his anxiety as well as improve cognitive functioning, although the latter is the least likely effect of antipsychotic treatment– In order to justify short term trials of antipsychotics, criteria will be established to determine whether continuing treatment is indicated– Specifically, over the next 6 months look to see if the following three items improve in order to define a positive outcome from medication treatment:– More flexibility– Less anxiety in social settings– More organizing skills

Atypical antipsychotics may also be useful in treating certain symptoms associated with pervasive developmental disorder, but this is also an “off label” use of antipsychotics

Started aripiprazole (Abilify) (can have less weight gain and sedation than some other choices, but actually not as well studied in the schizophrenia prodrome as other choices), dosed at 2.5 mg per day for 3–4 days, increasing then to 5 mg per day for several days to reach to a maximum of 10 mg per day

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

Patient is also advised to continue rehabilitative efforts:– Mathematics classes at a community college to supplement his training– Social skills settings to improve his interaction with peers

Case Outcome: Second and Subsequent Interim Followup, Over the Next 3 Months Minor improvements, no notable side effects

Sertraline (Zoloft) added for social anxiety and apathy

No dramatic changes, and no onset of psychosis (yet)

Case Debrief Asperger’s syndrome or pervasive developmental disorder is a subset of the broader autism phenotype

Many children, especially those with Asperger’s syndrome, are initially misdiagnosed with ADHD

Unlike Asperger’s syndrome, schizoid personality disorder does not involve an impairment in non-verbal communication (i.e., lack of eye-contact) or a pattern of restricted interests or repetitive behaviors

Prodrome refers to an early set of symptoms, and in schizophrenia has been characterized as the period of decreased functioning that precedes the onset of psychotic symptoms

This patient did exhibit lack of non-verbal communication at one appointment but not at the second one; he may not fit neatly into the diagnostic criteria of any specific disorder which makes this case interesting

Only the future will tell.…

Take-Home Points It is not possible to predict with great accuracy who will get schizophrenia, but certain symptoms such as social withdrawal and cognitive decline can identify teenagers and young adults at high risk

Genetic and neuroimaging tests of high risk individuals seek to predict who will get schizophrenia, but these remain research tools

To treat or not to treat: that is the question

No drug is approved for the social withdrawal and cognitive decline in the schizophrenia prodrome, but numerous studies of antipsychotics, antidepressants, anxiolytics and omega 3 fatty acids suggest that some patients can attain symptomatic relief and may even delay the onset of first episode psychosis, but there is little evidence of disease modification by these medications such that schizophrenia can be prevented

Nevertheless, it may be justified in some cases to treat symptomatically if risks are outweighed by the potential benefits, in recognizing that such use of these medications is not approved

Performance in Practice: Confessions of a Psychopharmacologist What could have been done better here?– Is false hope being raised by referral for genetic testing?– Is the possibility of an unproven therapeutic benefit short term justified by the costs and risks of psychotropic medications?– Is watchful waiting without treatment therapeutic nihilism or the correct approach?

Possible action item for improvement in practice– Have available written materials for the patient and parents to read about genetic testing and prodromal treatment studies in schizophrenia– Utilize more aggressive approaches to psychotherapy and rehabilitation

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

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

Schizophenia, is well known for its positive symptoms of delusions and hallucinations, which in turn are proven to improve with antipsychotic medications; however it is actually a disease beginning with cognitive and negative symptoms, erupting into positive symptoms later, but with functional outcome more clearly linked to severity of cognitive and negative symptoms than to positive symptoms

Two-Minute Tute: A brief lesson and psychopharmacology tutorial (tute) with relevant background material for this case – Clinical and genetic predictions of schizophrenia

– Genetic influences on cognition in schizophrenia

Table 1: Criteria for Ultra High Risk of Psychosis (One or More of the Following)1. 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 yearTable 2: Susceptibility Genes for SchizophreniaGenes for Dysbindin (dystrobrevin binding protein1 or DTNBP1)

Neuregulin (NRG1)

DISC-1 (disrupted in schizophrenia 1)

DAOA (d-amino acid oxidase activator;G27/G30)

DAO (d-amino acid oxidase)

RGS4 (regulator of G protein signaling 4)

COMT (catechol-0-methyl transferase)

CHRNA7 (alpha-7 nicotinic cholinergenic receptor)

GAD1 (glutamic acid decarboxylase 1)

GRM3 (mGluR3)

PPP3CC

PRODH2

AKT1

ERBB4

FEZ1

MUTED

MRDS1 (OFCC1)

BDNF (brain-derived neurotrophic factor)

Nur77

MAO-A (monoamine oxidase A)

Spinophylin

Calcyon

Tyrosine hydroxylase

Dopamine D2 receptor (D2R)

Dopamine D3 receptor (D3R)

Figure 1: Clinical Course of Schizophrenia The stage of schizophrenia are shown here over a lifetime. The progressive nature of schizophrenia supports a neurodegenerative basis for the disorder. Stage I: The patient has full (100%) functioning early in life and is virtually asymptomatic. Stage II: During a prodromal phase that starts in the teens, there may be odd behaviors and subtle negative symptoms. Stage III: The acute phase of the illness usually announces itself fairly dramatically in the twenties with positive symptoms, remissions, and relapses. But the patient never quite returns to previous levels of functioning. This is often a chaotic stage of illness with a progressive downhill course. Stage IV: The final phase of the illness may begin in the forties or later, with prominent negative and cognitive symptoms. Although there is some waxing and waning, this is often more of a “burnout” stage of continuing disability. The illness may not necessarily take a continual and relentless downhill course, but the patient may become progressively resistant to treatment with antipsychotic medications during this stage.

Figure 2: COMT Genetic influence on circuits that regulate executive functioning can be demonstrated by comparing functional neuroimaging date from individuals with different variants of the catechol-O-methyl transferase (COMT) gene while they are performing the n-back test. COMT is an enzyme that metabolizes dopamine. Although COMT is active at all DA synapses, it is most important for regulating DA levels in brain areas that are relatively lacking in DA transporters, such as the PFC (prefrontal cortex). Thus, when COMT activity is high, dopamine levels are low. Since dopamine profoundly affects the information processing of pyramidal neurons in the PFC, it also profoundly influences cognitive functioning.

Figure 3: Interactive Effects of MTHFR (methylene-tetra-hydro-folate-reductase) and COMT (catechol-O-methyltransferase) on Executive Functioning in Schizophrenia Roffman and colleagues (2008) investigated the interactive effects of MTHFR and COMT genetic polymorphisms on Wisconsin Card Sorting Task (WCST) performance in 185 outpatients with schizophrenia. This figure shows the differences in perseverative errors, a WCST measure consistently associated with schizophrenia. Individuals homozygous for the COMT Val allele (i.e., those with high COMT activity and low prefrontal dopamine) who also carried at least one copy of the MTHFR T allele (i.e., those with low formation of the methyl donor L-methylfolate and presumably less methylation of the COMT promoter with thus more synthesis of COMT and even lower prefrontal dopamine) exhibited a significantly higher percentage of perseverative errors than patients in the other genotype groups. Thus, these two genotypes interact, hypothetically at the level of dopamine in prefrontal cortex, to worsen cognitive functioning in those schizophrenic patients with these genetic variants. Prodromal patients with these same genotypes could theoretically be at greater risk for progressing to schizophrenia, but this is yet unproven.

Posttest Self Assessment Question: Answer Individuals who ultimately develop schizophrenia typically exhibit what patter of cognitive functioning prior to disorder onset?

A. Normal cognitive functioning during premorbid and prodromal phases

B. Impaired cognitive functioning that is stable across premorbid and prodromal phases

C. Impaired cognitive functioning premorbidly with further decline during the prodromal phase

D. Progressive decline of cognitive functioning across premorbid and prodromal phases

Answer: C