References

Stahl SM, Mood Disorders, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 453–510Stahl SM, Antidepressants, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 511–666Stahl SM, Mood Stabilizers, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 667–720Stahl SM, Olanzapine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 387–92Stahl SM, Asenapine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 4th edition, Cambridge University Press, New York, 2011 in pressStahl, SM, Lurasidone, in Stahl’s Essential Psychopharmacology Prescriber’s Guide, 4th edition, Cambridge University Press, New York, 2011 in pressEinarson A. Risks/safety of psychotropic medication use during pregnancy. Can J Clin Pharmacol 2009; 16(1): e58–65Sharma V. Management of bipolar II disorder during pregnancy and the postpartum period. Can J Clin Pharmacol 2009; 16(1): e33–41

Patient FileThe Case: The girl who couldn’t find a doctor

The Question: How aggressive should medication treatment be in a child with an anxiety disorder?

The Dilemma: Can you justify giving high dose benzodiazepines plus SSRIs to a 12-year-old?

Pretest Self Assessment Question(answer at the end of the case) A dose of 3 mg lorazepam is too high for a thin twelve-year-old girl.

A. True

B. False

Patient Intake 12-year-old girl

Chief complaint: “fear”

Psychiatric History Symptoms of generalized fear and anxiety started at age seven, but then got better; returned at age eleven; no identifiable stressors

Currently prepubescent

Denies panic attacks; currently tearful, depressed

One year ago began “getting an overactive mind”

Rituals and obsessions also began a year ago

So distressed by these that withdraws from friends, cannot be in a classroom with others, so pulled out of the classroom and home schooled for the past year

Family History Mother, a physician: with generalized anxiety

Maternal grandmother: bipolar

Maternal great-grandmother: committed suicide

Maternal aunt: has schizophrenia

Paternal cousin: committed suicide

Social and Personal History Was an excellent student prior to dropping out for home schooling

No drug or alcohol abuse

Has a younger brother

Medical History and Medications None

Patient Intake Patient admits to have compelling thoughts; almost, but not clearly, a voice making her sense that something horrible was about to happen, something or somebody would die

She has to clean the cage of her rabbit perfectly or he will die

She has some counting rituals in which she walks a certain number of steps and needs to end on a certain number to prevent something horrible, like the brutal death of her parents

Has to have items facing her squarely and not at an angle, and has to move certain objects, like the remote control, so it does not face her at home, or even objects on the attending physician’s desk so that they are “straight”

These thoughts and rituals take most of the day every day and distract her from school work

Given just the information you have here, what do you think is her diagnosis?

Behavioral inhibition (a temperament at risk for developing an anxiety disorder)

Separation anxiety disorder

Generalized anxiety disorder

Obsessive compulsive disorder

Major depressive disorder

An overly involved mother

Other

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation Looks like OCD with comorbid GAD, possibly in a patient who had premorbid behavioral inhibition, although no clear history of separation anxiety

If anything, she has separation anxiety now

Characteristic of anxiety disorders in children, it appears as though this patient has an ever evolving polymorphic anxiety disorder that morphs from GAD to OCD and beyond

So far, does not admit to panic attacks, and does not have major depression

Social anxiety may play a role in her avoidance of school as well

Advised treatment with SSRI

The mother, a physician, had already anticipated this, and had gone to their pediatrician who will not prescribe SSRIs to children anymore because of the risk of suicide and suicidality

Told them only a child psychiatrist should do this now

The mother is at a distance from the attending physician, and so with the written consultation sent to the pediatrician recommending an SSRI fom this consultation, will go back to the pediatrician and see if she will prescribe the SSRI

Also referred to a local child psychiatrist

Would you be willing to prescribe an SSRI to this twelve-year-old child, presenting with OCD and anxiety?

Yes

No

If you would give an SSRI, which one would you prescribe to her?

Fluoxetine (Prozac)

Paroxetine (Paxil)

Sertraline (Zoloft)

Fluvoxamine (Levrox)

Citalopram (Celexa)

Escitalopram (Lexapro)

Any of the above

I would not give an SSRI.

Given the FDA warning and recommendations of caution prescribing antidepressants to children six to twelve, do you think that this patient, with a very positive family history of bipolar disorder, must be seen weekly if you prescribe an SSRI?

Yes

No

Case Outcome: First Interim Followup, Week 8 Pediatrician still will not prescribe SSRIs

After waiting for four weeks, the child psychiatrist was not available to see patient weekly for FDA-advised monitoring, so referred her back to her pediatrician with the recommendation to use an SSRI

Pediatrician continues to refuse to do so

Refers patient back to you

In desperation, mother gives her daughter an intermittent dose of lorazepam from her own prescription, with very robust but short-lasting relief of intense anxiety

Would you be willing to prescribe a benzodiazepine to this twelve-year-old child, presenting with OCD and anxiety?

Yes

No

Case Outcome: First Interim Followup, Week 8 Recommended escitalopram 10 mg and lorazepam 0.5 mg once or twice a day as needed in consultation letter to referring physician/pediatrician as well as to another child psychiatrist

Recommended weekly follow-ups locally as suggested by the FDA and some experts and some treatment guidelines

Called a second child psychiatrist in the patient’s area who agreed to see the patient within a week and then weekly

Case Outcome: Second Interim Followup, Week 12 Followup phone call

When patient finally seen 4 weeks later and not immediately as promised, child psychiatrist had to cancel and had partner see child; partner recommended cognitive behavioral therapy and refused to follow recommendations to prescribe meds

Mother calls, desperate

Immediate phone consultation of attending physician with local pediatrician, who agrees to see patient briefly, weekly, and to monitor for activation and suicidality, as long as she does not have to write prescriptions

Mother is medically sophisticated, understands risks and benefits, and agrees to monitor child closely as well

Prescriptions are phoned in by the attending physician, and patient begins escitalopram and lorazepam

Agrees to return for a face-to-face appointment in 4 weeks

Case Outcome: Third Interim Followup, Week 14 Seen after two weeks, because mother runs out of lorazepam, having given twice as much as was prescribed so 30 day supply lasted only 2 weeks

Lorazepam has robust, but short lived, effects, so mother gives 0.5 mg three or four times a day and shortly runs out

Pediatrician monitoring patient weekly

No side effects, no activation or suicidality

“A little better, but on summer break, so who knows”

Not crying, still anxious, sleeps very well at night now

Advised to continue escitalopram 10 mg and prescribed an increase of lorazepam to 0.5 mg four times a day

Even if you would have been willing to prescribe a benzodiazepine previously, do you agree with giving an increased dose of benzodiazepine in this situation?

Yes

No

Attending Physician’s Mental Notes: Third Interim Followup, Week 14 It is already controversial in the minds of some mental health experts to prescribe benzodiazepines at all, more controversial to prescribe for a child, even more controversial to prescribe at high doses, especially if the mother is escalating the dose before getting prior approval from the attending physician

Is this headed for disaster?

Is this too aggressive and not justified?

Case Outcome: Fourth Interim Followup, Week 18 Scheduled to be seen two months later, with pediatrician monitoring weekly for a few more weeks, then every other week for a few weeks, then monthly

However, seen after one month because runs out of lorazepam again; no sedation, no suicidality

“Has kicked in a bit” meaning decreases in compelling thoughts, less general worry about symmetry, contamination, and religious themes

In fact, now that she is a bit better, she is able to disclose many more obsessions and thoughts she had been too concerned about to express previously

“Maybe my OCD is 33% better”

Worst time is during the day, and mother gives her two or three tabs of 0.5 mg lorazepam on some days, in the middle of the day, with dramatic results

Attending Physician’s Mental Notes: Fourth Interim Followup, Week 18 Now a dilemma

Here we finally have a patient who is responding but due to a second dose increase in lorazepam by the physician-mother taking things into her own hands without prior approval again

Many would stop the benzodiazepine or refuse to continue to treat this situation, referring to another psychiatrist

Nevertheless, nothing disputes the irrefutable logic of results

Looked at objectively, if anything, the benzodiazepine dose may be still too low

Lorazepam may have also been useful in masking potentially activating side effects of escitalpram if taken alone

Mother is honest about what she is doing with the lorazepam

If mother is willing to have her child take strictly as prescribed, will actually increase dose of lorazepam, realizing this is controversial and may generate criticism by other physicians involved in the case

Now 6 weeks on the SSRI, could recommend increasing the dose of that too; if the escitatopram becomes more efficacious, lorazepam may be tapered.

Attending Physician’s Mental Notes: First Interim Followup, Week 18, Continued Advised to increase escitalpram to 20 mg/day

Increased lorazepam strictly to 0.5 mg in the morning/1.0 mg late morning or early afternoon/1.0 mg late afternoon or early evening for homework/0.5 mg at night (3 mg total daily dose)

Patient weighs 80 pounds

Case Outcome: Fifth Interim Followup, Week 22 Seen one month later, situation improving

Seeming compliance to dosing as prescribed

Case Outcome: Sixth Interim Followup, Week 26 Seen in another month, “doing well”

Rating herself 85% better

At this point only taking 2 mg lorazepam per day

Only a few obsessive thoughts in the background

Only occasional “down” days in terms of mood

Lorazepam is still very helpful

Sleep is good

Case Outcome: Seventh Interim Followup, Week 38 Three months later: tired, on spring break, but otherwise doing well

Still on escitalopram 20 mg and lorazepam 2 mg/day

Case Outcome: Eighth Interim Followup, Week 50 Three months later, about a year since the initial psychiatric evaluation

A bit nervous, some peer problems

Now age 13, still no menstrual periods

Worried about school in general, but no depression

Obsessive thoughts still in the background

Meds continued unchanged

Case Outcome: Ninth Interim Followup, Week 62 Patient and her mother decide cautiously to return to public school

Has been anxiety provoking

Has increased lorazepam back to 3 mg/day

Worried about whether she will make the transition

Case Outcome: Tenth Interim Followup, Week 74 Attending high school

Highly strung, anxious

Afraid that her homework is not perfect

Has some friends but not boyfriends

Thinks some of her peers are “pure jerks”

Wants to become a pediatric intensive care nurse

Planning to go to college and taking college prep courses

Actually, looks and acts and functions the closest to normal ever

Case Debrief This adolescent had the onset of a polymorphic and disabling anxiety disorder

These conditions are often trivialized as being less disabling than other psychiatric conditions such as psychosis and thus not warranting aggressive psychopharmacological treatment

It is difficult to get even standard approved treatments to children and adolescents given the lack of experts and the fear of prescribers in giving SSRIs and benzodiazepines to children and adolescents

Aggressive treatment with a benzodiazepine and an SSRI were ultimately quite successful

Treatment did not require an atypical antipsychotic which could be justified here if the SSRI and benzodiazepine were ineffective

Treatment did not involve CBT which the daughter refused and the mother felt was not credible given her problems with child psychiatrists whom she felt did not help her or her daughter

Take-Home Points FDA warnings of suicidality in children on SSRIs has sent a chill through prescribers, making it difficult sometimes to find someone willing to prescribe them

Also it is controversial to many clinicians to prescribe daily high doses of a benzodiazepine to any child

Paradoxically, atypical antipsychotic prescribing in children has skyrocketed and seems to be less controversial

Treating children can feel like “damned if you do, damned if you don’t”

Psychopharmacologists comfortable with risks and benefits can prescribe with confidence as experts realize the FDA regulates the sale of medicine by pharma, not the practice of medicine by licensed prescribers

The flurry of warnings of suicidality now for antidepressants, antipsychotics approved as antidepressants, all anticonvulsants, varenicline for smoking cessation, and others, is producing “label fatigue” among prescribers who look to medical standards and common sense, not to the package insert and product label alone for practice guidelines

Performance in Practice: Confessions of a Psychopharmacologist What could have been done better here?– Should SSRIs have been started earlier and not worry about the need to set up close monitoring since that caused a great delay in initiating treatment?– Should a bigger push have been made for CBT despite the mother’s lack of confidence both in the CBT and in the child psychiatrists or child therapists who would have administered it?– Should an anxiolytic/sedating atypical antipsychotic such as quetiapine been prescribed rather than the benzodiazepine lorazepam?

Possible action item for improvement in practice– Make a concerted effort to find psychopharmacologists comfortable in treating children and adolescents– Make a more concerted effort to find CBT therapists who are experts in treating OCD and GAD in children and adolescents

Tips and Pearls SSRIs and benzodiazepines are effective in children and adults alike

Good documentation of efficacy of SSRIs in children and adolescents for OCD

Controversy exists for treating children with SSRIs, less controversy exists for treating adolescents and young adults under 25 with SSRIs

Controversy exists for treating children and adolescents with benzodiazepines as few if any studies of them in various anxiety disorders in children

Off-label prescribing, or nonpharmaceutical approaches may be the only rational choices in cases as disabled as this one

Anxiety disorders also deserve to be treated and to have symptoms go into sustained remission so that normal development of the child and adolescent can proceed, even at the cost of taking controversial medications

Two-Minute Tute: A brief lesson and psychopharmacology tutorial (tute) with relevant background material for this case – Anxiety disorders in children

Table 1: What is Generalized Anxiety Disorder in a Child? Called overanxious disorder in the past

Is a generalized and persistent anxiety that is not the result of separation or recent stress

Characterized by self-consciousness

Obsessive concern over past behavior, future events, personal health, and competence in athletics, social, or academic arenas but not obsessions or compulsions per se

Table 2: What is Behavioral Inhibition An early temperamental trait characterized by the tendency to withdraw when exposed to unfamiliar situations

Longitudinal studies of behaviorally inhibited children indicate that it tends to be an enduring temperamental trait

Children classified as behaviorally inhibited at age 21 months continue to be shy, timid, and fearful in unfamiliar settings at the ages of 4 and 7

Children who are inhibited may have a lower threshold of responsivity in the limbic and hypothalamic circuits and, as a result, they react with greater sympathetic activation when exposed to novel situations

Children of parents with panic disorder with agoraphobia have a higher rate of behavioral inhibition than children of parents without panic disorder with agoraphobia

Multiple anxiety disorders are found at increased rates in children classified as behaviorally inhibited

Thus, behavioral inhibition may indicate increased vulnerability for anxiety disorders

Behavioral inhibition is linked to a familial predisposition to anxiety disorders, because behavioral inhibition in children is associated with increased rates anxiety disorders in their first-degree relatives

Table 3: What is Separation Anxiety Disorder (SAD)? One of the most common childhood anxiety disorders

Reported prevalence ranging from 3.5% to 5.4%

The defining feature is developmentally inappropriate, excessive, and unrealistic anxiety regarding separation from home or from major attachment figures, usually a parent

Children with SAD become extremely distressed when separated from a parent

This distress can reach panic proportions, with accompanying autonomic symptoms of anxiety

Often these children actively resist or refuse to be separated from important attachment figures

For example, they may follow a parent around the house and refuse to sleep alone

Children with SAD worry excessively that their parents will die or suddenly disappear, or that they will be abducted, causing permanent separation

When these children are separated from their parents, even for a brief period of time, they spend much of this time worrying about the safety of their parents and anxiously await the parents – return

Because these children avoid situations involving separation, school refusal frequently accompanies SAD

Separation anxiety disorder and “school refusal” or “school phobia” are terms that have been used interchangeably, even though they are not necessarily the same thing

For example, not all children with “school refusal” have SAD, and not all children with SAD have “school refusal”

In fact, “school refusal” can be due to social phobia, anxiety about competence or performance in school, and other disorders, such as conduct disorder (truancy) or depression (social withdrawal)

Furthermore, depression and overanxious disorder are frequent comorbid conditions of SAD

Unfortunately, no firm conclusions about the usefulness of psychotropic medications for separation anxiety disorder can be drawn from treatment studies because of problems with:– diagnostic heterogeneity– small sample size– brief duration of treatment– inclusion of cases of “school refusal” secondary to truancy or depression

If pharmacotherapy is used, it should be in the context of a multimodal treatment plan that includes behavioral interventions

Posttest Self Assessment Question: Answer A dose of 3mg lorazepam is too high for a twelve-year old girl.

A. True

B. False

In psychopharmacology, you never say “never” – even though this is not standard treatment, and would be controversial to many, the risks and benefits in this case and the obvious good outcome, justified the use of this agent at this dose here.

Answer: B