In this drawing in addition to the vivid use of color

• Note the complex and abundant detail. This is an indication of this child’s intelligence as well as his imagination.

• Note his depiction of “spells” being cast by the Wizard on the lower right. His representaion of force exerted at a distance may indicate an awareness of the powerful impact he imagines his anger has on people. The spells are also a representation of the power he wishes to have.

• Note his depiction of small warriors battling huge monsters or dangerous depths (e.g. the tiny figure hanging from the bridge at lower middle of the drawing). These figures are an indication of his sense of himself (small but not intimidated) battling the powerful and dangerous forces that define his world. Those forces arise from within him as well as from the adults around him. The fierceness and courage with which these small figures fight suggest that Eric is NOT depressed. He does not feel helpless or even overpowered. Contrast Eric’s drawing, for example, with that of the black and white drawing of the other eight year old, or even with that of the accomplished artist in her twenties. Both those drawings display passivity and a sense of helplessness.

• Note the variety of figures he uses–swordsmen, archers, skeletons, a wizard, a serpent, a dragon, a sea monster, and a bird of some kind. This variety displays Eric’s complex imaginative life.

[The large realistic—but rather wooden—figure in the middle of the drawing was drawn by me. As I look at Eric's drawing now, his more primitive figures are far more lively and energetic.]

“An Oppositional 8 y.o. pictures himself in the face of authority” (Eric p. 210)

This is the same artist as in the first drawing.

• He represents his anger both with the image of the volcano and with the defiant posture of the small figure in the foreground.
• At the very end of the session, just before he left, Eric put in the giant foot coming down on the volcano. I see this as his representation of the arbitrary authority he faces, an authority that crushes without recognizing or even noticing him. However, as in a dream, a single image can have opposite references: so the foot can also be Eric stamping his foot in defiance.
• Notice also the small palm tree bending over as if to shield itself from the volcano’s fury. That too is a representation of Eric. The flip side of the defiant child is the gentle cowering soul looking for safety.

Originally Eric had been brought to me because of his oppositional behavior. That behavior was, however, his reaction to what had—as in this picture—come down on him.

“A Shy 6 y. o. Depicts her Rejection by Peers” (p. 87)
In this drawing:

• Note the skill with which this very young child conveys the smiling nastiness of her peers. She clearly has a complex sense of another person’s emotional state. At the time she was quite unable to express this complexity in language.
• Note also the absence of hands on her figures may be a sign of this child’s feelings of helplessness. However, despite her depiction of herself as crying, the figures in this drawing fill page and are brightly colored. These features of the drawing suggest that this child is not depressed.

“An Eight Year Old Depicts his Toxic Sense of Self” (p. 56)

This boy was given a choice of colors but chose to use only black.

• He explained the shape in the upper left of the drawing as “fire,” almost always a depiction of anger. The “A” on the figure’s cap is also meant to represent anger. However, the angry figure is defined negatively as a devil. This boy’s accumulated rage is the source of his negative sense of himself.
• Notice also that the boy’s choice of a black outline and a rounded body (re-stated by the arc of the arms) renders a figure with a swollen emptiness–the self as zero.
• In this drawing, as in some of the others, the absence of hands and feet suggests a sense of helplessness, despite the boy’s apparent defiance. This contrasts sharply with the other eight-year old’s portrayal of himself as fighting back in the face of oppression.
• This boy’s use of black also indicates depression. Nonetheless, his talent and intelligence show through in the complexity and the bold statement of his drawing.
• Finally, note the convergence of the figure’s eyes. This convergence is, I believe, this boy’s uncanny representation of the faulty integration of the left and right cerebral hemispheres, in this case the left and right visual fields, commonly seen in bipolar disorder. [Click here: to read "The Sticky Switch" also given in the posting: Accumulating Evidence.]

“A Six Year Old Manic Child” (Klaus p. 10)

In this picture the child’s manic agitation is conveyed by the wildness of his lines in the drawing, including the representation of his face and hair.

• Contrast this wildness with the work of the other six year old in the third drawing.
• However, this child’s drawing is far from crude. Despite his agitation, notice that this child includes: ears, eyes with pupils (not simply dots), and similarly a nose that has a shape to it and is not a mere dot. This complexity is an indication of this child’s developed sense of himself.
• Notice also, however, that despite the complexity of the head this figure also lacks defined hands and feet. Again, a representation of helplessness.
• The drawing also skillfully depicts the child’s overwhelming distress and emotional agitation.

“My Thoughts are all a Case of Knives” (Charlotte, p. 160)

(The words above are a quotation from a poem—“Affliction”—by the 17th century poet, George Herbert. The artist, however, was not acquainted with Herbert’s poem. She later felt, however, that it was a fine title for her painting.)

Here we have a mature artist conveying the agony of mania.

• She does this, as in the previous drawing, with wild lines emanating from the figure.
• There is also, however, (as with the first drawing in this series) a wealth of intricate detail, corresponding to the artist’s intelligence and the complexity of what she means to convey.
• Unbearable anatomical detail collides with agitated lines and an explosion of color beyond to convey her tortured state of mind.
• Again, the lack of body, arms and legs together with the passivity of the figure indicate an intense sense of helplessness.

are not Mood Stabilizers!

Lately I have noticed a disturbing trend: more and more patients are referring to an atypical major tranquilizer—Abilify, Seroquel, Geodon, Zyprexa, Risperdol—as a “mood stabilizer.”

What is the difference? and Why is this disturbing?

There are crucial differences between these two classes of drugs:

• They have importantly different ways of affecting the brain
• They have different side effects
• They have different long-term effects

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First, bear in mind that the human body, and the brain in particular, is made up of marvelously intricate systems in dynamic equilibrium. These systems– muscles, hormones, fluids, and neural transmitters–create crucial balances, balances that continually interact, adjusting to one and other. Bear in mind also that when a system in equilibrium is pushed in one direction it responds by pushing back in an opposite direction, like a spring. The balance then shifts in that system and all the other systems that interact with it. So, even when a drug “selectively” targets a single neurotransmitter—serotonin, for example—it affects numerous other neural transmitters that are in equilibrium with that neural transmitter, sometimes unpredictably.

Mood Stabilizers: Mood stabilizers work by limiting the activity of key neurons but only when the neuron becomes overactive. They do not affect the activity of a cell when it is functioning at a normal pace.

Mood stabilizers accomplish this by limiting the neuron’s energy (electrical potential) or by limiting a neuron’s ability to accumulate substances (metabolites) that generate energy. Either way they do not affect normal equilibriums in the brain.

Major Tranquilizers: By contrast, atypical major tranquilizers affect the concentration of two or more neural transmitters, causing numerous shifts in the brain’s equilibriums. These shifts can result in immediate or long term side effects.

Mood stabilizers also have side effects but we are beginning to learn that several mood stabilizers—and perhaps others—have a long term effect of increasing regeneration of brain cells. They are neuro-protective.

The confusion between these two kinds of drug is not accidental.
Atypical major tranquilizers are being promoted for use in bipolar disorder.

• One motive for this promotion is a desire to have a single medication that will work on the various symptoms seen in bipolar disorder: manic arousal, depression, agitation, and anxiety. So much simpler for physicians and patients!

• Another motive promoting this trend is an old idea that the use of multiple medications—polypharmacy—is dangerous. It violates longstanding medical principles of parsimony. This older idea also dates from a time when less was understood about how drugs are metabolized and how they interact.

However, up to date understanding of bipolar disorder recognizes that different symptoms respond better to different drugs. Some forms of anxiety (for example, panic attacks) are best treated with a minor tranquilizer. Manic arousal requires the use of a major tranquilizer, but usually for a limited period of time. Symptoms of ADD will often respond to a stimulant, but often their use is safe only in combination with a mood stabilizer. Depression may require and antidepressant but also often for a limited period of time. As in cooking, several spices work better than a single one, but they need to be combined subtly and in sparing amounts.

There are circumstances in which an atypical (or typical) major tranquilizer is a crucial tool, but it needs to be recognized for what it is.

The following article on pharmacology are detailed and technical and may be unnecessarily complex for some visitors to this site.

Nonetheless because the use of multiple medications has become the standard of care for bipolar disorder, both in children and in adults, it may be important for some parents or professionals to master these complexities in order to understand what makes some combinations safe and others dangerous.

In most cases the prescribing physician or the pharmacist can give you a warning about drugs that interact dangerously. Still, some parents want to know for themselves.

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DRUG INTERACTIONS

Part I: METABOLISM OF PSYCHIATRIC MEDICATIONS

The CYP-450 System:

For the most part, psychiatric drugs are metabolized in the liver. In order to be psycho-active a drug must have a certain chemical activity and must be partially fat soluble, so it can pass through the blood-brain barrier and on into the central nervous system where it can affect the action of neurons.

Metabolism in the liver inactivates and eliminates a drug: that is, the enzymes in the liver change a drug’s chemical activity and make it water soluble in preparation for elimination either by the kidneys in urine or in the bowel in feces.

There are, however, different pathways for the metabolism of different drugs. One set of pathways is made up of an array of different enzymes, present in the gut and the liver, known as the CYP-450 system. Different drugs are metabolized by different CYP-450 enzymes, and some drugs are metabolized by more than one enzyme. When several medications are being used, it is important to know if their metabolisms interact in some way: to know if one drug slows down, inhibits, or speeds up the metabolism of the other.

Below is a chart showing some of the most important CYP-450 Enzymes and the drugs they metabolize. The chart also indicates which drugs inhibit the enzyme and which drugs induce an enzyme.

• If two drugs are metabolized by the same enzyme they compete for metabolism. The drugs must take turns with one another, waiting on line to be metabolized.
• If one drug inhibits the enzyme, the line moves more slowly for that drug and for any other drug metabolized by that enzyme.
• If a drug induces the enzyme the line moves more quickly for that drug and any other drug metabolized by that enzyme.
• An enzyme can also be inhibited or induced by a substance that is not usually considered to be a drug: for example grapefruit juice strongly inhibits one enzyme (3A4) and cigarette smoke induces another (1A2).

When an enzyme is inhibited or when two drugs compete for metabolism the circulating levels of those drugs go up. In some cases this can be dangerous or uncomfortable, so the dose of one or both medications may need to be lowered.

When an enzyme is induced, the circulating levels of drugs metabolized by that enzyme fall. That fall can cause a medication to lose its therapeutic effect. So the dose of those drugs metabolized by the enzyme may need to be raised.

For example:

Fluoxitine (Prozac) strongly inhibits the enzyme (2D6) that metabolizes metoprolol (Lopressor) a drug that lowers blood pressure and slows heart rate. The combination of these drugs will cause an increase in the level of metoprolol and consequently lower blood pressure; the increased level of metoprolol will also slow the heart rate possibly leading to a dangerously low blood pressure and even circulatory collapse.

Carbamazepine (Tegretol) induces the enzyme (2D6) that metabolizes hormones contained in oral contraceptives. When carbamazepine is combined with an oral contraceptive in a sexually active woman an unexpected pregnancy can occur.

Grapefruit juice strongly inhibits an enzyme (3A4) that metabolizes erythromycin and a similar antibiotic clarithromycin (Biaxin). If the level of either of those medicines is raised sharply nausea and vomiting can result, which can be uncomfortable but not dangerous.

In order to use the chart:

• Locate the medications being used (generic names are given).
• Determine if they are metabolized by the same enzyme (compete).
• or if one inhibits or induces another’s metabolism
• This can be done with two or three or more medications.
• If more information is desired use the links below the chart.

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METABOLISM BY CYTOCHROME P450 ENZYMES

(an asterisk * indicates a drug is metabolized by more than one enzyme)

Click Here for a thorough Guide to the CPY-450 System

Cick Here for a Guide to the Names and Properties of Drugs

The division between clinical and research psychiatry, especially in children, has been recently emphasized in the controversy about using antidepressants in children and the efficacy of antidepressant treatment in bipolar disorder. In an editorial in the current American Journal of Psychiatry distinguished child psychiatrist, Cynthia Pfeffer—“The FDA Pediatric Advisories and Changes in Diagnosis and Treatment of Pediatric Depression”—observes that research between 1990 and 2000 showed a decrease in suicide among children treated with antidepressants. Click here to read Pfeffer’s editorial Pfeffer goes on to note that a more recent study confirmed the benefits of combined psychotherapeutic and pharmacologic treatment of depressed children. [March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J: "Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) Team"JAMA 2004; 292:807–820].

However, “the U.K. Medicine and Health Care Products Regulatory Agency advised on June 10, 2003, that paroxetine [Paxil] not be prescribed for anyone under 18.” The British directive was based on a large retrospective study, a review of outcomes of a combined group of older studies. [click her for a summay of the British study] By October of 2004, based on mere statistical re-analysis, the FDA require pharmaceutical companies to provide a grave, “black box” warning for all antidepressants, warning about their danger to children.

Pfeffer observes: “Prior to the FDA’s October 2003 advisory, rates of depression diagnoses made by pediatricians and nonpediatrician primary care physicians steadily increased and accounted for the majority of diagnoses of pediatric depression. After the advisory, rates of diagnosing pediatric depression significantly decreased among primary care physicians, were unchanged among pediatricians, and significantly increased among psychiatrists. Prior to the advisory, 59% of depressive episodes were associated with an SSRI prescription filled within 30 days of diagnosis, and the rate increased significantly over time. After the advisory, the percentage of SSRI prescription fills after diagnosis gradually but significantly decreased, and by 2005, SSRI prescriptions were filled for only 28% of episodes.”

In other words, despite previous studies indicating that treatment with medication, and especially with medication and psychotherapy, resulted in children with depression being safer and more able to carry on developmentally, the (unintended) consequence of the British study and the FDA reaction to it has been a significant decrease in the diagnosis and treatment of depressed children. How should a parent respond to such conflicting opinions among experts?

My thoughts are these:

• Psychiatric research is quite different than clinical observation.

• Positively, psychiatric research bases itself on a far larger number of cases and commands a broader perspective. Research is also usually conducted under carefully controlled conditions.

• Negatively, psychiatric research arrives at the diagnosis and treatment of its subjects broadly as well. Rarely are the details of family history, developmental history, or the relationship between the doctor and patient weighed. Also the conditions of treatment, although carefully controlled, are controlled to provide statistical clarity. They are not always clinically optimal. In retropective studies, such as the ones done by the U.K. Medicine and Health Care Products Regulatory Agency and the FDA, the criteria for diagnosis, criteria for inclusion and exclusion, and the treatment protocols may differ among the studies gathered together for statistical review. The numbers being crunched are not comparable with one another.

• Clinical observation bases itself on subtleties that are only available with personal and family contact, and within an ongoing relationship with both parents and child.These observations include subtle observations of a child’s behavior as well as their symptoms, academic function, developmental history, family history, relationships between the child and the family, and knowledge of psychosocial stressors affecting a child. Clinical observation also is ongoing, from year to year, not simply for a matter of weeks or months. In appropriate pharmacologic care there is also the possibility of working with several medications with the opportunity to change one but not all if negative effects are seen. Such subtelty is not usually an option in research.

• Negatively, clinical observation can vary widely depending on the skills of the clinician, not only in prescribing medication but also in maintaining a relationship with parents and child, and with other people involved in caring for or educating the child. Clinicians possing this combination of skills are rare.

Finally, psychiatric illness is importantly different than other medical illness because it affects vastly more than a child’s biology. Quite separately from religious definitions, psychiatry deals with the soul of a person, the psyche: an individual, unquantifiable, exquisitely reactive reality. If one is more comfortable with the words personality, character or self, I have no difficulty with those terms, as long as their inherent subjectivity is preserved. In the end, good research strives to be objective; good clinical work strives to be supremely subjective.

An editorial in the American Journal of Psychiatry, also in April of 2007, observes that “pediatric bipolar disorder significantly affects the normal psychosocial development of the child and increases the risk for suicide and substance abuse as well as for behavioral, academic, social, and legal problems….” Although estimates of the incidence of bipolar disorder in children are controversial, the editorial observes that “…up to 60% of adults with bipolar disorder report the onset of their mood symptoms before age 20.” What is more, “An average of 10 years elapse before bipolar disorder is diagnosed and treatment begins….” Even more disturbing is the observation that: “For each year of illness, bipolar disorder youths have a 10% lower likelihood of recovery.” In other words, substantial harm can occur if the diagnosis of bipolar disorder is missed in a child , and that is more often the case than not—with an average of 10 years going by before diagnosis and treatment begin. [Click here to read the editorial.]

Nonetheless, Dr. Groopman warns, “the consequences of… treatment can be dire, particularly when parents are unaware of or ignore the dangerous side effects of the medications.” He goes on to cite the dangers of Depakote, Risperdal, and Lithium. But Groopman does not observe that there are alternatives to each of these medications that can avoid these side effects. It is also true that both lithium and depakote have been shown to promote proliferation of stem cells in the central nervous system resulting in neuroregeneration. These medicines have long term positive effects. More importantly, Groopman does not consider the effects of the untreated illness on a child’s developing brain.

[Click here to read "The Mood-Stabilizing Agents Lithium and Valproate Robustly Increase the Levels of the Neuroprotective Protein bcl-2 in the CNS" (1999) by G. Chen, W. Zeng, P. Yuan, L. Huang, Y. Jiang, Z. Zhao, and H. Manji in the Journal of Neurochemistry 72 (2), 879–882; click here to read abstract of "Lithium-induced increase in human brain grey matter" (2000) by G. Moore, J. Bebchuk, I. Wilds, G. Chen, H. Menji in The Lancet, Volume 356, Issue 9237, Pages 1241-1242.]

An article published in June of 2006 in the Proceedings of the National Academy of Sciences (PNAS | June 6, 2006 | vol. 103 | no. 23 | 8900-8905), “Limbic hyperactivation during processing of neutral facial expressions in children with bipolar disorder,” gives evidence—based on localized images of brain activity—that children with bipolar disorder have a heightened response in areas of the deep brain linked to rage and fear. Moreover, this over activity affects the child’s cognitive function in recognizing and articulating facial expressions. Put more directly, a bipolar child’s increased emotional sensitivity can cause misinterpretation of social circumstances and a decreased ability to talk about their perceptions. The article concludes that in bipolar children an over activity of the limbic system compromises cortical function. Feelings overwhelm perception, judgment, and language. It is just this over activity of the limbic system that is limited by many of the medications used to treat bipolar disorder. [Click here to read the article.]

An earlier study (1998), “A “sticky” interhemispheric switch in bipolar disorder?,” by John D. Pettigrew and Stephen M. Miller, offers evidence that individuals with bipolar disorder may have greater difficulty switching from one brain hemisphere to the other. This difficulty in coordinating the activity of one hemisphere with the other may contribute not only to abnormal alternations of mood but also to problems with visual and motor integration commonly seen in children with bipolar disorder and also to abnormal sensitivity to circadian and seasonal cycles. [Click here to read the article; click here to read an update.]

Overwhelming evidence that bipolar disorder is both neurologically and genetically based makes it more likely than not that biological predisposition exists at birth and that children will exhibit signs and symptoms of the disorder. It is already agreed that those signs and symptoms are different than those appearing in adults and that they appear differently at different ages. The increased diagnosis of bipolar disorder in children takes place within a context of increasing rates of mood disorders at all ages together with an earlier onset of these disorders. This increase has been observed for over ten years. [See "Increased prevalence and earlier onset of mood isorders among relatives of prepubertal versus adult probands,"Journal of the American Academy of Child and Adolescent Psychiatry, April, 1997 by Todd, Richard D.] Although both the appearance and the treatment of bipolar disorder in children can vary widely, diagnosis is not arbitrary and appropriate treatment protects a child’s brain and development.

The advances in the pharmacological treatment of bipolar disorder in the last twenty years are equivalent to those made with the use of antibiotics that took place sixty years ago. However, in psychiatry diagnoses are much more tentative because they do not yet include a full understanding of what takes place at a cellular level. Just as importantly, the treatment of psychiatric disorders includes vastly more than the use of medication. As psychiatrists we work with illnesses that become entwined with a person and with the person’s family.

Appropriate treatment of Bipolar Disorder in a child requires psychotherapy: personal expert care that addresses the problems the child has at home, in school, and with other children. In a child a psychiatric disorder crucially affects development at every stage. In treating children with Bipolar Disorder it is my experience that the developmental problems are ultimately more difficult to treat than the biologic ones. Without psychotherapy medication can become a hammer and the child becomes the nail. Without medication, however, psycho therapeutic care sometimes is not possible.

Bipolar Disorder is also an inherited condition, which means that a child with bipolar disorder may have one and sometimes two parents with the condition. Frequently enough parents are willing to give their child care they will not accept for themselves. An untreated mood disorder in a parent destabilizes the family, and the family is the crucial environment in which a child grows. Even when neither parent suffers from Bipolar Disorder, an affected child puts a great strain on a family. So, family therapy is a crucial part of delivering care to a child.

Bipolar Disorder is more frequently overlooked than over diagnosed. At present, most children with Bipolar Disorder—one estimate puts it at four out of five—go undiagnosed and untreated. Even when resources are not a problem it can take years before a child is properly diagnosed and treated. But resources are the greatest problem: in the midst of a biological enlightenment there is a dangerous tendency to minimize the importance of psycho therapeutic care. In most states and at the national level the insurance industry is permitted to treat psychiatric illness as a non-medical condition. Consequently, appropriate treatment—when it is available—is beyond the reach of families that need it.