Demitri Papolos, M.D.
Clearly, one of areas of greatest interest to people involved with velo-cardio-facial syndrome (VCFS), whether the interest be personal or scientific, is the possibility for the development of psychiatric disorders in affected individuals. We recently reported in the American Journal of Psychiatry on our findings from a study instituted nearly two years ago. This article will discuss that report and discuss several cases which may help to illustrate the kinds of problems which have been encountered. It should be mentioned up front, however, that not all patients with VCFS have debilitating psychiatric illness. Many do not. The actual percentage of those who do is unknown because all investigations, including the one we just published, are prone to biases based on how patients were ascertained for the investigation. Though we try to make sure that our samples represent the entire patient population, it is not possible to kn
ow if this is so.
Most individuals with VCFS who have molecular deletions of 22q11 and who were examined by standardized psychiatric methods share a common cluster of mood, anxiety and obsessive-compulsive symptoms. In our study, an unexpectedly high number of VCFS patients, 17/25 (68%) ages 5-34 were diagnosed with bipolar spectrum conditions (BPD), including bipolar I, bipolar II, schizoaffective or cyclothymic disorders. The prevalence rate excluding patients younger than age 12 was 94% (17/18). Of this group one 16 year old carried the diagnosis of attention deficit hyperactivity disorder (ADHD) which is often difficult to distinguish from BPD in adolescence. This makes BPD one of the most common conditions associated with VCFS, and raises important research and treatment questions. Does the loss of one or more gene(s) in the 22q11 region confer a vulnerability to develop BPD? If this is the case, should prophylactic treatment be instituted in adolescence for all VCFS pati
ents, those that manifest even mild symptoms, or only those that meet full criteria for bipolar disorder? When we compare the 94% rate with the prevalence of BPD in the general population it is logical to suspect that some gene in the 22q11 region has a strong effect, either directly or indirectly on the cause of BPD, and we must also consider the possibility of early intervention.
Bipolar disorder (BPD), previously known as manic-depressive illness, is a heritable condition estimated to occur in 1-1.5% of the general population. It is classically defined by cyclic periods of high and low energy where the persons mood may become excited, elated, irritable, or dysphoric. These mood states which can last hours to weeks are usually accompanied by an alteration in the sleep-wake cycle, hypertalkativeness, impulsive and compulsive behaviors, changes in appetite, and distractibility in thinking. The high states (hypomania or mania) are usually followed by periods of depression, marked by a sad or irritable mood, low energy, loss of interest in things that ordinarily give pleasure, insomnia or sleeping too much, and appetite loss or cravings for sweets and carbohydrates. Some of the more commonly observed features are illustrated in the histories of two VCFS patients that we evaluated.
During the second semester of the 10th grade this young woman dropped out and did not return to school. She recalls that prior to this she had trouble attending school because she did not have enough energy and had trouble concentrating in the classroom. Previously, in elementary school the patient had received group therapy for depression, and admits that she has had mood swings since the age of 11. She describes them as occurring several times a year. Her mother reported that they occurred every two to three months. During these episodes, she had periods of hypertalkativeness that alternated with sulking, withdrawal, and not wanting to talk at all.
Alternatively, there were periods where she would talk so incessantly that others would make remarks to her like “stop talking and “shut up. During these periods she described feeling very excited and full of energy, joking around, and feeling very elated. She was restless and would dance around the house. During these high energy periods when she experienced an elated mood, the patient would binge on carbohydrates. On several occasions she had impulsively gone on a shopping spree with a credit card and bought clothes which she did not need and has never worn since.
In addition to these periods of elation, she also became irritable when it was more difficult for her to get along with others and when she felt easily annoyed and/or rejected. She experienced her first episode of major depression at age 15. At that time she had suicidal thoughts, stopped eating, and within two weeks lost 15 lbs.. She locked herself in her room and never left, overslept day and night, lost interest in everything and had no energy. A second episode occurred a year later which she described as more severe than the first. She remembers during this episode of 4-5 weeks duration, dressing only in black. While she described chronic sleep problems, her insomnia was much worse when she was depressed when she ruminated about the day’s events, feeling useless and worthless. At the time of the evaluation she had been in a continuous state of depression for over a year, interrupted by brief periods of bursts of energy with elation or irritability lasting days to weeks.
Between the ages of 4 and 9 years, this young man experienced extreme separation anxiety and his parents had to sit by his bedside until he fell asleep at night. He would not allow them to leave while awake. In kindergarten he was observed by his teachers to be very restless. At age 7 he became quite distractible and was diagnosed as learning disabled. The school psychologist described him as “emotionally immature and very impulsive and he was easily provoked to anger, sometimes triggered by stressful situations. The parents described him as much more volatile at age 7 years, and that from this age forward, irritability was a constant feature of his emotional state.
He became easily irritated if someone tried to stop him from doing something that interested him, and he often had temper tantrums that culminated in some destructive act. His parents reported that “when he is really angry he is capable of putting a hole in the wall. At the age of 10 years, the parents consulted a child psychiatrist because of the learning disabilities and the behavioral problems. As a result, he was diagnosed as having ADHD and treated with Ritalin, 15 milligrams in the morning, with some mild improvement in his concentration. At the age of 11 to 12 years, he began to experience very high energy states which would fluctuate over a period of hours. He would typically get a burst of energy at night and would engage in uncharacteristic activities like cleaning his closet excessively, doing laundry, and making many plans for the next day. He would talk excessively and with great intensity during these periods, so much so that the parents would have to tell him to calm down and to be quiet. Such episodes occurred approximately 2-3 times per month.
The average age of onset for BPD in the group of VCFS patients that we evaluated was 12, although evidence of a milder form of the condition, cyclothymia, was retrospectively reported as early as age 9 years in four patients. In general, for those individuals diagnosed with childhood bipolar disorders, symptoms of sleep fragmentation and night-terrors often preceded the appearance of rapid mood swings. Clinical interviews with parents confirmed the presence of frequent spontaneous or reactive oscillations in mood and psychomotor activity. This cyclic pattern typically preceded and persisted beyond the first manifestation of frank episodes of mania or hypomania.
In addition to the 17 cases diagnosed with bipolar spectrum disorders, almost half of the sample (12/25), 48%, had a high symptom profile for ADHD. Six patients (24%) reached diagnostic levels for ADHD, three were previously treated for this diagnosis. Of these three VCFS patients, two had manic symptoms following the introduction of methylphenidate (Ritalin) including hypersexuality, restlessness, increased psychomotor activity, anxiety, sleep disturbance, pressured speech, flight of ideas and marked mood lability which culminated in an ultra-rapid-cycling course (24-48 hr. cycles). This cycling pattern continued for a period of two to ten days beyond discontinuation of the drug. Both cases subsequently followed a bipolar course. Methylphenidate, a piperidine derivative that is structurally related to amphetamine and which has a prominent central nervous system stimulant effect via the noradrenergic and dopaminergic neurotransmitter systems, has been reported to induce mania in prepubertal children. This phenomenon has led some clinical investigators to point to the potential usefulness of this reaction as a biologic marker for bipolar disorder in this age group. Our findings certainly raise serious questions about the use of stimulants in VCFS, and the importance of clearly distinguishing between early onset BPD and ADHD and may also provide a new and fruitful line of investigation into the molecular basis of these conditions.
In summary, it has become clear to us that psychiatric disorders are clearly a part of the symptom complex associated with VCFS and that the most common finding is bipolar disorder. While this psychiatric disorder is not always of a debilitating nature, in its worst forms, it may be very difficult to treat which stresses the need for early detection and correct diagnosis. Insights into the genetic basis for the psychiatric problems associated are of enormous importance to both the scientific and lay community because bipolar disorder is so common among the general population. It may be that the continued intense study of VCFS will have implications which stretch way beyond this common genetic syndrome.