Jules Angst on the Long-Term Progressive Course of Mood Disorders
At a symposium celebrating the retirement of Willem Nolen, a researcher who spent 40 years studying unipolar and bipolar disorder, from his position at Groningen Hospital in the Netherlands, his colleague Jules Angst discussed some recent findings. Angst is perhaps the world’s leading authority on the long-term course of unipolar and bipolar disorders based on his multiple prospective follow-up studies, some lasting 20-30 years.
The Sensitization-Kindling Model
Angst described evidence that supports the sensitization-kindling model of recurrent mood disorders, which this editor (Robert Post) described in 1992. Episodes tend to recur faster over time, i.e. the well interval between episodes becomes progressively shorter. While stressors often precipitate initial episodes, after multiple occurrences, episodes also begin to occur spontaneously (in the absence of apparent stressors).
This type of progressive increase in response to repetition of the same stimulus was most clearly seen in animal studies, where repeated daily electrical stimulation of the amygdala eventually produced major motor seizures (i.e. amygdala kindling). Daily electrical stimulation of rodents’ amygdala for one second initially produced no behavioral change, but eventually, minor and then full-blown seizures emerged. Once enough of the stimulated full-blown amygdala-kindled seizures had occurred, seizures began to occur spontaneously (i.e. in the absence of the triggering stimulation).
The analogy to human mood disorders is indirect, but kindling provides a model not only for how repeated triggers eventually result in full-blown depressive episodes, but also for how these triggered depressive episodes may eventually occur spontaneously as well.
Long-Term Treatment of Mood Disorders
Angst also discussed long-term treatment of mood disorders. He has found that long-term lithium treatment not only reduces suicides in patients with bipolar disorder, but also reduces the medical mortality that accompanies bipolar disorder.
Angst noted his previous surprising observations that in unipolar disorder, long-term maintenance treatment, even with low doses of tricyclic antidepressants, prevents suicide. Previously, researchers Ellen Frank and David Kupfer of Western Psychiatric Institute and Clinic at the University of Pittsburgh Medical Center had found that when patients with recurrent unipolar depression who had been stable for 5 years on the tricyclic antidepressant nortriptyline were blindly switched to half their original dose, about 90% rapidly relapsed into a new episode of depression. Their data helped establish the prevailing view that maintenance treatment with the full-dose regimen required to achieve a good initial acute response is also the optimal approach to long-term continuation and prophylactic treatment.
Angst found good results even at low doses, but his data may not be in conflict with Frank and Kupfer’s, as a person who responds well acutely to low doses may also be able to maintain good enough response to them to prevent recurrences in the long term.
Incidence of Bipolar Disorder in Adolescents Similar to Incidence in Adults
Angst also presented data from the Adolescent Supplement to the National Comorbidity Study (NCS-A), which analyzed interviews with approximately 10,000 adolescents (aged 13-17) in the US. He found a 7.6% incidence of major depression, a 2.5% incidence of bipolar I or II disorder, and a 1.7% incidence of mania. There was an even higher incidence of sub-threshold bipolar disorder, when there are not enough symptoms or a long enough duration of symptomatology to meet diagnostic criteria for bipolar I or II disorder. These data published by Merikangas et al. in 2009 provide clear epidemiological data that there is a substantial incidence of bipolar disorder in adolescents in the US, roughly similar to that seen in adults.
Episodic vs. Continuous Social Stress Result in Different Rates of Cocaine Use
In a study of rodents exposed to stress (by being forced to enter another rodent’s territory) and given the opportunity to self-administer cocaine, those exposed to a few brief episodes of stress increased their cocaine use and engaged in binge-like episodes, while those exposed to stress chronically showed suppressed cocaine use.
At the American College of Neuropsychopharmacology meeting in December 2009, Klaus Miczek and colleagues from Tufts University in Boston presented a fascinating study indicating that the temporal aspects of the experience of social stress may have dramatic impact not only on defeat stress behaviors and the associated biochemistry, but also on the likelihood that an animal adopts cocaine self-administration. These investigators compared episodic versus chronic defeat stress in rodents.
Episodic social defeat stress consisted of four brief confrontations between an intruding animal and an aggressive resident rat over the course of a period of ten days. In contrast, chronic subordination stress involved the continuous exposure of the intruder rat to an aggressive resident over five weeks, during which time the intruder lived in a protective cage within the resident’s home cage.
The episodically defeated intruder rats showed increases in intravenous cocaine self-administration and prolonged binge-like episodes, along with increases in brain-derived neurotropic factor (BDNF), which is necessary for long-term learning and memory, in the midbrain ventral-tegmental area (VTA) and increased dopamine release in the nucleus accumbens, the reward area of the brain. In contrast, the continuously subordinate rats showed the opposite pattern of suppressed cocaine intake, suppression of dopamine release in the n. accumbens, and reduced BDNF in the VTA.