TORONTO, May 24 ??” Atypical depression affects up to about 40% of depressed patients. It differs from typical depression in symptoms, sleep characteristics, age of onset, and response to treatment.
Atypical depression is defined as being characterized by mood reactivity and at least two of these symptoms: hyperphagia, hypersomnia, leaden paralysis, or rejection sensitivity. Patients may be more functionally impaired than those with non-atypical depression.
Speaking at a symposium titled “Atypical Depression: Merging Evidence and Public Policy,” held during the American Psychiatric Association meeting, authorities on the subject reviewed the neurobiology, symptomatology, and management of the illness, including future directions and characteristics of a new drug formulation.
Charles Nemeroff, M.D., Ph.D., presented a detailed view of the neurobiology of the disease with a view toward understanding its unique pathophysiology and how to develop rational treatments. Dr. Nemeroff is professor and chairman of the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine in Atlanta.
He said the underpinnings of depression are complex, including genetic factors, hormonal abnormalities, alterations in neurotransmitter systems and neural circuits, early life trauma, and recent stressors. He attributed about a third of the etiology to genetic factors and two-thirds to environmental ones. This is just the opposite of bipolar disorder.
Evidence indicates disturbances in the three major monoamine neurotransmitter systems: serotonin (5-hydroxytryptamine, 5-HT), norepinephrine (NE), and dopamine (DA). The hypothalamic-pituitary-adrenal axis also is involved, based on findings of a relative deficiency of corticotropin-releasing factor. Someday, anticipating being able to measure specific neurotransmitter disturbances, Dr. Nemeroff said, “I hope we get to the point where we can say in a given patient, ‘Here’s what your problem is… and this is the prescription that we’re going to write for you,’ …instead of the incessant trial and error that we partake in every day in our practices.”
Already, a relative 5-HT deficiency is known to be linked to depression. Low levels of its major metabolite are found in the cerebrospinal fluid (CSF) of affected patients, and there is a compensatory increase in the density of 5-HT2 receptors on platelets and in tissue. Furthermore, from a scientific and practical standpoint, all 5-HT reuptake inhibitors (e.g., selective serotonin reuptake inhibitors, SSRIs) are effective antidepressants.
Dr. Nemeroff then showed histochemical and neuroimaging evidence for the localization of the serotonin system in the brain. He showed that the dorsal raphe serotonin neurons are the source of the bulk of serotonin in the human central nervous system, sending about 70% of their product forward.
He said the biggest recent development in the field was the discovery of polymorphism in the serotonin transporter. Two forms of the gene exist: a short form (s, resulting from a 44 base pair deletion in the promoter region) and a long form (l). Therefore, people may be homozygous for either form or heterozygous with one copy of each gene in their cells. Heterozygotes or people homozygous for the short form have reduced numbers of transporter sites.
Imaging studies have shown that these patients had exaggerated amygdala responses when they were shown scary faces while in a scanner, suggesting a mechanism for their relatively excessive fearfulness, neuroticism, and anxiety. Furthermore, adult subjects with the s/s or s/l genotype were more susceptible to later depression in a gene dose-dependent fashion if they had experienced childhood abuse. “Turn[ing] this on its head, if you have the l/l allele, you are immune to the consequences of child abuse,” Dr. Nemeroff concluded. “This is the ultimate resilience gene. It protects you.”
He discussed the NE system and showed that these neurons arise mainly from the locus coeruleus. In depressed patients, a decrease in a major metabolite of NE occurs in the urine, plasma, and CSF. Other NE metabolite levels are decreased in plasma as well, compared with healthy people. Compensatory elevations in ??-adrenoreceptors occur on lymphocytes, and there is decreased epinephrine-induced platelet aggregation.
The final neurotransmitter system that Dr. Nemeroff discussed was DA, which he views as central to depression. “Dopamine is the pleasure neurotransmitter, and what else is depression except a disease in which patients have an inability to experience pleasure?” he asked. “Anhedonia is the cardinal feature of depression.”
Evidence for the pathophysiological involvement of the DA system in depression comes from imaging, postmortem, and biological fluid studies. Furthermore, antidepressants such as monamine oxidase inhibitors (MAOIs) affect DA neuronal circuits. Dr. Nemeroff showed postmortem evidence for dopaminergic abnormalities in amygdaloid nuclei in major depression, as well as lower dopamine transporter binding potential in the striatum of depressed people compared to healthy individuals. He said that up to now, the DA system has not been addressed in depression except by the use of SSRIs intended to inhibit serotonin reuptake from the synapse.
He concluded by showing that negative mood, the primary symptom of depression, resides in the anterior cingulate of the cortex. Imaging shows “clearly altered activity” in this area. The abnormality is reversed in patients who respond to antidepressants but not in non-responders.
Dr. Nemeroff predicted that modern molecular neurobiology and genetics will transform clinical practice within the next five years. “You’ll be able to order imaging tests and genomic tests that will guide you in predicting what the best treatment will be for your patients, be it pharmacotherapy, psychotherapy, and which type of each,” he said.
Phenomenology of Atypical Depression
According to DSM-IV, atypical depression requires the absence of melancholic or catatonic features, the presence of mood reactivity, plus at least two more features: increase in appetite or weight gain, hypersomnia, leaden paralysis, or long-standing interpersonal rejection sensitivity.
However, Hans-J??rgen M?¶ller, M.D., professor and chairman of psychiatry at Ludwig-Maximilians University in Munich, Germany, said this definition and its clinical significance have come into question.
Mood reactivity does not always appear to be central to the diagnosis and the lack of interdependency of accessory features have been cited as a reason not to consider atypical depression a true syndromal construct. A lack of consensus about symptom patterns adds to the clinical conundrum. Dr. M?¶ller, therefore, sought to integrate established and emerging definitions of atypical depression to help the audience develop strategies for diagnosis and treatment selection for this historically “treatment-resistant” form of depression.
He summarized cohort study results and concluded that mood reactivity was not significantly associated with other atypical symptoms and that it may not be specific for atypical depression or even a prominent and exclusive criterion. Therefore, he (along with other authors) questioned the diagnostic value of mood reactivity.
This situation makes comparisons of studies of atypical depression difficult because of varying definitional criteria and sampling methods. He also noted that ICD-10 has no operational criteria for atypical depression. In addition the Hamilton Rating Scale for Depression (HAM-D), the most frequently used one, does not refer to atypical symptoms and may underrate the condition. Dr. M?¶ller said the Inventory for Depressive Symptomatology-Clinician (IDS-C) may be a better alternative rating scale. Finally, reversal of vegetative symptoms (e.g., hypersomnia, hyperphagia, weight gain) and the relative mildness of symptoms and psychiatric comorbidity may lead to under diagnosis, as may the prominence in DSM-IV of the criterion of mood reactivity, which may not always be present.
A number of studies have revealed neurobiological differences between typical and atypical depression, most notably the lack of response to psychopharmacotherapy among atypical depression patients, but in a manner different from typical depressive patients. While atypical patients have lower responses to tricyclic antidepressants, MAOIs have better efficacy in this form of depression.
Dr. M?¶ller suggested that ICD-10 criteria for atypical depression should be modified according to the DSM-IV, and he said more professional education is needed to enhance recognition of the features of atypical depression.
Evidence-Based Management of Atypical Depression
Most studies on atypical depression have focused on younger patients. But late-onset disease is particularly troublesome as this patient population has less favorable responses to treatment and is more likely to develop resistance to medications. Because of its generally chronic course, atypical depression patients often require long term treatment. Besides pharmacotherapy, cognitive behavior therapy has been used successfully although evidence for its efficacy has been lacking.
Justine Kent, M.D., an adjunct assistant professor of psychiatry at Columbia College of Physicians and Surgeons in New York and vice-president and medical director at Comprehensive NeuroScience, Inc. in White Plains, N.Y., reviewed some pharmacologic and behavioral approaches to the management of atypical depression.
She began with a discussion of cognitive therapy (CT). In a study of 27 patients meeting the Columbia criteria for atypical depression, 56% responded to CT. Non-responders were given pharmacotherapy, to which 63% responded. She concluded that there may be subpopulations among atypical depression patients who respond better to one form of therapy or another.
In another study both CT and Nardil (phenelzine), an MAOI, produced similar positive results on HAM-D scores at 10 weeks when compared with placebo. Therefore, CT can be a viable alternative to drugs for some patients, and the two modalities may effectively treat differing populations of patients with atypical depression.
MAOIs have long been considered the gold standard in the treatment of atypical depression based on numerous efficacy studies. But because of the “tyramine effect,” in which a build up of tyramine from inhibition of monoamine oxidase in the gut can cause hypertensive crisis and other untoward effects, MAOI use has required inconvenient dietary restrictions.
More modern antidepressants include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), and, still in development, gepirone. Alternative or “nutriceutical” treatments include chromium picolinate and St. John’s wort. Among the tricyclic antidepressants, imipramine is the best studied but has been shown to be less effective than the MAOI Nardil in several placebo-controlled trials in atypical depression. In typical depression, imipramine has been shown to be effective.
Moclobemide, a reversible MAOI, was shown to have superior efficacy compared to fluoxetine in a controlled trial. One study found no difference between Prozac (fluoxetine) and Nardil.
Gepirone is a 5-HT1A partial agonist. When dosed at 30 to 120 mg/day in a randomized, placebo controlled trial of 60 patients, the response rate for the intent-to-treat sample was 62% for gepirone and 20% for placebo (P