Depression Research
Brain.Com
Modern brain imaging technologies are revealing that in
depression, neural circuits responsible for moods, thinking, sleep, appetite,
and behavior fail to function properly, and that the regulation of critical
neurotransmitters is impaired. Genetics research indicates that vulnerability to
depression results from the influence of multiple genes acting together with
environmental factors.
Studies of brain chemistry, mechanisms of action of antidepressant medications,
and the cognitive distortions and disturbed interpersonal relationships commonly
associated with depression, continue to inform the development of new and better
treatments. The hormonal system that regulates the body's response to stress -
the hypothalamic-pituitary-adrenal (HPA) axis - is overactive in many patients
with depression. The hypothalamus, the brain region responsible for managing
hormone release from glands throughout the body, increases production of a
substance called corticotropin releasing factor (CRF) when a threat to physical
or psychological well-being is detected. Elevated levels and effects of CRF lead
to increased hormone secretion by the pituitary and adrenal glands which
prepares the body for defensive action. The body's responses include reduced
appetite, decreased sex drive, and heightened alertness.
Research suggests that persistent over activation of this hormonal system may
lay the groundwork for depression. The elevated CRF levels detectable in
depressed patients are reduced by treatment with antidepressant drugs, and this
reduction corresponds to improvement in depressive symptoms.
Studies on the mechanisms of action of antidepressant medication comprise an
important area of depression research. Knowing how and where in the brain
antidepressants work can aid the development of more targeted and potent
medications that may help reduce the time between first dose and clinical
response. Further, clarifying the mechanisms of action can reveal how different
drugs produce side effects and can guide the design of new, more tolerable,
treatments.
As one route toward learning about the distinct biological processes that go
awry in different forms of depression, researchers are investigating the
differential effectiveness of various antidepressant medications in people with
particular subtypes of depression. For example, this research has revealed that
people with atypical depression, a subtype characterized by reactivity of mood
(mood brightens in response to positive events) and at least two other symptoms
(weight gain or increased appetite, oversleeping, intense fatigue, or rejection
sensitivity), respond better to treatment with MAOIs, and perhaps with SSRIs
than with TCAs.
Many patients and clinicians find that combinations of different drugs work most
effectively for treating depression, either by enhancing the therapeutic action
or reducing side effects.
Untreated depression often has an accelerating course, in which episodes become
more frequent and severe over time. Researchers are now considering whether
early intervention with medications and maintenance treatment during well
periods will prevent recurrence of episodes. To date, there is no evidence of
any adverse effects of long-term antidepressant use.
Like the process of learning, which involves the formation of new connections
between nerve cells in the brain, psychotherapy works by changing the way the
brain functions. Research has shown that certain types of psychotherapy,
particularly cognitive-behavioral therapy (CBT) and interpersonal therapy (IPT),
can help relieve depression. CBT helps patients change the negative styles of
thinking and behaving often associated with depression. IPT focuses on working
through disturbed personal relationships that may contribute to depression.
Research on children and adolescents with depression supports CBT as a useful
initial treatment, but antidepressant medication is indicated for those with
severe, recurrent, or psychotic depression. Studies of adults have shown that
while psychotherapy alone is rarely sufficient to treat moderate to severe
depression, it may provide additional relief in combination with antidepressant
medication. In one recent study, older adults with recurrent major depression
who received IPT in combination with an antidepressant medication during a
three-year period were much less likely to experience a recurrence of illness
than those who received medication only or therapy only. For mild depression,
however, a recent analysis of multiple studies indicated that combination
treatment is not significantly more effective than CBT or IPT alone. Preliminary
evidence from an ongoing study indicates that IPT may hold promise in the
treatment of dysthymia.
Electroconvulsive therapy (ECT) remains one of the most effective yet most
stigmatized treatments for depression. Eighty to ninety percent of people with
severe depression improve dramatically with ECT. ECT involves producing a
seizure in the brain of a patient under general anesthesia by applying
electrical stimulation to the brain through electrodes placed on the scalp.
Repeated treatments are necessary to achieve the most complete antidepressant
response. Memory loss and other cognitive problems are common, yet typically
short-lived side effects of ECT. Although some people report lasting
difficulties, modern advances in ECT technique have greatly reduced the side
effects of this treatment compared to earlier decades. Research on ECT has found
that the dose of electricity applied and the placement of electrodes (unilateral
or bilateral) can influence the degree of depression relief and the severity of
side effects.
A current research question is how best to maintain the benefits of ECT over
time. Although ECT can be very effective for relieving acute depression, there
is a high rate of relapse when the treatments are discontinued. NIMH is
currently sponsoring two multicenter studies on ECT follow-up treatment
strategies. One study is comparing different medication treatments, and the
other study is comparing maintenance medication to maintenance ECT. Results from
these studies will help guide and improve follow-up treatment plans for patients
who respond well to ECT.
In recent years, the search for a single, defective gene responsible for each
mental illness has given way to the understanding that multiple gene variants,
acting together with yet unknown environmental risk factors or developmental
events, account for the expression of psychiatric disorders. Identification of
these genes, each of which contributes only a small effect, has proven extremely
difficult.
However, new technologies, which continue to be developed and refined, are
beginning to allow researchers to associate genetic variations with disease. In
the next decade, two large-scale projects that involve identifying and
sequencing all human genes and gene variants will be completed and are expected
to yield valuable insights into the causes of mental disorders and the
development of better treatments. In addition, NIMH is currently soliciting
researchers to contribute to the development of a large-scale database of
genetic information that will facilitate efforts to identify susceptibility
genes for depression and other mental disorders.
Psychosocial and environmental stressors are known risk factors for depression.
Research has shown that stress in the form of loss, especially death of close
family members or friends, can trigger depression in vulnerable individuals.
Genetics research indicates that environmental stressors interact with
depression vulnerability genes to increase the risk of developing depressive
illness. Stressful life events may contribute to recurrent episodes of
depression in some individuals, while in others depression recurrences may
develop without identifiable triggers.
Other research indicates that stressors in the form of social isolation or
early-life deprivation may lead to permanent changes in brain function that
increase susceptibility to depressive symptoms.
Recent advances in brain imaging technologies are allowing scientists to examine
the brain in living people with more clarity than ever before. Functional
magnetic resonance imaging (fMRI), a safe, noninvasive method for viewing brain
structure and function simultaneously, is one new technique that researchers are
using to study the brains of individuals with and without mental disorders. This
technique will enable scientists to evaluate the effects of a variety of
treatments on the brain and to associate these effects with clinical outcome.
Brain imaging findings may help direct the search for microscopic abnormalities
in brain structure and function responsible for mental disorders. Ultimately,
imaging technologies may serve as tools for early diagnosis and subtyping of
depression and other mental disorders, thus advancing the development of new
treatments and evaluation of their effects.
The hormonal system that regulates the body’s response to stress, the
hypothalamic-pituitary-adrenal (HPA) axis, is overactive in many patients with
depression, and researchers are investigating whether this phenomenon
contributes to the development of the illness.
The hypothalamus, the brain region responsible for managing hormone release from
glands throughout the body, increases production of a substance called
corticotropin releasing factor (CRF) when a threat to physical or psychological
well-being is detected. Elevated levels and effects of CRF lead to increased
hormone secretion by the pituitary and adrenal glands which prepares the body
for defensive action. The body’s responses include reduced appetite, decreased
sex drive, and heightened alertness. Research suggests that persistent over
activation of this hormonal system may lay the groundwork for depression. The
elevated CRF levels detectable in depressed patients are reduced by treatment
with antidepressant drugs or ECT, and this reduction corresponds to improvement
in depressive symptoms.
Scientists are investigating how and whether the hormonal research findings fit
together with the discoveries from genetics research and monoamine studies.
from brain.com and the NIH