Lecture 11
Mood Disorders: Etiology
Biological Factors
Lecture Outline
I. Introduction
II. Neurotransmitters: "The too little - too much" hypothesis
III.Hormones
A. Hypercortisolism
B. Other hormones
IV. Biological Rhythms
A. The sleep cycle
B. Seasonal affective disorder
V. Genetic factors
VI. Conclusions
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I. Introduction
There is a long-standing debate over whether the Mood Disorders
(depression in particular) should be classified along a single continuum
from mild to severe, or as two biologically distinct types: Type A and
Type B (see Handout 11-1) (Akiskal, 1983; Goodwin & Guze, 1979; Winokur,
1985). There seems to be growing evidence that there may be at least
two distinct types of depressive disorders (Akiskal, 1983; McNeal &
Cimbolic, 1986).
Type A: This type has been given various names (autonomous,
psychotic, vital, endogenomorphic, endogenous, melancholic). There are
important differences in the specific meanings for each of these terms
(Akiskal, 1983), but in general, Type A depression refers to a disorder
with a genetic or biochemical basis. As such, we shall use the term
"endogenous" (caused from within) to refer to this type of depression.
Although the DSM-III-R makes no etiological claims, the term
"melancholia" overlaps significantly with the symptoms of endogenous
depression. Research suggests the following distinguishing
characteristics for endogenous depression:
tends to recur - acute episodes, severe
may become psychotic, or switch to mania
hereditary background
once established, pursues autonomous course
abnormal hormone secretion
psychomotor disturbances
sleep disturbances: worse in morning, early morning wakening
marked weight loss
loss of ability to experience pleasure
favorable response to drug therapies
psycho-social provoking factors are absent or trivial
(Akiskal, 1983)
Type B: This type of depression refers, in general, to depression
externally caused. It has been called exogenous, characterologic,
personal, reactive and neurotic (Akiskal, 1983), again, each with
certain important differences in specific meaning. We will use the term
reactive depression to highlight the presumed importance of
environmental precipitating events. In other words, something occurs in
the person's life, and he or she reacts to it. In this case, the
reaction is depression. Characteristics include:
chronic
less incapacitating
long-standing personality instability
reactive to environment
insomnia at beginning of sleep
variable prognosis
more responsive to psychotherapy
precipitated by some event
(Akiskal, 1983)
[But if only things were so simple...Although we have divided depression
into two types, it is still very far from clear just exactly how to
divide up depression. The endogenous-reactive distinction is not nearly
as neat as I have decribed it. There is still a lot of debate in the
field concerning the subtyping of depression].
In today's lecture, we will examine biological factors of the Mood
Disorders. Endogenous depression most neatly fits in with this
discussion. Reactive depression fits well in our discussion of stress
provoked depression covered in the previous lecture. Does this mean
there is a clear distinction between these types of depression and their
etiologies? No, certainly not in all cases. However, one of the
possible and hoped for outcomes of identifying biological "markers" of
the Mood Disorders is the specification of meaningful sub-types (eg:
various types of depression) (Carroll, 1983; Weissman, Gershon, Kidd, et
al., 1984).
On the other hand, perhaps biological dysfunction should be seen as
another vulnerability factor. Possessing a genetic or biological
disorder does not necessarily mean you will express the disorder
(develop all the full-blown symptoms). Psycho-social-environmental
input is often also required to set the whole thing in motion (Akiskal,
1983).
II. Neurotransmitters: "The Too Little-Too Much Hypothesis"*
(* Zis & Goodwin, 1982)
There are two major neurotransmitter theories of depression:
1. low levels of catecholamines ---> depression
excess ---> mania
2. low levels of indolamines ---> depression
Background: There are two classes of neurotransmitters that have been
connected with emotion:
1. The Catecholamines, which include
norepinephrine, epinephrine, and dopamine
2. The Indolamines, which include
serotonin and tryptamine
As you will recall from our earlier discussion, neurotransmitters are
the chemicals that "transmit" information from one neuron to the next.
Once they have been released into the synapse and done their job, the
question arises, what next? What happens to the neurotransmitter now?
A number of things can happen:
1. Re-uptake: the neurotransmitter is pumped back into the
neuron from where it came.
2. Monoamine Oxidase (MAO): MAO, an enzyme naturally
occurring in the neuron, breaks the neurotransmitter
down.
In either case, the neurotransmitter is "deactivated".
The Catecholamine hypothesis has implicated, in particular,
norepinephrine in the etiology of depression, and serotonin has been the
key indolamine identified. The etiological importance of these
substances was discovered when the drug resperine (a hypertension
medication) was used to treat schizophrenia, during the 1960's. This
was one of the first drugs used to combat schizophrenic symptoms, but
unexpectedly, it also frequently led to depression. Among its other
biochemical effects, resperine facilitates the effects of MAO, thereby
reducing serotonin and norepinephrine. Thus, these neurotransmitters
were implicated as etiological factors in depression: too little of them
leads to depression. Other drugs were soon identified that would
decrease the symptoms of depression, by increasing the amounts of these
neurotransmitters:
1. Tricyclics: blocks reuptake of the neurotransmitters
eg: amitriptyline, imipramine
2. MAO Inhibitors: prevents MAO from breaking down the
neurotransmitters
So, it would appear that decreased amounts of neurotransmitters such as
serotonin and norepinephrine are associated with depression.
Evidence for the "too little - too much" hypothesis is mostly
indirect (direct measurement of neurotransmitter levels in a living
human brain is not yet possible). Measurement of the byproducts of the
neurotransmitters in urine, blood and spinal fluid are used as evidence
of brain chemistry activity. (Problem: measures more than just brain
activity). Two byproducts that gain most of the attention:
1. MHPG: the main byproduct of norepinephrine
2. 5-HIAA: byproduct of serotonin
Other evidence comes from observing the effects of drugs that are known
to increase or decrease levels of the neurotransmitters. What direct
evidence there is comes from animal research. A sampling of the
findings (Gold, Goodwin & Chrousos, 1988; McNeal & Cimbolic, 1986):
Bipolars: Urinary levels of norepinephrine decrease during
depression, increase during mania
Urinary levels of MHPG are low during depression
Unipolars:Spinal levels of 5-HIAA are low during depression
Ingestion of chemicals that help produce serotonin
relieves depression
Chemical that block the production of serotonin reduces
the effectiveness of the antidepressants
Note: these findings are far from absolute - they don't always
replicate in other studies.
The latest wrinkle: Tricyclics and MAO inhibitors do increase
norepinephrine and serotonin, but only initially. After a few days the
neurotransmitters return to their previous levels. Yet, the tricyclics
and MAO inhibitors don't actually take effect (ie: decrease depression)
for another 1 to 2 weeks! So things look more complex than a simple
"too little-too much" hypothesis. One possible explanation (see McNeal
& Cimbolic, 1986): The drugs are making the norepinephrine and
serotonin receptors more sensitive. This may account for why depression
is relieved even though the neurotransmitters return to their previous
low levels.
III. Hormones
The region of the brain known as the hypothalamus is responsible
for various things: food intake, sexual drive, sleep rhythms, and the
synthesis and release of certain hormones. Abnormal functioning of this
region is associated with depression. Thus, we have corresponding
symptoms in depression (particularly endogenous): anorexia, decreased
sexual interest, early morning wakening, and abnormal amounts of certain
hormones (Gold, et al., 1988).
A. Hypercortisolism: The hormone cortisol is hyper- ("overly")
secreted in persons with endogenous depression. Evidence for the
importance of cortisol in depression comes from experiments where
substances that cause cortisol to be released produce many of the
symptoms associated with depression. Research evidence suggests
that depressed persons may have chronic high levels of cortisol -
indeed, that the brain mechanisms that regulate cortisol secretion
are actually damaged or destroyed (Gold, et al., 1988)
Dexamethasone is a substance known to suppress cortisol in humans.
However, there is considerable evidence that seriously depressed
persons (esp. endogenous) will still fail to suppress or sustain
suppression of cortisol after receiving dexamethasone. This has
led to the development of a biological test for depression: the
dexamethasone suppression test (DST) (Carroll, 1983). Initially a
promising test, recent criticisms have emerged: Dexamethasone
nonsuppression is found in other types of psychiatric problems
(Thase, Frank & Kupfer, 1985); the DST is far from reliable
(Ritchie, Carroll, Olton, et al., 1985); and nonsuppression can be
due to other factors, such as excessive coffee drinking (Uhde,
Bierer, & Post, 1985).
B. Other hormones: Several other hormone abnormalities have been
identified (Gold, et al., 1988), but none of these have as much
support as hypercortisolism.
examples: growth hormone
thyroid-stimulating hormone
somatostatin
Note: Hormones and neurotransmitters can not be viewed
independently. Neurotransmitters such as the catecholamines and
indolamines influence the synthesis and release of hormones, and
the hormones influence the effects of the neurotransmitters.
Hormones and neurotransmitters undoubtedly reinforce one another's
activity (Gold, et al., 1988).
IV. Biological Rhythms
There exist in us all certain daily biological cycles or rhythms
(eg: body temperature) known as Circadian Rhythms. (Circadian is Latin
for "daily"). Some of these cycles appear to be abnormal in depressed
persons, especially the sleep cycle.
A. The sleep cycle: Recall that a characteristic symptom of
depression is sleep disturbances. The normal cycle of
sleep/arousal goes through a series of stages, cycling us back and
forth from rapid eye movement (REM) sleep to non-REM sleep. After
sleep begins (a non-REM period), the first REM period begins after
70 to 100 minutes of non-REM sleep. This period prior to REM is
known as REM latency. People with Major Depression usually have
difficulty entering into the initial REM stage (ie: difficulty
falling asleep), they have a shortened REM latency, and they are
likely to awaken early in the morning and have difficulty falling
back to sleep. For example (Akiskal, 1983):
Mean REM latency
89 minutes normals
57 " acute depression
53 " chronic depression
The theory is that these people are in a abnormal state of arousal,
a condition associated with these abnormal sleep patterns. A
depressed person's "need" for REM early in sleep may be an effort
to compensate for this hyperarousal during the day (Gold, et al.,
1988). Because of the advance timing of REM sleep, we also find
early awakening.
B. Seasonal affective disorder: A broader cycle is the seasonal
pattern seen in certain disorders. A relatively new area of
research has linked some depression to the seasons: depression in
the fall and winter, and normal or possibly manic in the spring and
summer (Wehr, Jacobsen, Sack, et al., 1986; although sometimes it
goes the other way: depression in spring/summer, normal in
fall/winter, eg: Wehr, Sack & Rosenthal, 1987). The term Seasonal
Affective Disorder (SAD) has been used to describe this phenomena.
One theory (eg: Rosenthal, Sack, Gillin, et al., 1984) suggests
that the key variable is available light: less light (typical in
fall and winter) leads to depression, possibly through some
interaction with the visual system and its accompanying
neurophysiology. This has led some psychologists to investigate
the therapeutic effects of exposure to bright light (natural and
artificial), and there seem to be promising results (eg: Rosenthal,
et al., 1984).
V. Genetic factors
A consistent finding is that the incidence of depression and the
other Mood Disorders is higher in individuals who have relatives with
Mood Disorders (and other psychological problems) than for people who
are not related to someone with a Mood Disorder (or other problem) (eg:
Weissman, et al., 1984). Problem: is this due to genes or to one's
upbringing? To answer this, investigations of identical (monozygotic)
twins (ie: identical genetic makeup) and fraternal (dizygotic) twins
(ie: dissimilar genetic makeup) have been conducted. If there is in
fact a genetic factor, then a twin with a depressed identical twin
should be more likely to have the disorder than a twin with a depressed
fraternal twin, even if the twins were reared in separate environments
(through adoption or other separation). Thus genes and environment can
be controlled for in these studies. Results typically have shown a
genetic component:
For example (Nurnberger & Gershon, 1984):
65% of identical twins have a twin with a Mood Disorder
14% of fraternal twins " " " " " " "
A fascinating but much debated recent study (Egeland, Gerhard, Pauls, et
al., 1987) has claimed to have actually identified the specific gene
responsible for a Bipolar Disorder predisposition, located on the tip of
the short arm of chromosome 11. These researchers went to a small Amish
community in southern Pennsylvania. This community had detailed
genealogical records that indicated that all of the 12,000 members were
descended from the same 30 persons who emigrated from Europe in the
early 18th century. It was found that everyone currently with a Mood
Disorder had relatives going back several generations who also had the
same disorder. Those who had committed suicide were traced back to just
four families. Through rather complex procedures, the researchers were
able to locate a place on chromosome 11 that was abnormal in those
individuals with Mood Disorders. A major question, however, about
research on such an unusual sample is its generalizability to the rest
of Mood Disorder.
VI. Conclusions
So, where are we left? We have reviewed some psycho-social
factors and some biological and genetic factors that may be involved in
the etiology of the Mood Disorders. There is a growing body of
literature comparing biological/genetic theories with psycho-social
theories. To sum up all these studies in one sentence, we would have to
say something like: "Both approaches appear to be important in
understanding the etiology of the Mood Disorders" (McNeal & Cimbolic,
1986). Biology and heredity seem to "set us up" for certain disorders,
but psycho-social input is necessary for the program to run. Indeed,
cognitive processes can play an important role in guiding and moderating
the physiological processes that ensue in a Mood Disorder (™hman, 1987).
However, it's equally plausable that psycho-social factors "set us up",
and it is our biology that provides the mechanism to run the program.
It is not at all clear in which direction the arrows point.