The depressive mood disorder would be worthy of study even if it were presented only in its
clinically important stages. It is not, however, a distinct disease entity that afflicts only a few
individuals. As in the case of the anxiety disorders discussed in the previous chapter, depression
lies along the normal continuum of behavior, and few individuals will avoid the occasional grasp
of depression. Thus, depression is a vital area of study for both its day to day and its clinical
manifestations, and as it will become apparent later, a better understanding of the disorder can
itself provide some measure of treatment.
Clues for a Laboratory Model
Seligman tested this hypothesis by combining the procedures of classical and instrumental
conditioning. The experimental dogs were first trained to jump back and forth in the testing
chamber. Each excursion reset a timer for a specified period of safety (no shock), while a failure
to continue shuttling back and forth resulted in a pulsating foot shock until the subject jumped
over the barrier. This free operant avoidance procedure (also termed Sidman avoidance)
eventually leads to a stable rate of jumping back and forth, with most of the potential shocks
being avoided. The assumption of the two factor theory of avoidance is that the relatively
constant rate of jumping back and forth is being maintained by the reduction of Pavlovian fear.
Presumably a greater fear of impending shock would increase the frequency of jumping, while a
lesser fear would decrease it.
Once the subjects had been trained in the shuttle box, they were taken to a different experimental
room and placed in a Pavlovian conditioning harness. The dogs were then exposed to traditional
Pavlovian conditioning procedures with specific stimuli being paired with the presence or absence
of shock to the paw. For example, a tone might precede the delivery of a brief shock (signaling
fear), while a buzzer might indicate a period of time that was free from shock (signaling safety).
When the dogs were returned to the shuttle box task, three important observations were made:
(a) The additional Pavlovian training did not change the previously learned response of jumping
back and forth over the barrier,
(b) presentation of the Pavlovian shock signal increased the rate of jumping, and
(c) presentation of the Pavlovian safety signal decreased the rate of jumping.
Thus, signals that had acquired the values of fear or safety had the expected results on the
instrumental behavior, even though the buzzer and tone had never been used in the training of the
shuttle box avoidance response.
The onus of this failure to behave was placed squarely on the Pavlovian conditioning procedure.
In this procedure, the electrode is actually taped to the dog's paw and both the signal that predicts
the shock and the occurrence of the shock are completely under the control of the experimenter.
Although the subjects typically struggle during the early trials and perform the well known leg
flexion response during the later trials, none of these behaviors has any effect on the occurrence of
the shock. The subject, therefore has the opportunity to learn two things: (a) the relationship
between the stimulus and the shock, and (b) the fact that its behavior has no effect on the
occurrence of shock. When the subject is then placed in a situation in which a behavioral
response could change the likelihood of shock occurrence, the previous learning that behavior has
no effect on shock prevails, and the dog simply does not respond. In the insightful description of
Solomon and his associates, the dogs exhibit learned helplessness.
The learned helplessness effect is not an all or none phenomenon. Not all of the subjects showed
the effect, but over 95 percent of the naive subjects learn the shuttling response, whereas only one
third of the Pavlovian trained animals learned the response. Furthermore, it should be emphasized
that the Pavlovian procedure per se does not render the subjects incapable of instrumental
learning. In the first series of experiments, the dogs that had already learned the shuttle box
avoidance maintained this behavior without deficit, despite the intervening sessions of Pavlovian
conditioning. Presumably, having once learned that a particular behavior can change the
likelihood of shock, the subjects show a degree of immunity to the otherwise dramatic effects of
Pavlovian conditioning. There are other concessions that must be made. For example, the effect
is less pronounced in other species and is not necessarily permanent. However, the basic findings
have withstood the ravages of time and the assaults of opposing theoretical interpretations to
provide some important insights into the mood disorder of depression.
The learned helplessness phenomenon provides an anchor point for the importance of
environmental control, but a more global consideration requires an analysis of what has been
termed a contingency space. Suppose, for example, that a subject is in a situation in which a
particular response (e.g., pressing a lever) results in a consistent change in the environment (e.g.,
the termination of shock). This one-to-one correspondence is easily learned by the organism. It
is possible (indeed, common) to alter the situation such that not every response is effective in
changing the environment. These partial reinforcement schedules do not have a detrimental effect
on behavior. In fact, they usually tend to energize the behavior.
There is, however, another side to the environment that frequently is overlooked. It is possible to
arrange a situation such that a particular change in the environment only occurs if a particular
response is NOT made. Both situations provide equal predictability, and both afford the organism
the opportunity to learn about and control the environment. However, the middle ground
provides a problem: If the situation is arranged such that an environmental change is equally
likely to occur whether or not a response is made, there is no predictability, except that the
organism can learn that its behavior has no influence on the environment. This is the realm of
The conditioned helplessness effect was quickly seen as an important model of behavioral
depression in humans. The failure to respond to the environment is one of the major symptoms of
depression, and the intriguing evidence that this effect is learned captured the imagination of
researchers in the area. The ensuing experiments showed that the conditioned helplessness
phenomenon is not simply a laboratory curiosity that is restricted to animals in shock avoidance
There have been a number of experiments involving human subjects which demonstrate the
generality of the response to lack of control of the environment. One of the more instructive
series of experiments exposed human subjects to bursts of noise (e.g., Klein & Seligman, 1976).
In one of the conditions, the subjects could terminate the noise by pressing a button. The subjects
in the other group could not control the noise, but were exposed to the mildly noxious stimulus
until it was terminated by the subject in the other condition. When compared to the shock that is
experienced in the Pavlovian conditioning procedure, this may seem like a rather trivial
manipulation, but the effects were clear. The subjects who had been exposed to noise that they
could not control were found to be deficient in a variety of tests. When tested later in situations
in which their behavior actually could control the environment, they were less able to recognize
the contingencies: They were less successful and less persistent in solving complex problems.
They were slower in reaching the solution of an anagram (e.g, unscrambling KCRUT into
TRUCK,) and when given a series of these, were less able to recognize a consistent rule (e.g., that
PSRIC and RIHAC can be unscrambled into CRISP and CHAIR by rearranging the letters in the
same sequence as in the case of changing KCRUT into TRUCK). Thus, a single exposure to a
situation in which a lack of control is evident can have demonstrable effects on a variety of
cognitive tasks that follow this experience (see Figure 6-1).
The generalization of helplessness from one situation to another has important implications for the
clinic. Although nobody would entertain seriously the notion that a few minutes of exposure to
uncontrollable noise could produce clinical depression, it is not unreasonable to expect similar
occurrences in the normal progression of the disorder. The initial exposure to a situation in which
one's behavior is ineffective makes it more likely that other situations will be interpreted in the
same way. This interpretation is somewhat self fulfilling, because it reduces the attempts to
engage in coping responses. Gradually, these effects can spread, until there results a pervasive
feeling of helplessness or, if we might coin a term, "omnimpotence".
Clues for the Chemical Foundations of Depression
The first demonstration of pharmacological intervention into behavioral depression came
(curiously enough) from attempts to treat tuberculosis. In 1951, isoniazid and a derivative called
iproniazid were developed for the treatment of tuberculosis. Iproniazid was thought to be
especially effective, but the enthusiasm about these results was short-lived when it became
apparent that the drug had little or no effect on the actual symptoms of tuberculosis, but rather
was elevating the understandably depressed mood of the patients (Delay & Deniker, 1952;
With this clue from the tuberculosis patients, it was found that iproniazid (but not isoniazid)
inhibited MAO activity. Although iproniazid is no longer the treatment of choice for depressive
disorders, these results set the stage for the neurochemical view of the disorder that has been
maintained (with considerable modifications) up to the present time.
One of the major pharmacological actions of iproniazid and related compounds is the inhibition of
monoamine oxidase (MAO). As outlined in Chapter 2, there are two enzymes that degrade or
break down catecholamines. These are MAO and COMT (catecholamine O-methyl transferase).
As shown in Figure 6.2, these enzymes are differentially distributed with MAO occurring
primarily within the cell, while COMT is distributed in the extracellular space. Neither of these
enzymes is a major factor in the inactivation of neurotransmission (see Chapter 2 discussion of
reuptake), but probably serve more of a general housekeeping function by preventing the buildup
of pharmacologically active compounds from free floating transmitters that escape the synaptic
field (in the case of COMT) or from compounds that are not compartmentalized in the cells
storage system (in the case of MAO). In any event, the MAO inhibitors seem to produce a
gradual enhancement of catecholamine systems, and this effect is correlated with an elevation of
In summary, we have seen that the disorder of depression can be linked to an inability to control
the environment, and one of the early treatments of depression suggests a link to the
catecholamine systems. The next section will examine these observations in more detail.
One line of evidence that supports the role of catecholamines comes from brain stimulation experiments while under the influence of various drugs. One of the more important drugs in this regard is amphetamine, which enhances the activity of norepinephrine and dopamine systems by several different pharmacological actions. In general, amphetamine enhances the lever pressing for electrical brain stimulation. However, amphetamine increases performance in many different behavioral situations, so this effect alone provided only weak support for the notion that the reward system is mediated by catecholamines.
More convincing evidence for catecholamine involvement comes from experiments that interfere
with the action of these systems. Reserpine is a compound that has a broad spectrum of
pharmacological actions, the most notable of which include the progressive depletion of the
transmitters norepinephrine, dopamine, and serotonin. It comes as no surprise that the behavioral
results of such depletion are widespread, but one of the behaviors that is lost is the lever pressing
for rewarding brain stimulation. The important point is not so much the loss of the behavior, but
the return of the behavior. The administration of serotonin precursors have no effect on lever
pressing, but the administration of l-DOPA, a precursor of dopamine and norepinephrine, will
restore these transmitter substances and restore the lever pressing for brain stimulation and other
rewards (see Figure 6-3).
As the neurochemists developed more and more precision in their chemical assays, it became
apparent that there was a highly systematic organization of neurotransmitter systems that had their
cell bodies in the brainstem regions and projected forward into the forebrain regions, including the
neocortex. As shown in Figure 6.4, both dopamine and norepinephrine producing cells
contribute to the medial forebrain bundle. It is possible to separately disrupt dopamine or
norepinephrine systems by either pharmacological manipulation or discrete anatomical lesions.
The results of these experiments are weighing in favor of dopamine, but it seems unlikely that
norepinephrine will be ruled out as a major contributor to the operation of the reward system.
Patients who suffer from certain forms of depression (especially melancholia) may show
abnormalities in the functioning of this system. In particular, the circulating levels of cortisol may
be higher than normal. More importantly, dexamethasone does not suppress the production of
cortisol. This so-called dexamethasone suppression test may be useful in diagnosing the type of
depression and in verifying the effectiveness of various treatments (e.g., Carroll, Curtis and
In summary, the evidence shows that the response to reward (either conventional or brain
stimulation) requires the structural and pharmacological integrity of a brain system that has its cell
bodies in the brain stem, projects forward via the medial forebrain bundle, and releases dopamine
and norepinephrine at its terminals.
But what about the Brain-Behavior-Environment triangle in Figure 6-5? It is one thing to show
that interference with this system interferes with behavior, but can it be shown that the presence
or absence of reward can influence this system? To answer these questions, we will return to
experiments that involve conditioned helplessness.
The effects of isolation are severe, and certainly go beyond a simple parallel to depression. But
the interaction with catecholamines continues the thread of continuity between depression and
brain chemistry. Furthermore, these experiments suggest that the self isolation that results in
depressed patients may exacerbate the underlying neurochemical causes of the disorder--a point
that we shall return to later.
(a) No Shock: These rats had electrodes taped to their tails, but did not receive electric shock.
(b) Avoidance-Escape: These rats were exposed to signalled tail shock that could be avoided or
escaped by pressing a lever.
(c) Yoked Control: These subjects received shocks that were identical to those that were
received by the avoidance-escape subjects, but they had no control over its occurrence.
The rationale was that the rats in the yoked control condition would learn that their behavior was
ineffective and become less likely to exhibit appropriate coping responses in other situations.
The second phase of the study was modeled after Richter's swimming test, but rather than
bombarding the rats with a seemingly impossible task, Weiss and his associates outfitted the rats
with a flotation device that served as a sort of life jacket. The rats were placed in the swimming
tank for 15 minutes, during which time they could either swim around or float passively. As
predicted, the rats that had been in the yoked condition spent more time floating passively, while
those from the other two groups spent a great deal of time swimming, struggling, and (apparently)
attempting to escape from the situation (Fig. 6-6).
Sometimes, a tidbit of data emerges that makes the major results of an experiment even more
salient. All of the rats in these experiments had electrodes fastened to their tails with a band of
adhesive tape. When the shock session was over, the electrode leads were simply snipped off,
rather than further traumatizing the rats by attempting to remove several layers of tape from their
tails. Over the course of the experiment, nearly half of the rats in the avoidance-escape group and
the no shock group removed the tape from their tails. By contrast, none of the rats that had
experienced a lack of control removed the tape!
Further tests revealed that this decline is the result of a reduction of tyrosine hydroxylase, the
rate limiting enzyme in the chain of synthesis of norepinephrine. Although the details have not yet
been worked out, the transient effect outlined above probably can be made more permanent
through repeated exposure to a lack of control. Furthermore, repeated exposure to controllable
stress (sometimes referred to as positive stress or eustress) seems to increase the level of tyrosine
hydroxylase. Thus, behavioral manipulations appear to have a profound influence on the integrity
of the neuropharmacological systems of reward, a matter which will be dealt with more fully at
the end of this chapter.
An additional problem is that the antidepressant drugs are dangerous. Both the tricyclic
compounds and the MAO inhibitors have strong autonomic and cardiovascular effects, increasing
the risk of cardiac failure. This is especially the case with MAO inhibitors, which greatly
potentiate the effects of adrenergic drugs, and even amines that occur in foods such as cheeses
and some wines. The final irony is that the antidepressant drugs do not enjoy a high therapeutic
ratio. Unlike the antianxiety and antipsychotic drugs which can be withstood in heroic dosages, a
few dosages of the antidepressant drugs can be lethal--and this is the population of patients that
tends to be suicidal.
The mood of depressed patients seems resistant to the effects of drugs that elevate the mood in
normal individuals. Two of the most potent drugs in this category are amphetamine and cocaine.
Both of these drugs can produce a rapid and potent elevation of mood in normal individuals, with
the resulting effects frequently being described as euphoria. In addition to the direction of mood
changes produced by these drugs, they also come with good biochemical credentials for the
treatment of depression. The evidence is strong that both of these drugs act through facilitation
of catecholamine systems. Figure 6-9 summarizes the effects of these two drugs. Despite the
evidence cited above for a model of depression that involves a catecholamine dysfunction, the
drugs do not work. Neither cocaine nor amphetamine show any useful degree of clinical efficacy
for the treatment of depression.
The interaction of reserpine and the MAO inhibitors has served as a model, albeit not a very
convincing one, of the development and treatment of behavioral depression. As noted earlier,
reserpine results in the gradual release and depletion of transmitter substance from the neuron.
When administered to humans, this effect is paralleled by the development of severe depression, a
so-called side effect.
In experimental animals, there is a comparable decline in behavior, especially under conditions in
which behavioral activity is maintained by delivery of discrete reinforcement. Animals that have
been trained to press a lever to obtain water, food, or electrical brain stimulation will stop
responding as the level of catecholamines decline following reserpine administration. Animals that
have stopped lever pressing for reward show a prompt renewal of the behavior when a MAO
inhibitor is administered (much like that following l-DOPA administration shown previously in
Figure 6-3 above). In fact, the effect is almost too good to be true. The theoretical difficulty of
this phenomenon is that the MAO inhibitors produce a rapid and transient reversal of the behavior
that was lost through reserpine treatment, whereas the effects of these compounds in the clinic are
characterized by a slow onset and more chronic duration of action.
The major effect of the tricyclic compounds on adrenergic neurons is to block the reuptake
mechanism (see Figure 6-12), but as in the case of the MAO inhibitors, the evidence that this
forms the basis of the antidepressant effect is less than conclusive. The blockade of the reuptake
pathway avoids the dangerous effects of tyramine ingestion via food intake, but leaves the patient
vulnerable to a host of other drug interactions. In general, the patients must avoid a wide range
of drugs that influence either adrenergic or cholinergic transmitter systems because of potentially
life threatening cardiovascular and central nervous system effects.
Whatever the mechanism that accounts for the antidepressant effects, the tricyclic compounds are
like the MAO inhibitors in that they typically require two to three weeks to become clinically
effective. Furthermore, the elevation of mood seems to have depression as a prerequisite, because
the drugs are ineffective in normal subjects. In fact, normal subjects are likely to experience
general feelings of discomfort and anxiety rather than an elevation of mood.
Choosing The Drug
One of the major difficulties facing the clinician who is treating depression is the selection of the
best drug. Clearly, a part of the decision can be based upon the general health picture that is
presented, and some drugs may be contraindicated because of potential interactions with the
patient's ongoing medical treatment (e.g., drugs) or with dietary habits (e.g., wine and cheese).
There still remains the problem that some drugs may be more effective than others, and it will take
a few weeks to find out. Several investigators (cf., Schildkraut, Orsulak, Schatzberg &
Rosenbaum, 1984; Leckman & Maas, 1984) have attempted to find biochemical markers that
will provide a clue for drug selection. Not surprisingly, this search has centered around the
metabolites of catecholamine neurotransmitters.
As indicated in Figure 6-13, there are several alternative pathways for the normal degradation of
catecholamines that are not bound in storage sites or synaptic vesicles. There is some evidence
that patients exhibiting different symptoms of depression show different levels of particular
metabolites. One clue came from patients who were being treated for amphetamine overdose.
These patients showed very high levels of MHPG while the drug was running its course, followed
by very low levels for two to three days afterward. These low levels of MHPG were
accompanied by marked depression. Patients suffering from unipolar depression show a wide
range of MHPG levels. Those with low levels tend to respond favorably to tricyclic compounds,
or even to amphetamines. Those with high levels respond more favorably to the MAO inhibitors.
Another type of marker serves more to indicate the success of therapy rather than predicting the
success of the particular drug. Robinson (see Maugh, 1984) has found that another metabolite
(DHPG) is low in depressed patients, but consistently increases before the mood level increases.
In each of these cases, there is some degree of controversy; some groups of investigators
corroborate the results, while others fail. There are, however, sufficient clues to make this a
potentially fruitful approach for the selection of therapy.
The model of depression presented here has been deliberately biased toward the catecholamine
systems, in part because of the historical emphasis on this system, and in part because it coincides
more clearly with the behavioral models that are currently available. It is clear, however, that any
comprehensive model of depression must also consider the serotonergic systems of the brain. The
major drugs that alter mood levels frequently influence both the catecholamines and serotonin.
Reserpine, as indicated earlier, depletes both norepinephrine and serotonin and causes severe
depression. The tricyclic antidepressants block the reuptake of both norepinephrine and
serotonin, and relieve depression. Some of the newer forms of antidepressants seem to
specifically block serotonin reuptake and, as you might guess by now, there are some effective
antidepressants that have not been shown to influence either system.
These superficial inconsistencies do not necessarily mean that the catecholamine model is wrong.
Rather, they suggest that we need a neurochemical model that matches the complexity of the
disorder as seen in the clinic. Although there is a commonality of symptoms among patients who
suffer from depression, it may be possible (and necessary) to analyze these symptoms and various
biochemical markers in some detail before selecting the treatment. One of the metabolites of
serotonin, 5-HIAA (5-hydroxy indole acetic acid), has been correlated with suicide attempts of
depressed patients (e.g., Traeksman et al, 1981). In a population of patients who are all
suffering from depression, those with the lowest levels of 5-HIAA in their cerebrospinal fluid (i.e.,
lowest utilization of serotonin) are the most likely to attempt suicide-- especially by violent means.
On the other hand, the results shown in Figure 6-3 suggest that norepinephrine is more important
for the recovery of a normal response to rewards. It seems possible, that the lack of
responsiveness to reward and, perhaps, the decline in activity levels may be attributable to
dysfunction of the catecholamine systems. The preoccupation with thoughts of death, the
attempts to commit suicide, and disorders of sleep may be attributable to dysfunction of
serotonergic systems. If this type of dissociation is valid, then a detailed appraisal of behavioral
attributes and blood/csf chemistry may greatly increase the likelihood of prescribing an effective
drug on the first attempt.
Why the Delay?
Some of the peculiar features of the MAO inhibitors and the tricyclic antidepressants suggest that
their effects may not be understood by a straightforward description of their interaction with
synapses. Several observations are at odds with an explanation that is based simply on their
immediate interference with monoamine oxidase or with the reuptake mechanism:
(a) The antidepressant drugs are more effective than either cocaine or amphetamine, both of which produce more immediate and more potent stimulation of the catecholamine systems.
(b) The antidepressant drugs, especially the tricyclic compounds, are ineffective in elevating the mood of normal (i.e., non-depressed) subjects, and seem to have rather selective effects on different forms of depression.
(c) Although both classes of compounds produce a variety of neurochemical effects and are
eliminated from the body within hours (or certainly within days), effective therapeutic regimens
frequently require as much as several weeks before the abatement of clinical symptoms becomes
It seems likely that such a delayed onset of effectiveness reflects some long term, tonic change in
the neuronal substrate that is being affected. One likely candidate for such a change is a general
increase in the storage and release of the transmitter substance (see Chapter 3 for a discussion of
functional pools). As mentioned above, Weiss and associates suggest that helplessness may
involve a change in the activity of the alpha-2 autoreceptors in the region of the locus coeruleus.
The antidepressant compounds may act upon this and other neuromodulatory systems to allow
the transmitter system to develop (slowly) the cellular mechanisms that bring it back normal levels
of responsiveness. This process might be triggered by a short term action such as the inhibition of
MAO or the blockade of the reuptake mechanism, but not be manifested until the long term
changes in the neuron's metabolic machinery have been accomplished. In this particular case, a
change in the autoreceptor activity at the cells of origin in the locus coeruleus could alter the level
of norepinephrine that is released in more anterior regions of the brain. This effect, in turn, could
change the number and sensitivity of the postsynaptic receptors that are involved in regulating the
organism's behavioral interaction with the environment (see Figure 6.14). This idea of long term
modulation of the catecholamine neurons is also consistent with Anisman's (1984) suggestion
that stressors can lead to reduced sensitivity of receptors to catecholamines. All of these effects
may be reversible by drugs, but the requirement of metabolic and structural change in the neurons
could easily account for the observed delay in the therapeutic effects of the drugs.
The long therapeutic delay that characterizes the antidepressant drugs is more than an
inconvenience. In cases of severe depression, the threat of suicide is so real that more heroic
approaches to therapy are sometimes necessary. One such approach is electroconvulsive therapy
(ECT), more colloquially referred to as shock treatment.
Electroconvulsive therapy was introduced by an Italian physician named Cerletti (e.g., Cerletti
and Bini, 1938) A vagrant, wandering in apparent confusion through the local train station, had
been arrested by the police and presented for psychiatric treatment. Cerletti had noted the
calming effects of electric shock on animals that were stunned by electricity at the slaughterhouse,
and had tried the procedure experimentally on a few dogs. He decided to try the procedure on
the newly presented patient, whose identity was unknown. Cerletti concluded that the treatment
must have been beneficial, because when the patient was brought in for the second treatment, the
previously noncommunicative man exclaimed something to the effect of "My God, No! It's
deadly!" It was on this somewhat shaky foundation that ECT began to be used for a variety of
psychiatric treatments and as an experimental tool in animal research.
The convulsions that accompanied the early methods of ECT were traumatic. The uncontrolled
muscular activity was so powerful that it damaged tendons, dislocated joints, or even broke bones
unless the patients were pre-treated with muscle relaxants. The convulsions were followed by
obvious (though short term and transient) losses of memory in both humans and experimental
animals. There was histological evidence that some neurons died as a result of the procedure.
Given the serious nature of the ECT treatment, there could have been only one legitimate reason
for using the procedure--it worked.
Modern versions of ECT bear little resemblance to the early methods. The electrical currents are
much lower, are restricted to smaller portions of the brain, and are given following pretreatment
with anesthesia and muscle relaxants. Unlike the slow acting drug therapies, electroconvulsive
therapy can produce a prompt reversal of the symptoms of severe depression, allowing the patient
to return to family and job situations much more quickly. More importantly, the rapid effects
greatly diminish the risk of suicide that might occur before other forms of therapy would have a
chance to become effective.
Experimental studies of ECT in animals provides further support for the role of catecholamines in
depression. Neurochemical assays have revealed that ECT stimulates the synthesis of
norepinephrine by increasing the level of tyrosine hydroxylase (Masserano, Takimoto and
Clearly, the dangers inherent in ECT should not be minimized, and this form of treatment should
not be administered casually. However, it will continue to be used as long as there is no
alternative treatment that is as fast and as effective in reversing the symptoms of severe
Lithium is a simple salt that has had a stormy history as a drug. Because of its similarity to
sodium, it was used initially as a substitute for table salt in the diet of cardiac patients. Many of
these patients died, because the lithium readily replaces sodium in the body but it does not support
cellular functions in the same manner as sodium. The use of lithium as a treatment in psychiatric
disorders has its origins in a series of (misguided) experiments of an Australian psychiatrist named
John Cade (cf., Snyder, 1986). Although the rationale was wrong, the clinical results proved to
be very effective.
Lithium is still a dangerous drug, but it can be used successfully when care is taken to monitor and
manage the serum levels of sodium (and lithium). The drug is very effective in reducing and
preventing manic behavior. In cases of bipolar disorders of cycling manic depression, the drug is
seems to eliminate both aspects of the mood disorder. It appears that the depressive phase of the
disorder is largely the result of the preceding manic phase. The stabilizing effects of the lithium
treatment directly controls the mania and indirectly controls the depression (see Figure 6-15).
The manic behavior may reflect a high level of noradrenergic activity. Behaviorally, this phase is
characterized by excessive talking, flights of ideas, excessive and sustained levels of activity, and
sometimes prodigious physical and mental accomplishments. When patients "come down" from
this phase, the mood may not stop at the normal level, but more typically may continue, dropping
into the depths of depression. It is as though the manic behavior continues until the
neurotransmitter systems are depleted and unable to continue supporting the behavior. In this
regard it should be noted that unipolar mania is rare.
The dramatic impairments of behavior that are triggered by environmental conditions become
even more impressive when viewed in the context of related behavioral histories. In the initial
experiments of Overmeir and Seligman (1967), the learned helplessness effect had an interesting
aspect that has not been generally viewed as a central feature of the phenomenon. As long as the
dogs were tested in the shuttle-box within 24 hours after the Pavlovian conditioning, they showed
the typical learned helplessness effect and would continue to show this failure to respond in the
shuttle-box even when tested again weeks later. However, if a delay of 48 or 72 hours was
interposed between the Pavlovian and instrumental conditioning phases, the dogs acquired the
shuttle-box normally. Thus the debilitating effects of the Pavlovian conditioning experience were
transient in nature.
In a related experiment, Anisman and Sklar (1979) have shown that the neurochemical systems
of rats will recover rather quickly from a single session of exposure to stressful electrical shocks.
Rats that received 60 shocks showed a transient decline in norepinephrine levels, but after 24 hrs,
their norepinephrine levels were indistinguishable from that of control animals that had received
no shocks. However, these animals were much more vulnerable to stress than the controls.
When both groups of animals were given 10 additional shocks, the control rats showed only a
small, transient effect, whereas the previously shocked animals showed a precipitous and more
long lasting decline in norepinephrine levels.
In each of these examples, exposure to failure renders these neurochemical systems more fragile
and they become increasingly vulnerable to environmental influences (see Fig. 6-16).
These results may also be related to the so-called "freeloader" experiments in which rats given a
choice between free (noncontingent) food and food that is contingent upon pressing a lever will
frequently choose the option of working for the pellets. Work ethics and social implications
aside, these results suggest that the interaction with a rewarding environment is a positive
feedback situation that makes it more rewarding to interact with the environment.
The False Perception of Control
Are the symptoms of depression caused by a dysfunction of the reward system, or does the lack of
behavior that characterizes depression result in the atrophy of the reward system? Lauren Alloy,
working in Solomon's laboratory, developed the intriguing idea that individuals who suffer from
depression may not recognize the effectiveness of their own behavior (cf., Solomon, 1980; Alloy
& Abrahamson, 1982). In other words, they might be exposed to the same rewards, but because
of some deficit, fail to fully recognize the rewards. This idea was investigated in a series of
experiments that used college students as subjects. These were not clinical patients. Rather, the
students were selected on the basis of their scores on a questionnaire that assessed symptoms of
depression. The two ends of the distribution formed the "depressed" and "non-depressed" groups
of subjects. These subjects were tested on a sort of computer game in which they attempted to
control a light. The actual degree of control ranged from 0-100 percent. Alloy's theory was that
the depressed subjects would consistently underestimate the degree of control that was actually
present. However, these subjects were very accurate in their estimates. Surprisingly, it was the
normal (non-depressed) subjects who were inaccurate: They consistently overestimated the
degree of control! These results suggest that the reward system has a built-in bias to "recognize"
control even when it does not exist. This perceived control almost certainly has the same tonic
effects on the neurochemical systems as real control. This systematic bias should not be viewed
too suspiciously, because such errors are rather commonplace within the nervous system. One of
the recurrent features of design within the sensory systems is an organization that exaggerates
borders, color differences, frequency differences, and other features of the environment. It is not
unreasonable to assume that the system that interprets our control over the environment also
presents us with little white lies about the nature of the world around us.
The challenge to therapists is to develop situations that immerse the depressed patient in control.
It probably matters little whether the control is real or perceived, or whether it serves a genuine
biological need or the trivial manipulation of a monster on a computer screen. The behavioral
approaches will not always be successful. They will sometimes need to be administered in
conjunction with drug therapies or even with the more drastic approaches of electroconvulsive
therapy or surgery. It seems clear, however, that the breakdown of a neurochemical system that
interacts so richly with behavior should be treated with behavior whenever possible.
2. Learning that behavior is ineffective in one situation can generalize to other situations where
the behavior actually has an effect.
3. The reversal of depression with the MAO inhibitor, iproniazid, provided the first important link
between depression and the catecholamines.
4. Rewards appear to be mediated by catecholamine fibers that lie in the medial forebrain bundle.
5. Acute episodes of stress lower the level of catecholamines in the reward system.
6. These short term behavioral treatments can lead to long term changes via neuromodulation.
7. The treatment of depression is complicated by the cyclic nature of the disorder, the dangerous
side effects of the available drug treatments, and individual differences in response to the drugs.
8. The MAO inhibitors appear to facilitate the activity of the catecholamine systems by slowing
the metabolism of these compounds. The tricyclic drugs appear to interfere with the reuptake of
catecholamines. It remains unclear whether these biochemical actions account for the clinical
effects of the drugs.
9. The metabolites of catecholamines (e.g., MHPG) and of serotonin (e.g., 5-HIAA) may serve
as biochemical markers to aid in both the diagnosis and treatment of the various forms of
10. The long therapeutic delay of the antidepressant drugs suggests that they trigger
neuromodulatory changes rather than directly ameliorating the condition.
11. Bipolar depression frequently responds well to lithium treatment, possibly because of the
drug's ability to prevent catecholamine depletion by preventing the manic phase of the disorder.
12. Electroconvulsive therapy produces an almost immediate reversal of depression as well as an
increase in tyrosine hydroxylase levels.
13. Behavioral therapies are effective not only in changing the patient's interpretation of the
environment, but also because they are likely to reverse some of the neurochemical changes that
provide the foundation for depression.