MOOD DISORDER

This chapter discusses disorders characterized by abnormalities of mood: namely,

depression, mania, or both. Included here are descriptions of a wide variety of mood
disorders that occur over a broad clinical spectrum. Also included in this chapter is an
analysis of how monoamine neurotransmitter systems are hypothetically linked to the
biological basis of mood disorders. The three principal monoamine neurotransmitters
are norepinephrine (NE; also called noradrenaline or NA), discussed in this chapter,
dopamine (DA), discussed in Chapter 4, and serotonin (also called 5-hydroxytryptamine
or 5HT), discussed in Chapter 5.

The approach taken here is to deconstruct each mood disorder into its component
symptoms, followed by matching each symptom to hypothetically malfunctioning brain
circuits, each regulated by one or more of the monoamine neurotransmitters. Genetic
regulation and neuroimaging of these hypothetically malfunctioning brain circuits are
also discussed. Coverage of symptoms and circuits of mood disorders in this chapter is
intended to set the stage for understanding the pharmacological concepts underlying
the mechanisms of action and use of antidepressants and mood stabilizing drugs, which
will be reviewed in the following two chapters (Chapters 7 and 8).

Clinical descriptions and criteria for how to diagnose disorders of mood will only be
mentioned in passing. The reader should consult standard reference sources for this
material.

Description of mood disorders

Disorders of mood are often called affective disorders, since affect is the external
display of mood, an emotion that is felt internally. Depression and mania are often seen
as opposite ends of an affective or mood spectrum. Classically, mania and depression
are “poles” apart, thus generating the terms unipolar depression (i.e., patients who just
experience the down or depressed pole) and bipolar (i.e., patients who at different times
experience either the up [i.e., manic] pole or the down [i.e., depressed] pole).
Depression and mania may even occur simultaneously, which is called a mixed mood
state. Mania may also occur in lesser degrees, known as hypomania, or switch so fast
between mania and depression that it is called rapid cycling

Mood disorders can be usefully visualized not only to contrast different mood disorders
from one another, but also to summarize the course of illness for individual patients by
showing them mapped onto a mood chart. Thus, mood ranges from hypomania to
mania at the top, to euthymia (or normal mood) in the middle, to dysthymia and
depression at the bottom(Figure 6-1). The most common and readily recognized mood
disorder is major depressive disorder (Figure 6-2), with single or recurrent episodes.
Dysthymia is a less severe but long-lasting form of depression (Figure 6-3). Patients
with a major depressive episode who have poor inter-episode recovery, only to the level
of dysthymia, followed by another episode of major depression are sometimes said to
have “double depression,” alternating between major depression and dysthymia, but not
remitting

Patients with bipolar I disorder have full-blown manic episodes or mixed episodes of
mania plus depression, often followed by a depressive episode (Figure 6-5). When
mania recurs at least four times a year, it is called rapid cycling (Figure 6-6A). Patients
with bipolar I disorder can also have rapid switches from mania to depression and back
(Figure 6-6B). By definition, this occurs at least four times a year, but can occur much
more frequently than that.

Bipolar II disorder is characterized by at least one hypomanic episode that follows a

depressive episode (Figure 6-7). Cyclothymic disorder is characterized by mood swings
that are not as severe as full mania and full depression, but still wax and wane above
and below the boundaries of normal mood (Figure 6-8). There may be lesser degrees of
variation from normal mood that are stable and persistent, including both depressive
temperament (below normal mood but not a mood disorder) and hyperthymic
temperament (above normal mood but also not a mood disorder) (Figure 6-9).
Temperaments are personality styles of responding to environmental stimuli that can be
heritable patterns present early in life and persisting throughout a lifetime;
temperaments include such independent personality dimensions as novelty seeking,
harm avoidance, and conscientiousness. Some patients may have mood-related
temperaments, and these may render them vulnerable to mood disorders, especially
bipolar spectrum disorders, later in life.

The bipolar spectrum

From a strict diagnostic point of view, our discussion of mood disorders could now be
mostly complete. However, there is the growing recognition thatmany patients seen in
clinical practice have a mood disorder not well described by the above categories.
Formally, they would be called “not otherwise specified” or “NOS,” but this creates a
huge single category for many patients that belies the richness and complexity of their
symptoms. Increasingly, such patients are seen as belonging in general to the “bipolar
spectrum” (Figure 6-10), and in particular to one of several additional descriptive
categories that have been proposed by experts such asHagop Akiskal (Figures 6-10
through 6-20).

Bipolar ¼ (0.25)

One mood disorder often considered to be “not quite bipolar” and sometimes called
bipolar ¼ (or 0.25) designates an unstable form of unipolar depression that responds
sometimes rapidly but in an unsustained manner to antidepressants, the latter
sometimes called antidepressant “poop-out” (Figure 6-11). These patients have
unstable mood but not a formal bipolar disorder, yet can benefit frommood-stabilizing
treatments added to robust antidepressant treatments.

Bipolar ½ (0.5) and schizoaffective disorder

Another type of mood disorder is called different things by different experts, from bipolar
½ (or 0.5) to “schizobipolar disorder” to “schizoaffective disorder” (Figure 6-12). For over
a century, experts have debated whether psychotic disorders are dichotomous from
mood disorders (Figure 6-13A) or are part of a continuous disease spectrum from
psychosis to mood (Figure 6-13B).

The dichotomous diseasemodel is in the tradition of Kraepelin and proposes that

schizophrenia is a chronic unremitting illness with poor outcome and decline in function
whereas bipolar disorder is a cyclical illness with a better outcome and good restoration
of function between episodes. However, there is great debate as to how to define the
borders between these two illnesses. One notion is that cases with overlapping
symptoms and intermediate disease courses can be seen as a third illness,
schizoaffective disorder.Today, many define this border with the idea that “even a trace
of schizophrenia is schizophrenia.” From this “schizophrenia-centered perspective,”
many overlapping cases of psychotic mania and psychotic depression might be
considered either to be forms of schizophrenia, or to be schizoaffective disorder as a
formof schizophreniawith affective symptoms. A competing point of view within the
dichotomous model is that “even a trace of mood disturbance is a mood disorder.” From
this “moodcentered perspective,” many overlapping cases of psychotic mania and
psychotic depression might be considered either to be forms of a mood/bipolar disorder
or to be schizoaffective disorder as a form of mood/bipolar disorder with psychotic
symptoms. Where patients have a mixture of mood symptoms and psychosis, it can
obviously be very difficult to tell whether they have a psychotic disorder such as
schizophrenia, amood disorder such as bipolar disorder, or a third condition,
schizoaffective disorder. Some even want to eliminate the diagnosis of schizoaffective
disorder entirely.

Proponents of the dichotomous model point out that treatments for schizophrenia differ
from those for bipolar disorder, since lithium is rarely helpful in schizophrenia, and
anticonvulsant mood stabilizers have limited efficacy for psychotic symptoms in
schizophrenia, and perhaps only as augmenting agents. Treatments for schizoaffective
disorder can include both treatments for schizophrenia and treatments for bipolar
disorder. The current debate within the dichotomous model is: If you have bipolar
disorder, do you have a good outcome? – but if you have schizophrenia, do you have a
poor outcome? – and what genetic and biological markers rather than clinical symptoms
can distinguish one dichotomous entity from the other?

The continuum disease model proposes that psychotic and mood disorders are both
manifestations of one complex set of disorders that is expressed across a spectrum, at
one end schizophrenia (plus schizophreniform disorder, brief psychotic disorder,
delusional disorder, shared psychotic disorder, subsyndromal/ultra-high-risk psychosis
prodrome, schizotypal, paranoid, schizoid, and even avoidant personality disorders),
and at the other end bipolar/mood disorders (mania, depression, mixed states,
melancholic depression, atypical depression, catatonic depression, postpartum
depression, psychotic depression, seasonal affective disorder), with schizoaffective
disorder in the middle, combining features of positive symptoms of psychosis with
manic, hypomanic, or depressive episodes (Figure 6-13B).

Modern genomics suggests that the spectrum is not a single disease, but a complex of
hundreds if not thousands of different diseases, with overlapping genetic, epigenetic,
and biomarkers aswell as overlapping clinical symptoms and functional outcomes.
Proponents of the continuum model point out that treatments for schizophrenia overlap
greatly now with those for bipolar disorder, since second-generation atypical
antipsychotics are effective in the positive symptoms of schizophrenia and in psychotic
mania and psychotic depression, and are also effective in nonpsychotic mania and in
bipolar depression and unipolar depression. These same second-generation atypical
antipsychotics are effective for the spectrum of symptoms in schizoaffective disorder.
From the continuum disease perspective, failure to give mood-stabilizing medications
may lead to suboptimal symptom relief in patients with psychosis, even those whose
prominent or eye-catching psychotic symptoms mask or distract clinicians fromseeing
underlying and perhaps more subtle mood symptoms. In the continuum disease model,
schizophrenia can be seen as the extreme end of a spectrum of severity of mood
disorders and not a disease unrelated to amood disorder. Schizophrenia can therefore
share with schizoaffective disorder severe psychotic symptoms that obscure mood
symptoms, a chronic course that eliminates cycling, resistance to antipsychotic
treatments, and prominent negative symptoms, yet be just a severe formof the same
illness. In the continuum disease model, schizoaffective disorder would be a milder form
of the illness with less severe psychotic features and more severe mood features.

The debate rages on

Bipolar I½ (1.5)

Although patients with protracted or recurrent hypomania without depression are not
formally diagnosed as bipolar II disorder, they are definitely part of the bipolar spectrum,
and may benefit from mood stabilizers that have been studied mostly in bipolar I
disorder (Figure 6-14). Eventually, such patients will often develop a major depressive
episode and their diagnosis will then change to bipolar II disorder, but in the meantime
they can be treated for hypomania while being vigilant to the future onset of a major
depressive episode.

Bipolar II½ (2.5)

Bipolar II½ is the designation for cyclothymic patients who develop major depressive
episodes (Figure 6-15). Many patients with cyclothymia are just considered “moody”
and do not consult professionals until experiencing full depressive episodes. It is
important to recognize patients in this part of the bipolar spectrum, because treatment of
their major depressive episodes with antidepressant monotherapy may actually cause
increased mood cycling or even induction of a full manic episode, just as can happen in
patients with bipolar I or II depressive episodes

Bipolar III (3.0)

Patients who develop a manic or hypomanic episode on an antidepressant are

sometimes called bipolar III (Figure 6-16). According to formal diagnostic criteria,
however, when an antidepressant causes mania or hypomania, the diagnosis is not
bipolar disorder, but rather, “substance-induced mood disorder.” Many experts disagree
with this designation and feel that patients who have a hypomanic or manic response to
an antidepressant do so because they have a bipolar spectrum disorder, and can be
more appropriately diagnosed as bipolar III disorder (Figure 6-16) until they experience
a spontaneous manic or hypomanic episode while taking no drugs, at which point their
diagnosis would be bipolar I or II, respectively. The bipolar III designation is helpful in
the meantime, reminding clinicians that such patients are not good candidates for
antidepressant monotherapy.

Bipolar III½ (3.5)

A variant of this bipolar III disorder has been called bipolar III½, to designate a type of
bipolar disorder associated with substance abuse (Figure 6-17).

Although some of these patients can utilize substances of abuse to treat depressive
episodes, others have previously experienced natural or drug-induced mania and take
substances of abuse to induce mania. This combination of a bipolar disorder with
substance abuse is a formula for chaos, and can often be the story of a patient prior to
seeking treatment from a mental health professional.

Bipolar IV (4.0)

Bipolar IV disorder is the association of depressive episodes with a pre-existing

hyperthymic temperament (Figure 6-18). Patients with hyperthymia are often sunny,
optimistic, high-output, successful individuals with stable temperament for years and
then suddenly collapse into a severe depression. In such cases, it may be useful to be
vigilant to the need for more than antidepressant monotherapy if the patient is
unresponsive to such treatment, or if the patient develops rapid cycling or hypomanic or
mixed states in response to antidepressants. Despite not having a formal bipolar
disorder, such patients may respond best to mood stabilizers.

Bipolar V (5.0)

Bipolar V disorder is depression with mixed hypomania (Figure 6-19). Formal diagnostic
criteria for mixed states require full expression of both depression and mania
simultaneously, but in the real world, many depressed patients can have additional
symptoms that only qualify as hypomania or subsyndromal hypomania, or even just a
few manic symptoms or only mild manic symptoms. Depression simultaneous with full
hypomania is represented in Figure 6-1 and Figure 6-5 and requires mood stabilizer
treatment, not antidepressant monotherapy. Under debate is whether there should be a
separate diagnostic category for depression with subthreshold hypomania; some
experts believe that up to half of patients with major depression also have a lifetime
history of subsyndromal hypomania, and that these patients are much more likely to
progress to a formal bipolar diagnosis. Patients with depression and subthreshold
hypomania generally have a worse outcome, more mood episodes, more work
impairment, are more likely to have a family member with mania or other bipolar
disorder, and to have an early onset of depression. For depression with subsyndromal
hypomania it may be more important to emphasize overactivity rather than just mood
elevation, and a duration of only 2 days as opposed to the 4 days required in most
diagnostic systems for hypomania. Whether these patients can be treated with
antidepressant monotherapy without precipitating mania, or instead require agents with
potentially greater side effects such as mood stabilizers, lithium, and/or atypical
antipsychotics, is still under investigation.

Related conditions to depression mixed with subsyndromal hypomania include other

mood states where full diagnostic criteria are not reached, ranging from full mixed states
(both full mania diagnostic criteria [M] and full depression diagnostic criteria [D]) to
depression with hypomania or only a few hypomanic symptoms (mD) as already
discussed. In addition, other combinations of mania and depression range from full
mania with only a few depressive symptoms (Md, sometimes also called “dysphoric”
mania), to subsyndromal but unstable states characterized by some symptoms of both
mania and depression, but not diagnostic of either (md) (Table 6-1). All of these states
differ from unipolar depression and belong in the bipolar spectrum; they may require
treatment with the same agents that are used to treat bipolar I or II disorder, with
appropriate caution for antidepressant monotherapy. Just because a patient is
depressed, it does not mean he or she should start with an antidepressant for
treatment. Patients with mixed states of depression and mania may be particularly
vulnerable to the induction of activation, agitation, rapid cycling, dysphoria, hypomania,
mania, or suicidality when treated with antidepressants, particularly without the
concomitant use of a mood stabilizer or an atypical antipsychotic.

Bipolar VI (6.0)

Finally, bipolar VI disorder (Figure 6-20) represents bipolarity in the setting of dementia,
where it can be incorrectly attributed to the behavioral symptoms of dementia rather
than recognized and treated as a comorbid mood state with mood stabilizers and even
with atypical antipsychotics. Many more subtypes of mood disorders can be described
within the bipolar spectrum. The important thing to take away from this discussion is that
not all patients with depression have major depressive disorder requiring treatment with
antidepressant monotherapy, and that there are many states of mood disorder within
the bipolar spectrum beyond just bipolar I and II disorders.

Can unipolar depression be distinguished from bipolar depression?

One of the important developments in the field of mood disorders in recent years in fact
is the recognition that many patients once considered to have major depressive disorder
actually have a form of bipolar disorder, especially bipolar II disorder or one of the
conditions within the bipolar spectrum (Figure 6-21). Since symptomatic patients with
bipolar disorder spend much more of their time in the depressed state rather than in the
manic, hypomanic, or mixed state, this means that many depressed patients in the past
were incorrectly diagnosed with unipolar major depression, and treated with
antidepressant monotherapy instead of being diagnosed as a bipolar spectrum disorder
and treated first with lithium, anticonvulsant mood stabilizers, and/or atypical
antipsychotics prior to adding an antidepressant, if an antidepressant is even used at
all.

Up to half of patients once considered to have a unipolar depression are now

considered to have a bipolar spectrum disorder (Figure 6-21), and although they would
not necessarily be good candidates for antidepressant monotherapy, this is often the
treatment that they receive when the bipolar nature of their condition is not recognized.
Antidepressant treatment of unrecognized bipolar patients may not only increase mood
cycling, mixed states, and conversion to hypomania and mania, as mentioned above,
but may also contribute to the increase in suicidality in younger patients treated with
antidepressants, i.e., children and adults younger than 25.

Thus it becomes important to recognize whether a depressed patient has a bipolar

spectrum disorder or a unipolar major depressive disorder. How can this be done? In
reality, patients with either unipolar or bipolar depression often have identical current
symptoms, so obtaining the profile of current symptomatology is obviously not sufficient
for distinguishing unipolar from bipolar depression. The answer may be in part to ask
the two questions shown in Table 6-2, namely, “Who’s your daddy?” and “Where’s your
mama?”

“Who’s your daddy?” can mean “what is your family history?” since a first-degree
relative with a bipolar spectrum disorder can give a strong hint that the patient also has
a bipolar spectrum disorder rather than unipolar depression. “Where’s your mama?” can
mean “I need to get additional history from someone else close to you,” since patients
tend to under-report their manic symptoms, and the insight and observations of an
outside informant such as a mother or spouse can describe a history quite different from
the one the patient is reporting, and thus help establish a bipolar spectrum diagnosis
that patients themselves do not perceive, or deny. Some hints, but not sufficient for
diagnostic certainty, can even come from current symptoms to suggest a bipolar
spectrum depression, such as more time sleeping, overeating, comorbid anxiety, motor
retardation, mood lability, psychotic symptoms or suicidal thoughts (Figure 6-22). Hints
that the depression may be in the bipolar spectrum can also come from the course of
the untreated illness prior to the current symptoms, such as early age of onset, high
frequency of depressive symptoms, high proportion of time spent ill, and acute
abatement or onset of symptoms. Prior response to antidepressants that suggests
bipolar depression can be multiple antidepressant failures, rapid recovery, and
activating side effects such as insomnia, agitation, and anxiety. Although none of these
features can discriminate bipolar depression from unipolar depression with certainty, the
point is to be vigilant to the possibility that what looks like a unipolar depression might
actually be a bipolar spectrum depression when investigated more carefully, and when
response to treatment is monitored.

Are mood disorders progressive?

One of the major unanswered questions about the natural history of depressive
illnesses is whether they are progressive (Figures 6-23 and 6-24). Some observers
believe that there is an increasing number of patients in mental health practices who
have bipolar spectrum illnesses rather than unipolar illnesses, especially compared to a
few decades ago. Is this merely the product of changing diagnostic criteria, or does
unipolar depression progress to bipolar depression (Figure 6-23)? A corollary of this
question is whether chronic and widespread undertreatment of unipolar depression,
allowing residual symptoms to persist and relapses and recurrences to occur, results
first in more rapidly recurring episodes of major depression, then in poor inter-episode
recovery, then progression to a bipolar spectrum condition, and finally to treatment
resistance (Figure 6-23). Many treatment-resistant mood disorders in psychiatric
practices have elements of bipolar spectrum disorder that can be identified, and many
of these patients require treatment with more than antidepressants, or with mood
stabilizers and atypical antipsychotics instead of antidepressants. For patients already
diagnosed with bipolar disorder, there is similar concern that the disorder may be
progressive, especially without adequate treatment. Thus, discrete manic and
depressive episodes may progress to mixed and dysphoric episodes, and finally to rapid
cycling, instability, and treatment resistance (Figure 6-24). The hope is that recognition
and treatment of both unipolar and bipolar depressions, causing all symptoms to remit
for long periods of time, might prevent progression to more difficult states. This is not
proven, but is a major hypothesis in the field at the present time. In the meantime,
practitioners must decide whether to commit “sins of omission,” and be conservative
with the diagnosis of bipolar spectrum disorder, and err on the side of undertreatment of
mood disorders, or “sins of commission,” and overdiagnose and overtreat symptoms in
the hope that this will prevent disease progression.

Neurotransmitters and circuits in mood disorders

Three principal neurotransmitters have long been implicated in both the

pathophysiology and treatment of mood disorders. They are norepinephrine, dopamine,
and serotonin, and comprise what is sometimes called the monoamine neurotransmitter
system. These three monoamines often work in concert. Many of the symptoms of
mood disorders are hypothesized to involve dysfunction of various combinations of
these three systems. Essentially all known treatments for mood disorders act upon one
or more of these three systems.

We have extensively discussed the dopamine system in Chapter 4 and illustrated it in

Figures 4-5 through 4-11. We have extensively discussed the serotonin system in
Chapter 5 and illustrated it in Figures 5-13, 5-14, 5-25, and 5-27. Here we introduce the
reader to the norepinephrine system, and also show some interactions among these
three monoaminergic neurotransmitter systems.

Noradrenergic neurons

The noradrenergic neuron utilizes norepinephrine (noradrenaline) as its

neurotransmitter. Norepinephrine (NE) is synthesized, or produced, from the precursor
amino acid tyrosine, which is transported into the nervous system from the blood by
means of an active transport pump (Figure 6-25). Once inside the neuron, the tyrosine
is acted upon by three enzymes in sequence. First, tyrosine hydroxylase (TOH), the
ratelimiting andmost important enzyme in the regulation of NE synthesis. Tyrosine
hydroxylase converts the amino acid tyrosine into DOPA. The second enzyme then
acts, namely, DOPA decarboxylase (DDC), which converts DOPA into dopamine (DA).
DA itself is a neurotransmitter in dopamine neurons, as discussed in Chapter 4 and
illustrated in Figure 4-5. However, for NE neurons, DA is just a precursor of NE. In fact
the third and final NE synthetic enzyme, dopamine β-hydroxylase (DBH), converts DA
into NE. NE is then stored in synaptic packages called vesicles until released by a nerve
impulse (Figure 6-25).

NE action is terminated by two principal destructive or catabolic enzymes that turn NE

into inactive metabolites. The first is monoamine oxidase (MAO) A or B, which is located
in mitochondria in the presynaptic neuron and elsewhere (Figure 6-26). The second is
catechol-O-methyl-transferase (COMT), which is thought to be located largely outside of
the presynaptic nerve terminal (Figure 6-26).

The action of NE can be terminated not only by enzymes that destroy NE, but also by a
transport pump for NE that removes NE from acting in the synapse without destroying it
(Figure 6-27). In fact, such inactivated NE can be restored for reuse in a later
neurotransmitting nerve impulse. The transport pump that terminates synaptic action
ofNE is sometimes called the “NE transporter” or NET and sometimes the “NE reuptake
pump.” This NE reuptake pump is located on the presynaptic noradrenergic nerve
terminal as part of the presynaptic machinery of the neuron,where it acts as a vacuum
cleanerwhiskingNE out of the synapse, off the synaptic receptors, and stopping its
synaptic actions. Once inside the presynaptic nerve terminal, NE can either be stored
again for subsequent reuse when another nerve impulse arrives, or destroyed by NE-
destroying enzymes (Figure 6-26).

The noradrenergic neuron is regulated by a multiplicity of receptors for NE (Figure 6-

27). The norepinephrine transporter or NET is one type of receptor, as is the vesicular
monoamine transporter (VMAT2) that transports NE in the cytoplasm of the presynaptic
neuron into storage vesicles (Figure 6-27). NE receptors are classified as α1 or α2A,
α2B, or α2C, or as β1, β2, or β3. All can be postsynaptic, but only α2 receptors can act
as presynaptic autoreceptors (Figures 6-27 through 6-29). Postsynaptic receptors
convert their occupancy by norepinephrine at α1, α2A, α2B, α2C, β1, β2, or β3
receptors into physiological functions, and ultimately into changes in signal transduction
and gene expression in the postsynaptic neuron (Figure 6-27).

Presynaptic α2 receptors regulate norepinephrine release, so they are called

autoreceptors (Figures 6-27 and 6-28). Presynaptic α2 autoreceptors are located both
on the axon terminal (i.e., terminal α2 receptors: Figures 6-27 and 6-28) and at cell body
(soma) and nearby dendrities; thus, these latter α2 presynapic receptors are called
somatodendritic α2 receptors (Figure 6-29). Presynaptic α2 receptors are important
because both the terminal and the somatodendritic α2 receptors are autoreceptors. That
is, when presynaptic α2 receptors recognize NE, they turn off further release of NE
(Figures 6-27 and 6-28). Thus, presynaptic α2 autoreceptors act as a brake for the NE
neuron, and also cause what is known as a negative-feedback regulatory signal.
Stimulating this receptor (i.e., stepping on the brake) stops the neuron from firing. This
probably occurs physiologically to prevent over-firing of the NE neuron, since it can shut
itself off once the firing rate gets too high and the autoreceptor becomes stimulated. It is
worthy to note that drugs can not only mimic the natural functioning of the NEneuron by
stimulating the presynaptic α2 neuron, but drugs that antagonize this same receptor will
have the effect of cutting the brake cable, thus enhancing release of NE.

Monoamine interactions: NE regulation of 5HT release

Norepinephrine clearly regulates norepinephrine neurons via α2 receptors (Figures 6-28

and 6-29); in Chapter 4, we showed that dopamine regulates dopamine neurons via D2
receptors (Figures 4-8 through 4-10); and in Chapter 5 we showed that serotonin
regulates serotonin neurons via 5HT1A and 5HT1B/D presynaptic receptors (Figures 5-
25 and 5-27) and via 5HT3 receptors (illustrated in Chapter 7) and 5HT7 postsynaptic
receptors (Figures 5-60A through 5-60C). Obviously, the threemonoamines are all able
to regulate their own release.

There are also numerous ways in which these three monoamines interact to regulate
each other. For example, in Chapter 5 we showed that serotonin regulates dopamine
release via 5HT1A receptors (Figures 5-15C and 5-16C), 5HT2A receptors (Figures 5-
15A, 5-16A, 5-17) and 5HT2C receptors (Figure 5-52A); we also showed that serotonin
regulates norepinephrine release via 5HT2C receptors (Figure 5-52A) and mentioned
that serotonin regulates dopamine and norepinephrine via 5HT3 receptors, which is
illustrated in Chapter 7 on antidepressants.

We now show that NE reciprocally regulates 5HT neurons via both α1 and α2 receptors
(Figures 6-30A through 6-30C): α1 receptors are the accelerator (Figure 6-30B), and α2
receptors the brake (Figure 6-30C) on 5HT release. That is, NE neurons from the locus
coeruleus travel a short distance to the midbrain raphe (Figure 6-30B, box 2) and there
they release NE onto postsynaptic α1 receptors on 5HT neuronal cell bodies. That
directly stimulates 5HT neurons and acts as an accelerator for 5HT release, causing
release of 5HT from their downstream axons (Figure 6-30B, box 1). Norepinephrine
neurons also innervate the axon terminals of 5HT neurons (Figure 6-30C). Here NE is
released directly onto postsynaptic α2 receptors that inhibit 5HT neurons, acting as a
brake on 5HT, thus inhibiting 5HT release (Figure 6-30C, box 1). Which action of NE
predominates will depend upon which end of the 5HT neuron receives more
noradrenergic input at any given time.

There are many brain areas where 5HT,NE, andDA projections overlap, creating
opportunities for monoamine interactions throughout the brain and at many different
receptor subtypes (Figures 6-31 through 6-33).

Numerous known inter-regulatory pathways and receptor interactions exist among the
three monoaminergic neurotransmitter systems in order for themto influence each other
and change the release not only of their own neurotransmitters, but also of other
monoamines
The monoamine hypothesis of depression

The classic theory about the biological etiology of depression hypothesizes that
depression is due to a deficiency of monoamine neurotransmitters. Mania may be the
opposite, due to an excess of monoamine neurotransmitters. At first, there was a great
argument about whether norepinephrine (NE) or serotonin (5- hydroxytryptamine, 5HT)
was the more important deficiency, and dopamine was relatively neglected. Now the
monoamine theory suggests that the entire monoaminergic neurotransmitter systemof
all threemonoamines NE, 5HT, and DA may be malfunctioning in various brain circuits,
with different neurotransmitters involved depending upon the symptom profile of the
patient.

The original conceptualization was rather simplistic and based upon observations that
certain drugs that depleted these neurotransmitters could induce depression, and that
all effective antidepressants act by boosting one or more of these three monoamine
neurotransmitters. Thus, the idea was that the “normal” amount of monoamine
neurotransmitters (Figure 6-34A) somehow became depleted, perhaps by an unknown
disease process, by stress, or by drugs (Figure 6-34B), leading to the symptoms of
depression.

Direct evidence for the monoamine hypothesis is still largely lacking. A good deal of
effort was expended especially in the 1960s and 1970s to identify the theoretically
predicted deficiencies of the monoamine neurotransmitters in depression and an excess
in mania. This effort to date has unfortunately yielded mixed and sometimes confusing
results, causing a search for better explanations of the potential link between
monoamines and mood disorders.

The monoamine receptor hypothesis and gene expression

Because of these and other difficulties with the monoamine hypothesis, the focus of
hypotheses for the etiology of mood disorders has shifted from the monoamine
neurotransmitters themselves to their receptors and the downstream molecular events
that these receptors trigger, including the regulation of gene expression and the role of
growth factors. There is also great interest in the influence of nature and nurture on
brain circuits regulated by monoamines, especially what happens when epigenetic
changes from stressful life experiences are combined with the inheritance of various risk
genes that can make an individual vulnerable to those environmental stressors.

The neurotransmitter receptor hypothesis of depression posits that an abnormality in the

receptors for monoamine neurotransmitters leads to depression (Figure 6-35). Thus, if
depletion of monoamine neurotransmitters is the central theme of the monoamine
hypothesis of depression (Figure 6-34B), the neurotransmitter receptor hypothesis of
depression takes this theme one step further: namely, that the depletion of
neurotransmitter causes compensatory upregulation of postsynaptic neurotransmitter
receptors (Figure 6-35). Direct evidence for this hypothesis is also generally lacking.
Postmortem studies do consistently show increased numbers of serotonin 2 receptors in
the frontal cortex of patients who commit suicide. Also, some neuroimaging studies
have identified abnormalities in serotonin receptors of depressed patients, but this
approach has not yet been successful in identifying consistent and replicable molecular
lesions in receptors focusing attention upon the three monoamine neurotransmitter
systems norepinephrine, dopamine, and serotonin. This has led to a much better
understanding of the physiological functioning of these three neurotransmitters, and
especially the various mechanisms by which all known antidepressants act to boost
neurotransmission at one or more of these three monoamine neurotransmitter systems,
and how certain mood-stabilizing drugs may also act on the monoamines. Research is
now turning to the possibility that in depression there may be a deficiency in
downstream signal transduction of the monoamine neurotransmitter and its postsynaptic
neuron that is occurring in the presence of normal amounts of neurotransmitter and
receptor. Thus, the hypothesized molecular problem in depression could lie within the
molecular events distal to the receptor, in the signal transduction cascade system, and
in appropriate gene expression (Figure 6-36). Different molecular problems may
account for mania and bipolar disorder.

Stress and depression

Stress, BDNF, and brain atrophy in depression

One candidate mechanism that has been proposed as the site of a possible flaw in
signal transduction from monoamine receptors in depression is the target gene for
brain-derived neurotrophic factor (BDNF) (Figures 6-36, 6-37, 6-38). Normally, BDNF
sustains the viability of brain neurons (Figure 6-37), but under stress, the gene for
BDNF may be repressed (Figure 6-38). Stress can lower 5HT levels and can acutely
increase, then chronically deplete, bothNE and DA. Thesemonoamine neurotransmitter
changes together with deficient amounts of BDNF may lead to atrophy and possible
apoptosis of vulnerable neurons in the hippocampus and other brain areas such as
prefrontal cortex (Figure 6-37). An artist’s concept of the hippocampal atrophy that has
been reported in association with chronic stress and with both major depression and
various anxiety disorders, especially PTSD, is shown in Figures 6-39A and 6-39B.
Fortunately, some of this neuronal loss may be reversible. That is, restoration of
monoamine-related signal transduction cascades by antidepressants (Figure 6-36) can
increase BDNF and other trophic factors (Figure 6-37) and potentially restore lost
synapses. In some brain areas such as the hippocampus, not only can synapses
potentially be restored, but it is possible that some lost neurons might even be replaced
by neurogenesis.
Neurons from the hippocampal area and amygdala normally suppress the
hypothalamic–pituitary–adrenal (HPA) axis (Figure 6-39A), so if stress causes
hippocampal and amygdala neurons to atrophy, with loss of their inhibitory input to the
hypothalamus, this could lead to overactivity of the HPA axis (Figure 6-39B). In
depression, abnormalities of the HPA axis have long been reported, including elevated
glucocorticoid levels and insensitivity of the HPA axis to feedback inhibition (Figure 6-
39B). Some evidence suggests that glucocorticoids at high levels could even be toxic to
neurons and contribute to their atrophy under chronic stress (Figure 6-39B). Novel
antidepressant treatments are in testing that target corticotropin-releasing factor 1
(CRF-1) receptors, vasopressin 1B receptors, and glucocorticoid receptors (Figure 6-
39B), in an attempt to halt and even reverse these HPA abnormalities in depression and
other stress-related psychiatric illnesses.

Stress and the environment: how much stress is too much stress?

In many ways the body is built for the purpose of handling stress, and in fact a certain
amount of “stress load” on bones, muscles, and brain is necessary for growth and
optimal functioning and can even be associated with developing resilience to future
stressors (Figure 6-40). However, certain types of stress such as child abuse can
sensitize brain circuits and render them vulnerable rather than resilient to future
stressors (Figure 6-41). For patients with such vulnerable brain circuits who then
become exposed to multiple life stressors as adults, the result can be the development
of depression (Figure 6-42). Thus, the same amount of stress that would be handled
without developing depression in someone who has not experienced child abuse could
hypothetically cause depression in someone with a prior history of child abuse. This
demonstrates the potential impact of the environment upon brain circuits. Many studies
in fact confirm that in women abused as children, depression can be found up to four
times more often than in never-abused women. Hypothetically, epigenetic changes
caused by environmental stress create relatively permanent molecular alterations in the
brain circuits at the time of the child abuse that do not cause depression per se, but
make brain circuits vulnerable to breakdown into depression upon exposure to future
stressors as an adult.

Stress and vulnerability genes: born fearful?

Modern theories of mood disorders do not propose that any single gene can cause
depression or mania, but as discussed for schizophrenia in Chapter 4 their inhibitory
input to the hypothalamus, this could lead to overactivity of the HPA axis (Figure 6-39B).
In depression, abnormalities of the HPA axis have long been reported, including
elevated glucocorticoid levels and insensitivity of the HPA axis to feedback inhibition
(Figure 6-39B). Some evidence suggests that glucocorticoids at high levels could even
be toxic to neurons and contribute to their atrophy under chronic stress (Figure 6-39B).
Novel antidepressant treatments are in testing that target corticotropin-releasing factor 1
(CRF-1) receptors, vasopressin 1B receptors, and glucocorticoid receptors (Figure 6-
39B), in an attempt to halt and even reverse these HPA abnormalities in depression and
other stress-related psychiatric illnesses. (see also Figure 4-33), mood disorders are
theoretically caused by a “conspiracy” among many vulnerability genes and many
environmental stressors leading to breakdown of information processing in specific
brain circuits and thus the various symptoms of a major depressive or manic episode.
There is a great overlap between those genes thought to be vulnerability genes for
schizophrenia and those thought to be vulnerability genes for bipolar disorder. A
comprehensive discussion of genes for bipolar disorder or for major depression is
beyond the scope of this book, but one of the vulnerability genes for depression is the
gene coding for the serotonin transporter or SERT (i.e., the serotonin reuptake pump),
which is the site of action of SSRI and SNRI antidepressants. The type of serotonin
transporter (SERT) with which you are born determines in part whether your amygdala
is more likely to over-react to fearful faces (Figure 6-43), whether you are more likely to
develop depression when exposed to multiple life stressors, and how likely your
depression is to respond to an SSRI/SNRI or whether you can even tolerate an
SSRI/SNRI (Figure 6-43).

Specifically, an excessive reaction of the amygdala to fearful faces for carriers of the s
variant of the gene for SERT is shown in Figure 6-43. Fearful faces can be considered a
stressful load on the amygdala and its circuitry, and can be visualized using modern
neuroimaging techniques. For those with the s genotype of SERT, they are more likely
to develop an affective disorder when exposed to multiple life stressors and may have
more hippocampal BDNF atrophy, more cognitive symptoms, and less responsiveness
or tolerance to SSRI/SNRI treatment. Exposure to multiple life stressors may cause the
otherwise silent overactivity and inefficient information processing of affective loads in
the amygdala to become an overt major depressive episode (Figure 6-43), an
interaction of their genes with the environment (nature plus nurture). The point is that
the specific gene that you have for the serotonin transporter can alter the efficiency of
affective information processing by your amygdala and, consequently, your risk for
developing major depression if you experience multiple life stressors as an adult (Figure
6-43). On the other hand, the l genotype of SERT is a more resilient genotype, with less
amygdala reactivity to fearful faces, less likelihood of breaking down into a major
depressive episode when exposed to multiple life stressors, as well as more likelihood
of responding to or tolerating SSRIs/SNRIs if you do develop a depressive episode
(Figure 6-43).

Whether you have the l or the s genotype of SERT accounts for only a small amount of
the variance for whether or not you will develop major depression after experiencing
multiple life stressors, and thus cannot predict who will get major depression and who
will not. However, this example does prove the importance of genes in general and
those for serotonin neurons in particular in the regulation of the amygdala and in
determining the odds of developing major depression under stress. Thus, perhaps one
is not born fearful, but born vulnerable or resilient to developing major depression in
response to future adult stressors, especially if they are chronic, multiple, and severe.

Symptoms and circuits in depression

Currently, the monoamine hypothesis of depression is now being applied to

understanding how monoamines regulate the efficiency of information processing in a
wide variety of neuronal circuits that may be responsible for mediating the various
symptoms of depression. Obviously, there are numerous symptoms required for the
diagnosis of a major depressive episode (Figure 6-44). Each symptom is hypothetically
associated with inefficient information processing in various brain circuits, with different
symptoms topographically localized to specific brain regions (Figure 6-45).

Not only can each of the nine symptoms listed for the diagnosis of amajor depressive
episode bemapped onto brain circuits whose inefficient information processing
theoretically mediates these symptoms (Figure 6-45), but the hypothetical
monoaminergic regulation of each of these various brain areas can also be mapped
onto each brain region they innervate (Figures 6-31 through 6-33). This creates a set of
monoamine neurotransmitters that regulates each specific hypothetically malfunctioning
brain region. Targeting each region with drugs that act on the relevantmonoamine(s)
that innervate those brain regions potentially leads to reduction of each individual
symptom experienced by a specific patient by enhancing the efficiency of information
processing in malfunctioning circuits for each specific symptom. If successful, this
targeting of monoamines in specific brain areas could even eliminate symptoms, and
cause a major depressive episode to go into remission.

Many of the mood-related symptoms of depression can be categorized as having either

too little positive affect, or too much negative affect (Figure 6-46). This idea is linked to
the fact that there are diffuse anatomic connections ofmonoamines throughout the
brain, with diffuse dopamine dysfunction in this system driving predominantly the
reduction of positive affect, diffuse serotonin dysfunction driving predominantly the
increase in negative affect, and norepinephrine dysfunction being involved in both.
Thus, reduced positive affect includes such symptoms as depressedmood but also loss
of happiness, joy, interest, pleasure, alertness, energy, enthusiasm, and self-confidence
(Figure 6-46, left). Enhancing dopamine function, and possibly also norepinephrine
function may improve information processing in the circuitsmediating this cluster of
symptoms. On the other hand, increased negative affect includes not only
depressedmood but guilt, disgust, fear, anxiety, hostility, irritability and loneliness
(Figure 6-46, right). Enhancing serotonin function, and possibly also norepinephrine
function, may improve information processing in the circuits that hypothetically mediate
this cluster of symptoms. For patients with symptoms of both clusters, they may require
triple-action treatments that boost all three of the monoamines.

Symptoms and circuits in mania

The same general paradigm of monoamine regulation of the efficiency of information

processing in specific brain circuits can be applied to mania as well as depression,
although this is frequently thought to be in the opposite direction and in some
overlapping but also some different brain regions compared to depression. The
numerous symptoms required for the diagnosis of a manic episode are shownin Figure
6-47. Like major depression, each symptom of mania is also hypothetically associated
with inefficient information processing in various brain circuits, with different symptoms
topographically localized to specific brain regions (Figure 6-48).

Generally, the inefficient functioning in these circuits in mania may be essentially the
opposite of the malfunctioning hypothesized for depression, but may be more accurately
portrayed as “out of tune” rather than simply excessive or deficient, especially since
some patients can simultaneously have both manic and depressed symptoms.
Generally, treatments for mania either reduce or stabilize monoaminergic regulation of
circuits associated with symptoms of mania.

Neuroimaging in mood disorders

It is not currently possible to diagnose depression or bipolar disorder with any

neuroimaging technique. However, some progress is being made in mapping inefficient
information processing in various circuits in mood disorders. In depression, the
dorsolateral prefrontal cortex, associated with cognitive symptoms, may have reduced
activity, and the amygdala, associated with various emotional symptoms including
depressed mood, may have increased activity (Figure 6-49). Furthermore, provocative
testing of patients with mood disorders may provide some insight into malfunctioning of
brain circuits exposed to environmental input, and thus required to process that
information. For example, some studies of depressed patients show that their neuronal
circuits at the level of the amygdala are over-reactive to induced sadness but under-
reactive to induced happiness (Figure 6-50). On the other hand, imaging of the
orbitofrontal cortex of manic patients shows that they fail to appropriately activate this
brain region in a test that requires them to suppress a response, suggesting problems
with impulsivity associated with mania and with this specific brain region (Figure 6-51).
In general, these neuroimaging findings support the mapping of symptoms to brain
regions discussed earlier in this chapter, but much further work is currently in progress
and must be completed before the results of neuroimaging can be applied to diagnostic
or therapeutic decision making in clinical practice.
Summary

This chapter has described the mood disorders, including those across the bipolar
spectrum. For prognostic and treatment purposes, it is increasingly important to be able
to distinguish unipolar depression from bipolar spectrum depression. Although mood
disorders are indeed disorders of mood, they are much more, and several different
symptoms in addition to a mood symptom are required to make a diagnosis of a major
depressive episode or a manic episode. Each symptom can be matched to a
hypothetically malfunctioning neuronal circuit. The monoamine hypothesis of depression
suggests that dysfunction, generally due to underactivity, of one or more of the three
monoamines DA, NE, or 5HT may be linked to symptoms in major depression. Boosting
one or more of the monoamines in specific brain regions may improve the efficiency of
information processing there, and reduce the symptom caused by that area’s
malfunctioning. Other brain areas associated with the symptoms of a manic episode can
similarly be mapped to various hypothetically malfunctioning brain circuits.
Understanding the localization of symptoms in circuits, as well as the neurotransmitters
that regulate these circuits in different brain regions, can set the stage for choosing and
combining treatments for each individual symptom of amood disorder, with the goal
being to reduce all symptoms and lead to remission.