Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 4th Ed.

Chapter 6. Mood disorders

   Description of mood disorders

   The bipolar spectrum

    The debate rages on . . .

   Can unipolar depression be distinguished from bipolar depression?

   Are mood disorders progressive?

   Neurotransmitters and circuits in mood disorders

    Noradrenergic neurons

    Monoamine interactions: NE regulation of 5HT release

    The monoamine hypothesis of depression

    The monoamine receptor hypothesis and gene expression

   Stress and depression

    Stress, BDNF, and brain atrophy in depression

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

    Stress and vulnerability genes: born fearful?

   Symptoms and circuits in depression

   Symptoms and circuits in mania

   Neuroimaging in mood disorders


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 (Figure 6-4).

Figure 6-1. Mood episodes. Bipolar disorder is generally characterized by four types of illness episodes: manic, major depressive, hypomanic, and mixed. A patient may have any combination of these episodes over the course of illness; subsyndromal manic or depressive episodes also occur during the course of illness, in which case there are not enough symptoms or the symptoms are not severe enough to meet the diagnostic criteria for one of these episodes. Thus the presentation of mood disorders can vary widely.

Figure 6-2. Major depression. Major depression is the most common mood disorder and is defined by the occurrence of at least a single major depressive episode, although most patients will experience recurrent episodes.

Figure 6-3. Dysthymia. Dysthymia is a less severe form of depression than major depression, but long-lasting (over 2 years in duration) and often unremitting.

Figure 6-4. Double depression. Patients with unremitting dysthymia who also experience the superimposition of one or more major depressive episodes are described as having double depression. This is also a form of recurrent major depressive episodes with poor inter-episode recovery.

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.

Figure 6-5. Bipolar I disorder. Bipolar I disorder is defined as the occurrence of at least one manic or mixed (full mania and full depression simultaneously) episode. Patients with bipolar I disorder typically experience major depressive episodes as well, although this is not necessary for the bipolar I diagnosis.

A. Rapid cycling mania. The course of bipolar disorder can be rapid cycling, which means that at least four episodes occur within a 1-year period. This can manifest itself as four distinct manic episodes, as shown here. Many patients with this form of mood disorder experience switches much more frequently than four times a year.

B. Rapid cycling switches. A rapid cycling course (at least four distinct mood episodes within 1 year) can also manifest as rapid switches between manic and depressive episodes.

Figure 6-6

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.

Figure 6-7. Bipolar II disorder. Bipolar II disorder is defined as an illness course consisting of one or more major depressive episodes and at least one hypomanic episode.

Figure 6-8. Cyclothymic disorder. Cyclothymic disorder is characterized by mood swings between hypomania and dysthymia but without any full manic or major depressive episodes.

Figure 6-9. Temperaments. Not all mood variations are pathological. Individuals with depressive temperament may be consistently sad or apathetic but do not meet the criteria for dysthymia and do not necessarily experience any functional impairment. However, individuals with depressive temperament may be at greater risk for the development of a mood disorder later in life. Hyperthymic temperament, in which mood is above normal but not pathological, includes stable characteristics such as extroversion, optimism, exuberance, impulsiveness, overconfidence, grandiosity, and lack of inhibition. Individuals with hyperthymic temperament may be at greater risk for the development of a mood disorder 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 that many 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 as Hagop Akiskal (Figures 6-10 through 6-20).

Figure 6-10. Bipolar spectrum. There is a huge variation in the presentation of patients with bipolar disorder. Historically, bipolar disorder has been categorized as I, II, or not otherwise specified (NOS). It may be more useful, instead, to think of these patients as belonging to a bipolar spectrum and to identify subcategories of presentations, as has been done by Akiskal and other experts and as illustrated in the next several figures.

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 from mood-stabilizing treatments added to robust antidepressant treatments.

Figure 6-11. Bipolar ¼. Some patients may present only with depressive symptoms yet exhibit rapid but unsustained response to antidepressant treatment (sometimes called rapid “poop out”). Although such patients may have no spontaneous mood symptoms above normal, they potentially could benefit from mood-stabilizing treatment. This presentation may be termed bipolar ¼ (or bipolar 0.25).

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).

Figure 6-12. Bipolar ½. Bipolar ½ (0.5) has been described as schizobipolar disorder, which combines positive symptoms of psychosis with manic, hypomanic, and depressive episodes.

A. Schizophrenia and bipolar disorder: dichotomous disease model. Schizophrenia and bipolar disorder have been conceptualized both as dichotomous disorders and as belonging to a continuum. In the dichotomous disease model, schizophrenia consists of chronic, unremitting psychosis, with poor outcomes expected. Bipolar disorder consists of cyclical manic and other mood episodes and has better expected outcomes than schizophrenia. A third distinct disorder is schizoaffective disorder, characterized by psychosis and mania as well as other mood symptoms.

B. Schizophrenia and bipolar disorder: continuum disease model. Schizophrenia and bipolar disorder have been conceptualized both as dichotomous disorders and as belonging to a continuum. In the continuum disease model, schizophrenia and mood disorders fall along a continuum in which psychosis, delusions, and paranoid avoidant behavior are on one extreme and depression and other mood symptoms are on the other extreme. Falling in the middle are psychotic depression and schizoaffective disorder.

Figure 6-13

The dichotomous disease model 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 form of schizophrenia with 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 “mood-centered 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, a mood 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 as well 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 from seeing 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 a mood 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 form of 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.

Figure 6-14. Bipolar I½. A formal diagnosis of bipolar II disorder requires the occurrence of not only hypomanic episodes but also depressive episodes. However, some patients may experience recurrent hypomania without having experienced a depressive episode – a presentation that may be termed bipolar I½. These patients may be at risk of eventually developing a depressive episode and are candidates for mood-stabilizing treatment, although no treatment is formally approved for this condition.

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.

Figure 6-15. Bipolar II½. Patients may present with a major depressive episode in the context of cyclothymic temperament, which is characterized by oscillations between hyperthymic or hypomanic states (above normal) and depressive or dysthymic states (below normal) upon which a major depressive episode intrudes (bipolar II½). Individuals with cyclothymic temperament who are treated for the major depressive episodes may be at increased risk for antidepressant-induced mood cycling.

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.

Figure 6-16. Bipolar III. Although the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), defines antidepressant-induced (hypo)mania as a substance-induced mood disorder, some experts believe that individuals who experience substance-induced (hypo)mania are actually predisposed to these mood states and thus belong to the bipolar spectrum (bipolar III).

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.

Figure 6-17. Bipolar III½. Bipolar III½ (3.5) is bipolar disorder with substance abuse, in which the substance abuse is associated with efforts to achieve hypomania. Such patients should be evaluated closely to determine if (hypo)mania has ever occurred in the absence of substance abuse.

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.

Figure 6-18. Bipolar IV. Bipolar IV is seen in individuals with longstanding and stable hyperthymic temperament into which a major depressive episode intrudes. Individuals with hyperthymic temperament who are treated for depressive episodes may be at increased risk for antidepressant-induced mood cycling, and may instead respond better 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.

Figure 6-19. Bipolar V. Bipolar V is defined as major depressive episodes with hypomanic symptoms occurring during the major depressive episode but without the presence of discrete hypomanic episodes. Because the symptoms do not meet the full criteria for mania, these patients would not be considered to have a full mixed episode, but they nonetheless exhibit a mixed presentation and may require mood stabilizer treatment as opposed to antidepressant monotherapy.

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.

Table 6-1 Mixed states of mania and depression




DSM-IV mixed


Full diagnostic criteria for both mania and depression

Depression with hypomania


Bipolar V

Depression with some manic symptoms


Bipolar NOS

Mania with some depressive symptoms


Dysphoric mania

Subsyndromal mania and subsyndromal depression


Prodrome or presymptomatic state of incomplete remission

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.

Figure 6-20. Bipolar VI. Another subcategory within the bipolar spectrum may be “bipolarity in the setting of dementia,” termed bipolar VI. Mood instability here begins late in life, followed by impaired attention, irritability, reduced drive, and disrupted sleep. The presentation may initially appear to be attributable to dementia or be considered unipolar depression, but it is likely to be exacerbated by antidepressants and may respond to mood stabilizers.

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.

Figure 6-21. Prevalence of mood disorders. In recent years there has been a paradigm shift in terms of the recognition and diagnosis of patients with mood disorders. That is, many patients once considered to have major depressive disorder (old paradigm, left) are now recognized as having bipolar II disorder or another form of bipolar illness within the bipolar spectrum (shifting paradigm, right).

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?”

Table 6-2 Is it unipolar or bipolar depression? Questions to ask

Who’s your daddy?

What is your family history of:

·        mood disorder?

·        psychiatric hospitalizations?

·        suicide?

·        anyone who took lithium, mood stabilizers, antipsychotics, antidepressants?

·        anyone who received ECT?

These can be indications of a unipolar or bipolar spectrum disorder in relatives.

Where’s your mama?

I need to get additional history about you from someone close to you, such as your mother or your spouse.

Patients may especially lack insight about their manic symptoms and under-report them.

“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.

Figure 6-22. Bipolar depression symptoms. Although all symptoms of a major depressive episode can occur in either unipolar or bipolar depression, some symptoms may present more often in bipolar versus unipolar depression, providing hints if not diagnostic certainty that the patient has a bipolar spectrum disorder. These symptoms include increased time sleeping, overeating, comorbid anxiety, psychomotor retardation, mood lability during episodes, psychotic symptoms, and suicidal thoughts.

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.

Figure 6-23. Is major depressive disorder progressive? A currently unanswered question is whether mood disorders are progressive. Does undertreatment of unipolar depression, in which residual symptoms persist and relapses occur, lead to progressive worsening of illness, such as more frequent recurrences and poor inter-episode recovery? And can this ultimately progress to a bipolar spectrum condition and finally treatment resistance?

Figure 6-24. Is bipolar disorder progressive? There is some concern that undertreatment of discrete manic and depressive episodes may progress to mixed and dysphoric episodes and finally to rapid cycling and treatment resistance.

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 5-135-145-25, 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 rate-limiting and most 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).

Figure 6-25. Norepinephrine is produced. Tyrosine (TYR) a precursor to norepinephrine (NE), is taken up into NE nerve terminals via a tyrosine transporter and converted into DOPA by the enzyme tyrosine hydroxylase (TOH). DOPA is then converted into dopamine (DA) by the enzyme DOPA decarboxylase (DDC). Finally, DA is converted into NE by dopamine β-hydroxylase (DBH). After synthesis, NE is packaged into synaptic vesicles via the vesicular monoamine transporter (VMAT2) and stored there until its release into the synapse during neurotransmission.

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).

Figure 6-26. Norepinephrine’s action is terminated. Norepinephrine’s action can be terminated through multiple mechanisms. Dopamine can be transported out of the synaptic cleft and back into the presynaptic neuron via the norepinephrine transporter (NET), where it may be repackaged for future use. Alternatively, norepinephrine may be broken down extracellularly via the enzyme catechol-O-methyl-transferase (COMT). Other enzymes that break down norepinephrine are monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B), which are present in mitochondria both within the presynaptic neuron and in other cells, including neurons and glia.

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 of NE 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 cleaner whisking NE 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).

Figure 6-27. Norepinephrine receptors. Shown here are receptors for norepinephrine that regulate its neurotransmission. The norepinephrine transporter (NET) exists presynaptically and is responsible for clearing excess norepinephrine out of the synapse. The vesicular monoamine transporter (VMAT2) takes norepinephrine up into synaptic vesicles and stores it for future neurotransmission. There is also a presynaptic α2 autoreceptor, which regulates release of norepinephrine from the presynaptic neuron. In addition, there are several postsynaptic receptors. These include α1, α2A, α2B, α2C, β1, β2, and β3receptors.

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 α2receptors 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 α2receptors: Figures 6-27and 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 NE neuron by stimulating the presynaptic α2neuron, but drugs that antagonize this same receptor will have the effect of cutting the brake cable, thus enhancing release of NE.

Figure 6-28. Alpha-2 receptors on axon terminal. Shown here are presynaptic α2-adrenergic autoreceptors located on the axon terminal of the norepinephrine neuron. These autoreceptors are “gatekeepers” for norepinephrine. That is, when they are not bound by norepinephrine, they are open, allowing norepinephrine release (A). However, when norepinephrine binds to the gatekeeping receptors, they close the molecular gate and prevent norepinephrine from being released (B).

Figure 6-29. Somatodendritic α2 receptors. Presynaptic α2-adrenergic autoreceptors are also located in the somatodendritic area of the norepinephrine neuron, as shown here. When norepinephrine binds to these α2 receptors, it shuts off neuronal impulse flow in the norepinephrine neuron (see loss of lightning bolts in the neuron in the lower figure), and this stops further norepinephrine release.

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 5we 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 5HT7postsynaptic receptors (Figures 5-60A through 5-60C). Obviously, the three monoamines 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 5-15A5-16A5-17) 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.

A. Alpha receptors mediate norepinephrine regulation of serotonin release. Norepinephrine regulates serotonin release. It does this by acting as a brake on serotonin release at cortical α2 receptors on axon terminals (1) and as an accelerator of serotonin release at α1 receptors at the somatodendritic area (2).

B. Raphe α1 receptors stimulate serotonin release. Alpha-1-adrenergic receptors are located in the somatodendritic regions of serotonin neurons. When these receptors are unoccupied by norepinephrine, some serotonin is released from the serotonin neuron. However, when norepinephrine binds to the α1 receptor (2), this stimulates the serotonin neuron, accelerating release of serotonin (1).

C. Cortical α2 receptors inhibit serotonin release. Alpha-2-adrenergic heteroreceptors are located on the axon terminals of serotonin neurons. When norepinephrine binds to the α2 receptor this prevents serotonin from being released (1).

Figure 6-30

There are many brain areas where 5HT, NE, and DA 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 them to influence each other and change the release not only of their own neurotransmitters, but also of other monoamines.

Figure 6-31. Major dopamine projections. Dopamine has widespread ascending projections that originate predominantly in the brainstem (particularly the ventral tegmental area and substantia nigra) and extend via the hypothalamus to the prefrontal cortex, basal forebrain, striatum, nucleus accumbens, and other regions. Dopaminergic neurotransmission is associated with movement, pleasure and reward, cognition, psychosis, and other functions. In addition, there are direct projections from other sites to the thalamus, creating the “thalamic dopamine system,” which may be involved in arousal and sleep. PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus; Hy, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem neurotransmitter centers; SC, spinal cord; C, cerebellum.

Figure 6-32. Major norepinephrine projections. Norepinephrine has both ascending and descending projections. Ascending noradrenergic projections originate mainly in the locus coeruleus of the brainstem; they extend to multiple brain regions, as shown here, and regulate mood, arousal, cognition, and other functions. Descending noradrenergic projections extend down the spinal cord and regulate pain pathways. PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus; Hy, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem neurotransmitter centers; SC, spinal cord; C, cerebellum.

Figure 6-33. Major serotonin projections. Like norepinephrine, serotonin has both ascending and descending projections. Ascending serotonergic projections originate in the brainstem and extend to many of the same regions as noradrenergic projections, with additional projections to the striatum and nucleus accumbens. These ascending projections may regulate mood, anxiety, sleep, and other functions. Descending serotonergic projections extend down the brainstem and through the spinal cord; they may regulate pain. PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus; Hy, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem neurotransmitter centers; SC, spinal cord; C, cerebellum.

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 system of all three monoamines 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.

A. Classic monoamine hypothesis of depression, part 1. According to the classic monoamine hypothesis of depression, when there is a “normal” amount of monoamine neurotransmitter activity, there is no depression present.

B. Classic monoamine hypothesis of depression, part 2. The monoamine hypothesis of depression posits that if the “normal” amount of monoamine neurotransmitter activity becomes reduced, depleted, or dysfunctional for some reason, depression may ensue.

Figure 6-34

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 for monoamines in depression. Thus, there is no clear and convincing evidence that monoamine deficiency accounts for depression – i.e., there is no “real” monoamine deficit. Likewise, there is no clear and convincing evidence that abnormalities in monoamine receptors account for depression. Although the monoamine hypothesis is obviously an overly simplified notion about mood disorders, it has been very valuable in 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.

Figure 6-35. Monoamine receptor hypothesis of depression. The monoamine receptor hypothesis of depression extends the classic monoamine hypothesis of depression, positing that deficient activity of monoamine neurotransmitters causes upregulation of postsynaptic monoamine neurotransmitter receptors, and that this leads to depression.

Figure 6-36. Monoamine signaling and brain-derived neurotrophic factor (BDNF) release. The neurotrophic hypothesis of depression states that depression may be caused by reduced synthesis of proteins involved in neurogenesis and synaptic plasticity. BDNF promotes the growth and development of immature neurons, including monoaminergic neurons, enhances the survival and function of adult neurons, and helps maintain synaptic connections. Because BDNF is important for neuronal survival, decreased levels may contribute to cell atrophy. In some cases, low levels of BDNF may even cause cell loss. Monoamines can increase the availability of BDNF by initiating signal transduction cascades that lead to its release. Thus, if monoamine levels are low, then BDNF levels may correspondingly be low. CaMK, calcium/calmodulin-dependent protein kinase; CREB, cAMP response element-binding protein; PKA, protein kinase A.

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 6-366-376-38). 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, both NE and DA. These monoamine 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.

Figure 6-37. Suppression of brain-derived neurotrophic factor (BDNF) production. BDNF plays a role in the proper growth and maintenance of neurons and neuronal connections (right). If the genes for BDNF are turned off (left), the resultant decrease in BDNF could compromise the brain’s ability to create and maintain neurons and their connections. This could lead to loss of synapses or even whole neurons by apoptosis.

Figure 6-38. Stress and brain-derived neurotrophic factor (BDNF). One factor that could contribute to potential brain atrophy is the impact that chronic stress can have on BDNF, which plays a role in the proper growth and maintenance of neurons and neuronal connections. During chronic stress, the genes for BDNF may be turned off, potentially reducing its production.

A. Hypothalamic–pituitary–adrenal (HPA) axis. The normal stress response involves activation of the hypothalamus and a resultant increase in corticotropin-releasing factor (CRF), which in turn stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary. ACTH causes glucocorticoid release from the adrenal gland, which feeds back to the hypothalamus and inhibits CRF release, terminating the stress response.

B. Hippocampal atrophy and hyperactive HPA axis in depression. In situations of chronic stress, excessive glucocorticoid release may eventually cause hippocampal atrophy. Because the hippocampus inhibits the HPA axis, atrophy in this region may lead to chronic activation of the HPA axis, which may increase risk of developing a psychiatric illness. Because the HPA axis is central to stress processing, it may be that novel targets for treating stress-induced disorders lie within the axis. Mechanisms being examined include antagonism of glucocorticoid receptors, corticotropin-releasing factor 1 (CRF-1) receptors, and vasopressin 1B receptors.

Figure 6-39

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.

Figure 6-40. Development of stress resilience. In a healthy individual, stress can cause a temporary activation of circuits which is resolved when the stressor is removed. As shown here, when the circuit is unprovoked, no symptoms are produced. In the presence of a stressor such as emotional trauma, the circuit is provoked yet able to compensate for the effects of the stressor. By its ability to process the information load from the environment, it can avoid producing symptoms. When the stressor is withdrawn, the circuit returns to baseline functioning. Individuals exposed to this type of short-term stress may even develop resilience to stress, whereby exposure to future stressors provokes the circuit but does not result in symptoms.

Figure 6-41. Development of stress sensitization. Prolonged activation of circuits due to repeated exposure to stressors can lead to a condition known as “stress sensitization,” in which circuits not only become overly activated but remain overly activated even when the stressor is withdrawn. Thus, an individual with severe stress in childhood will exhibit transient symptoms during stress exposure, with resolution of the symptoms when the stressor is removed. The circuits remain overly activated in this model, but the individual exhibits no symptoms because these circuits can somehow still compensate for this additional load. However, the individual with “stress-sensitized” circuits is now vulnerable to the effects of future stressors, so that the risk for developing psychiatric symptoms is increased. Stress sensitization may therefore constitute a “presymptomatic” state for some psychiatric symptoms. This state might be detectable with functional brain scans of circuits but not from psychiatric interviews or patient complaints.

Figure 6-42. Progression from stress sensitization to depression. It may be that the degree of stress one experiences during early life affects how the circuits develop and therefore how a given individual responds to stress in later life. No stress during infancy may lead to a circuit that exhibits “normal” activation during stress and confers no increased risk of developing a psychiatric disorder. Interestingly, mild stress during infancy may actually cause the circuits to exhibit reduced reactivity to stress in later life and provide some resilience to adult stressors. Overwhelming and/or chronic stress from child abuse, however, may lead to stress-sensitized circuits that may become activated even in the absence of a stressor. Individuals with stress sensitization may not exhibit phenotypic symptoms but may be at increased risk of developing a mental illness if exposed to future stressors.

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 (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).

Figure 6-43. Serotonin genetics and life stressors. Genetic research has shown that the type of serotonin transporter (SERT) with which you are born can affect how you process fearful stimuli and perhaps also how you respond to stress. Specifically, individuals who are carriers of the s variant of the gene for SERT appear to be more vulnerable to the effects of stress or anxiety, whereas those who carry the l variant appear to be more resilient. Thus, s carriers exhibit increased amygdala activity in response to fearful faces and may also be more likely to develop a mood or anxiety disorder after suffering multiple life stressors. The higher risk of depression may also be related to increased likelihood of cognitive symptoms, brain atrophy, increased cortisol, and, if depressed, poor response to selective serotonin reuptake inhibitors (SSRIs).

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 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).

Figure 6-44. Symptoms of depression. According to the Diagnostic and Statistical Manual of Mental Disorders, a major depressive episode consists of either depressed mood or loss of interest and at least four of the following: weight/appetite changes, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feelings of guilt or worthlessness, executive dysfunction, and suicidal ideation.

Figure 6-45. Matching depression symptoms to circuits. Alterations in neuronal activity and in the efficiency of information processing within each of the eleven brain regions shown here can lead to symptoms of a major depressive episode. Functionality in each brain region is hypothetically associated with a different constellation of symptoms. PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus; Hy, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem neurotransmitter centers; SC, spinal cord; C, cerebellum.

Not only can each of the nine symptoms listed for the diagnosis of a major depressive episode be mapped 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 relevant monoamine(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 of monoamines 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 depressed mood 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 circuits mediating this cluster of symptoms. On the other hand, increased negative affect includes not only depressed mood 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.

Figure 6-46. Positive and negative affect. Mood-related symptoms of depression can be characterized by their affective expression – that is, whether they cause a reduction in positive affect or an increase in negative affect. Symptoms related to reduced positive affect include depressed mood; loss of happiness, interest, or pleasure; loss of energy or enthusiasm; decreased alertness; and decreased self-confidence. Reduced positive affect may be hypothetically related to dopaminergic dysfunction, with a possible role of noradrenergic dysfunction as well. Symptoms associated with increased negative affect include depressed mood, guilt, disgust, fear, anxiety, hostility, irritability, and loneliness. Increased negative affect may be linked hypothetically to serotonergic dysfunction and perhaps also noradrenergic dysfunction.

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 shown in 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).

Figure 6-47. Symptoms of mania. According to the Diagnostic and Statistical Manual of Mental Disorders, a manic episode consists of either elevated/expansive mood or irritable mood. In addition, at least three of the following must be present (four if mood is irritable): inflated self-esteem/grandiosity, increased goal-directed activity or agitation, risk taking, decreased need for sleep, distractibility, pressured speech, and racing thoughts.

Figure 6-48. Matching mania symptoms to circuits. Alterations in neurotransmission within each of the eleven brain regions shown here can be hypothetically linked to the various symptoms of a manic episode. Functionality in each brain region may be associated with a different constellation of symptoms. PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus; Hy, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem neurotransmitter centers; SC, spinal cord; C, cerebellum.

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.

Figure 6-49. Neuroimaging of brain activation in depression. Neuroimaging studies of brain activation suggest that resting activity in the dorsolateral prefrontal cortex (DLPFC) of depressed patients is low compared to that in nondepressed individuals (left, top and bottom), whereas resting activity in the amygdala and ventromedial prefrontal cortex (VMPFC) of depressed patients is high compared to that in nondepressed individuals (right, top and bottom).

Figure 6-50. Depressed patient’s neuronal response to induced sadness versus happiness. Emotional symptoms such as sadness or happiness are regulated by the ventromedial prefrontal cortex (VMPFC) and the amygdala, two regions in which activity is high in the resting state of depressed patients (left). Interestingly, provocative tests in which these emotions are induced show that neuronal activity in the amygdala is over-reactive to induced sadness (bottom right) but under-reactive to induced happiness (top right).

Figure 6-51. Mania patient’s neuronal response to no-go task. Impulsive symptoms of mania, such as risk taking and pressured speech, are related to activity in the orbitofrontal cortex (OFC). Neuroimaging data show that this brain region is hypoactive in mania (bottom right) versus healthy (bottom left) individuals during the no-go task, which is designed to test response inhibition.


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 a mood disorder, with the goal being to reduce all symptoms and lead to remission.