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Mood Disorders and the Neurotransmitter Networks Norepinephrine and γ-Aminobutyric Acid (GABA)
This chapter discusses disorders characterized by abnormalities of mood: namely, depression, mania, or mixtures of both. Included here are descriptions of a wide variety of mood disorders that occur over a broad clinical spectrum. 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. Also included in this chapter is an analysis of how monoamine neurotransmitter systems have long been hypothetically linked to the biological basis of mood disorders. We will also cover more recent advances in neurobiology that link mood disorders to glutamate, GABA (γ-aminobutyric acid), neurotrophic factors, neuroinflammation, and stress.
Mood disorders have many symptoms and approaching them clinically involves first constructing a diagnosis from a given patient’s symptom profile, but then deconstructing that patient’s mood disorder into its component symptoms so each symptom can be individually targeted therapeutically. We will discuss how to combine this clinical approach to diagnosis with a neurobiological approach to treatment by first matching every symptom to its hypothetically malfunctioning brain circuit, regulated by one or more neurotransmitters. The strategy is next to select drugs that target the specific neurotransmitters in the specific symptomatic brain circuits in a given patient. The goal is to improve the efficiency of information processing in those brain circuits and thereby reduce symptoms. Covering the neurobiological basis of mood disorders in this chapter sets the stage for understanding the mechanisms of action and how to select specific drug treatments in Chapter 7.
Disorders of mood are often called affective disorders, since affect is the external display of mood, an emotion that is, however, felt internally and called mood. Mood disorders are not just about mood. The diagnosis of a major depressive episode requires the presence of at least five symptoms, only one of which is depressed mood (Figure 6-1). Similarly, a manic episode requires more than just an elevated, expansive, or irritable mood; there must be at least three or four additional symptoms (Figure 6-2).
Classically, the mood symptoms of mania and depression are “poles” apart (Figures 6-3 through 6-6). This concept has generated the terms “unipolar” depression (i.e., patients who experience just the down or depressed pole) (Figures 6-3 and 6-4) and “bipolar” (i.e., patients who at different times experience the up pole, or mania (Figures 6-3 and 6-5) or hypomania (Figures 6-3 and 6-6) and the down pole, i.e., depressed pole (Figures 6-3, 6-5, and 6-6). Bipolar I patients have full-blown manic episodes usually followed by depressive episodes (Figure 6-5). Bipolar II disorder is characterized by at least one hypomanic episode and one major depressive episode (Figure 6-6). Depression and mania may even occur simultaneously, which is called a “mixed” mood state or, in DSM-5, “mixed features” (Figure 6-7; Table 6-1). Introduction of the mixed-features modifier has moved the field away from considering depression and mania as distinct categories and towards the concept that they are opposite ends of a spectrum, with all degrees of mixtures in between (Figure 6-7). Many real patients are neither purely depressed nor purely manic, but some mixture of both, with the specific mix of symptoms changing along the mood spectrum over the course of illness. This is similar to the evolution in the conceptualization of schizophrenia versus bipolar disorder, where the old dichotomous model (Figure 6-8) has been largely replaced with a continuous disease model spectrum, ranging from pure psychotic disorder to pure mood disorder (Figure 6-9).
|Manic or hypomanic episode, with mixed features|
|Full criteria for manic or hypomanic episode|
|At least three of the following symptoms of depression:|
|Loss of interest or pleasure|
|Fatigue or loss of energy|
|Feelings of worthlessness or excessive or inappropriate guilt|
|Recurrent thoughts of death or suicidal ideation/actions|
|Full criteria for a major depressive episode|
At least three of the following manic/hypomanic symptoms:
|Elevated, expansive mood (e.g., feeling high, excited, or hyper)|
|Inflated self-esteem or grandiosity|
|More talkative than usual or feeling pressured to keep talking|
|Flight of ideas or subjective experience that thoughts are racing|
|Increase in energy or goal-directed activity|
|Increased or excessive involvement in activities that have a high potential for painful consequences|
|Decreased need for sleep|
|(*Not included: psychomotor agitation)|
|(*Not included: irritability)|
|(*Not included: distractibility)|
Other than a history of a prior manic/hypomanic episode, patients with unipolar depressive episodes (Figure 6-4) are diagnosed using the same symptom criteria (Figure 6-1) as patients with bipolar depressive episodes (Figures 6-5 and 6-6). Despite similar symptoms, patients with unipolar versus bipolar depression have different long-term outcomes and should generally receive different treatments. Unfortunately, missed diagnosis or delayed diagnosis of bipolar depression is all too common. Over a third of patients with unipolar depression are eventually re-diagnosed as having bipolar disorder and maybe as many as 60% of depressed patients with bipolar II disorder are initially diagnosed as having unipolar depression. In some cases, this is because the patient had depressive episodes before they had manic or hypomanic episodes, and a bipolar diagnosis could not be made. In other cases, the diagnosis of a past manic or hypomanic episode is missed because patients with bipolar disorder often present in the depressed phase and past hypomania is often pleasant for patients and may not be mentioned.
Why do you want to make an early accurate diagnosis of bipolar disorder? Although unipolar versus bipolar depression cannot be readily distinguished on the basis of a patient’s current symptomatology, there are some hints that can raise suspicion of a bipolar depressive episode rather than a unipolar depressive episode (Figure 6-10). Missing the diagnosis of bipolar depression early may lead to worse quality of life due to giving the wrong treatment (for unipolar depression rather than for bipolar depression) and this may be ineffective or even dangerous. That is, delay of appropriate treatment in bipolar depression can increase the risk of mood cycling, relapse, and suicide, and even decrease the chances of responding to appropriate bipolar treatments once they are given later.
Thus, it is important to tell unipolar from bipolar depression. Is there any way to do this when the patient is in the depressed state other than to find a prior history of mania/hypomania? The short answer is no. The long answer is that there are certain clinical characteristics that favor the likelihood of a bipolar depressive episode instead of a unipolar depressive episode, and these factors can be clues to the diagnosis of a bipolar depressive episode when the past history of a manic/hypomanic episode is unclear (Figure 6-10). Some additional tips about how to determine whether a depressed patient is unipolar or bipolar might be to ask two questions (Table 6-2):
“Who’s your daddy?” and “Where’s your mama?”
“Who’s your daddy?” means more precisely, “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. Although the majority of patients with bipolar depression do not have a family history of bipolar disorder, when it is present, it is arguably the most robust and reliable risk factor for bipolar depression. Individuals with a first-degree relative with bipolar disorder are at an 8–10-fold greater risk of developing bipolar disorder compared to the general population.
The second question, “Where’s your mama?,” really means “I need to get additional history from someone else close to you,” since patients tend to under-report their manic symptoms. The insight and observations of an outside informant such as a mother or spouse who can give past history might indeed prove to be quite different from the one the patient is reporting, and thus help establish a bipolar spectrum diagnosis that patients themselves deny or do not perceive.
|Who’s your daddy?|
|What is your family history of:|
|•anyone who took lithium, mood stabilizers, drugs for psychosis or depression?|
|•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.|
In addition to the importance of distinguishing unipolar depression from bipolar depression, it is also very important to look for mixed features in your depressed patients, whether those patients have a unipolar or bipolar illness. This is because there are big differences in the outcome for patients if mixed features are present. For one thing, there is evidence that unipolar depression can progress to mixed features, mixed features progress to bipolar disorder, and bipolar disorder progress to treatment resistance (Figure 6-11). The presence of even subthreshold manic symptoms is strongly associated with conversion to bipolar disorder, with each manic symptom increasing risk by 30%. We don’t know if we can halt this march towards a bad outcome, but the best chance may be early recognition and effective treatment that reduces or eliminates all symptoms, whether manic or depressed, and to do this as early in the course of illness as possible.
How many depressed patients have mixed features? The estimates are about a quarter of all patients with unipolar depression and a third of all patients with bipolar I or II depression have subsyndromal symptoms of mania. Estimates of mixed features in unipolar depression in children and adolescents are even higher. Compared to those with “pure” depression, those with depression plus some manic symptoms may have a more complex illness and less favorable course and outcome. For example, mixed features may compound the already high risk of suicide in depressed patients. Non-euphoric manic symptoms such as psychomotor agitation, impulsivity, irritability, and racing/crowded thoughts combined with depressive symptoms are a recipe for suicidality. Suicide rates are twice as high in bipolar than in unipolar depression and up to 20 times higher in bipolar disorder compared to the general population. Sadly, up to a third of bipolar patients attempt suicide at least once in their life, and 10–20% of them succeed.
What about those subsyndromal manic symptoms and suicide? In the presence of mixed features there is a fourfold increased risk of suicidality in both unipolar and bipolar depression. Studies show specifically a worrisome association of mixed episodes with suicide attempts, so it is not only important to identify who has mixed features, but also to treat appropriately. Treatment for mixed features is discussed in Chapter 7 and surprisingly is NOT the same as the treatment for unipolar depression without mixed features. That is, neither unipolar nor bipolar depression with mixed features are treated first-line with standard monoamine reuptake inhibiting drugs used widely in unipolar depression and discussed in Chapter 7, but rather with serotonin/dopamine antagonists/partial agonists used widely for the treatment of psychosis and discussed in Chapter 5. Thus, it cannot be emphasized too strongly that major depressive episodes need to be correctly diagnosed as part of a unipolar or bipolar illness and as having or lacking mixed features, and that the correct treatment be given (details of treatment of mood disorders are given in Chapter 7). The hope is that recognition and appropriate treatment of both unipolar and bipolar depression – whether that depressive episode has mixed features or not – will cause all symptoms to remit for long periods of time and that this might prevent progression to more difficult states (Figure 6-11). This is not proven, but is a major hypothesis in the field at the present time.