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