On the Edge of Insanity

1. 1 On the Edge of Insanity Exploring the Pathophysiology of Major Unipolar Depression My purpose in researching Major Unipolar Depression has been to investigate the validity of the commonly used term �chemical imbalance� as a description of the mood disorder referred to as major depression� For the duration of this semester it has been my goal to not only develop an understanding of the topic in general, but perhaps encounter the limits of the field to find out how the symptomatic diagnosis of depression might eventually be linked to a pathological diagnosis. My purpose in researching Major Unipolar Depression has been to investigate the validity of the commonly used term �chemical imbalance� as a description of the mood disorder referred to as major depression� For the duration of this semester it has been my goal to not only develop an understanding of the topic in general, but perhaps encounter the limits of the field to find out how the symptomatic diagnosis of depression might eventually be linked to a pathological diagnosis.

2. 2 Why should we be concerned about depression? Disability. It is estimated that 20 million people ~ that�s 1 in 5 American adults - suffer from severe depression each year� Statistics published by The National Institute of Mental Health demonstrate that major unipolar depression is the leading cause of disability in the US and market economies worldwide and represents a major issue to the health care industry. These statistics are not subtle in their suggestion that major depression is a problem affecting a considerable portion of the world�s population. Although the specific study of depression has rapidly accelerated in the latter half of the 20th century, this is not the first we�ve heard of depression� It is estimated that 20 million people ~ that�s 1 in 5 American adults - suffer from severe depression each year� Statistics published by The National Institute of Mental Health demonstrate that major unipolar depression is the leading cause of disability in the US and market economies worldwide and represents a major issue to the health care industry. These statistics are not subtle in their suggestion that major depression is a problem affecting a considerable portion of the world�s population. Although the specific study of depression has rapidly accelerated in the latter half of the 20th century, this is not the first we�ve heard of depression�

3. 3 History of Depression: Science or Serendipity?  400 B.C.E Hippocrates: black bile 18th century Albrecht von Haller: opium 19th century Reserpine: hypertension 1950�s Imipramine: tuberculosis Iproniazid : tuberculosis Prototypes for MAOIs MAUIs Advent of electron microscope In the times of Hippocrates, depressive symptoms were referred to as melancholia: an imbalance of black bile - one of four humors or fluids of the body. Interestingly, 2,500 years later, we still believe the cause of depressive symptoms relates to a chemical imbalance in the body � specifically, the brain. In the 18th century: Albrecht von Haller recognized opium as responsible for the soothing effects of Laudanum elixirs derived from the poppy. In the nineteenth century, reserpine, a drug used to treat hypertension, was noted for its effectiveness in alleviating anxiety and depression. In the late 1950�s two drugs used in treating tuberculosis, iproniazid and imipramine (tricyclic drugs) were noted as having euphoric and hyperactive effects in patients, and became the prototypes of two of the major classes of antidepressants: monoamine oxidase inhibitors (MAOIs), and monoamine reuptake inhibitors (MAUIs). By the mid 1960�s the MAOIs had become unpopular due to serious side effects and are now rarely used. The monoamines Serotonin, and norepinephrine were investigated during this time, and this began the search for more specific reuptake inhibitors. In the 1970s, the belief that inhibition of enzymes which degrade neurotransmitters and increase NT concentration in the synapse formed the basis of the Monoamine Theory and attempted to explain the cause of depressive symptoms. The advent of the electron microscope in the 1950s and brain imaging techniques supported this theory, enabling researchers to study brain activity and neurobiology, comparing normal and depressed patients. Eventually, non-selective NRIs were replaced with selective NRIs and then with selective serotonin reuptake inhibitors which dominated the 1990s. Currently, despite the popularity of SSRIs, side effects and yet unanswered questions about the mechanisms of action of antidepressant medications has led to the re-introduction of SNRIs such as Reboxetine, and non-selective monoamine inhibitors such as Venlafaxine� Other types of new antidepressants include selective receptor blockers like nefazadone and mirtazepine. Over 20 antidepressants are now available worldwide� In the times of Hippocrates, depressive symptoms were referred to as melancholia: an imbalance of black bile - one of four humors or fluids of the body. Interestingly, 2,500 years later, we still believe the cause of depressive symptoms relates to a chemical imbalance in the body � specifically, the brain. In the 18th century: Albrecht von Haller recognized opium as responsible for the soothing effects of Laudanum elixirs derived from the poppy. In the nineteenth century, reserpine, a drug used to treat hypertension, was noted for its effectiveness in alleviating anxiety and depression. In the late 1950�s two drugs used in treating tuberculosis, iproniazid and imipramine (tricyclic drugs) were noted as having euphoric and hyperactive effects in patients, and became the prototypes of two of the major classes of antidepressants: monoamine oxidase inhibitors (MAOIs), and monoamine reuptake inhibitors (MAUIs). By the mid 1960�s the MAOIs had become unpopular due to serious side effects and are now rarely used. The monoamines Serotonin, and norepinephrine were investigated during this time, and this began the search for more specific reuptake inhibitors. In the 1970s, the belief that inhibition of enzymes which degrade neurotransmitters and increase NT concentration in the synapse formed the basis of the Monoamine Theory and attempted to explain the cause of depressive symptoms. The advent of the electron microscope in the 1950s and brain imaging techniques supported this theory, enabling researchers to study brain activity and neurobiology, comparing normal and depressed patients. Eventually, non-selective NRIs were replaced with selective NRIs and then with selective serotonin reuptake inhibitors which dominated the 1990s. Currently, despite the popularity of SSRIs, side effects and yet unanswered questions about the mechanisms of action of antidepressant medications has led to the re-introduction of SNRIs such as Reboxetine, and non-selective monoamine inhibitors such as Venlafaxine� Other types of new antidepressants include selective receptor blockers like nefazadone and mirtazepine. Over 20 antidepressants are now available worldwide�

4. 4 MAOIs monoamine oxidase inhibitors MAUIs monoamine uptake inhibitors NRIs norepinephrine reuptake inhibitors SARIs serotonin-2 antagonists/reuptake inhibitors SNRIs selective norepinephrine reuptake inhibitors SSRIs selective serotonin reuptake inhibitors NaSSAs noradrenergic specific serotonin agent NDRIs norepinephrine dopamine reuptake inhibitors There is a lot of terminology that is somewhat tedious in neuroscience so I have summarized some of the common abbreviations used in discussing antidepressants here�  There is a lot of terminology that is somewhat tedious in neuroscience so I have summarized some of the common abbreviations used in discussing antidepressants here�

5. 5 In an attempt to discuss a manageable amount of information, my research focuses on major depression because it is characterized by a number of symptoms that differentiate it from other common types of depression listed here In an attempt to discuss a manageable amount of information, my research focuses on major depression because it is characterized by a number of symptoms that differentiate it from other common types of depression listed here

6. 6 Symptomsof UnipolarDepression  Difficulty sleeping or oversleeping Recurrent thoughts of death or suicide Major Depression is characterized by the following symptoms which, by definition, interfere with normal activity and persist for at least two weeks. These symptoms impair a persons ability to function normally but the disorder often goes undiagnosed, leaving the suffering person unable to explain or cope with their dysfunction. Several separate fields of study are combining their resources to try and link these symptoms to the microscopic environment which controls them. A basic knowledge of neuronal physiology is essential to understanding the rapidly increasing body of knowledge concerning mental illness. Major Depression is characterized by the following symptoms which, by definition, interfere with normal activity and persist for at least two weeks. These symptoms impair a persons ability to function normally but the disorder often goes undiagnosed, leaving the suffering person unable to explain or cope with their dysfunction. Several separate fields of study are combining their resources to try and link these symptoms to the microscopic environment which controls them. A basic knowledge of neuronal physiology is essential to understanding the rapidly increasing body of knowledge concerning mental illness.

7. 7 The physical foundation for mental illness lies deep within the nervous system. Here we travel from a macroscopic view of the brain, through the midbrain, to a microscopic view of the synaptic cleft that links two neurons. This is the target area of study for depression research. The physical foundation for mental illness lies deep within the nervous system. Here we travel from a macroscopic view of the brain, through the midbrain, to a microscopic view of the synaptic cleft that links two neurons. This is the target area of study for depression research.

8. 8 The brain communicates with the rest of the body via nerve cells, electrical impulses, and chemicals that act within and upon those nerve cells. These chemicals - called neurotransmitters � perform several functions vital to the tiniest details of human life and normal functioning. A normal neuron contains enzymes which synthesize neurotransmitter precursors. Upon activation of the neuron, the vesicles storing neurotransmitters fuse with the membrane and release the neurotransmitter into the synapse where it binds to one of several types of receptors. Once its job is done, it is either degraded or reabsorbed into the presynaptic neuron. In depressive patients any one of these steps in NT action may be disrupted and interfere with the transmission of signals from neuron to neuron.The brain communicates with the rest of the body via nerve cells, electrical impulses, and chemicals that act within and upon those nerve cells. These chemicals - called neurotransmitters � perform several functions vital to the tiniest details of human life and normal functioning. A normal neuron contains enzymes which synthesize neurotransmitter precursors. Upon activation of the neuron, the vesicles storing neurotransmitters fuse with the membrane and release the neurotransmitter into the synapse where it binds to one of several types of receptors. Once its job is done, it is either degraded or reabsorbed into the presynaptic neuron. In depressive patients any one of these steps in NT action may be disrupted and interfere with the transmission of signals from neuron to neuron.

9. 9 AntidepressantAction This slide shows a common SSRI, commonly known as Prozac as it prevents the reuptake of serotonin. This causes serotonin neurotransmitters to remain in the synapse� Here is where the details become sketchy� This slide shows a common SSRI, commonly known as Prozac as it prevents the reuptake of serotonin. This causes serotonin neurotransmitters to remain in the synapse� Here is where the details become sketchy�

10. 10 When one of most modern antidepressants goes to work, it normally prevents reuptake of a neurotransmitter. This diagram shows a simplified map of the complex steps taking place during synaptic transmission in which neurotransmitters are seen as just one member of the transmission team. Recent research suggests that at any point in the process of synaptic transmission something can go wrong and may be linked to depressive symptoms. Further research into the entire complex electrochemical process of neurotransmission is leading to new and more effective treatments of depression.When one of most modern antidepressants goes to work, it normally prevents reuptake of a neurotransmitter. This diagram shows a simplified map of the complex steps taking place during synaptic transmission in which neurotransmitters are seen as just one member of the transmission team. Recent research suggests that at any point in the process of synaptic transmission something can go wrong and may be linked to depressive symptoms. Further research into the entire complex electrochemical process of neurotransmission is leading to new and more effective treatments of depression.

11. 11 We�ve just seen that there are several steps in the process of synaptic transmission: a malfunction in any one of these steps may lead to depressive symptoms. There are other gaps in our knowledge about this mental illness: Currently we have no standard pathological indicators of disease � no blood tests, no urine samples � no biomarkers. Many antidepressants prescribed do not �work� until the patient has been taking them for a few weeks despite the fact that the chemical changes take place almost instantly.(#) Another problem is that people suffering from the same symptoms may react differently to the same medication and some antidepressant medications relieve only a portion of depressive symptoms. While the rate of recurrence (#) is discouraging, progress is being made on a major scale on the forefront of depression research� We�ve just seen that there are several steps in the process of synaptic transmission: a malfunction in any one of these steps may lead to depressive symptoms. There are other gaps in our knowledge about this mental illness: Currently we have no standard pathological indicators of disease � no blood tests, no urine samples � no biomarkers. Many antidepressants prescribed do not �work� until the patient has been taking them for a few weeks despite the fact that the chemical changes take place almost instantly.(#) Another problem is that people suffering from the same symptoms may react differently to the same medication and some antidepressant medications relieve only a portion of depressive symptoms. While the rate of recurrence (#) is discouraging, progress is being made on a major scale on the forefront of depression research�

12. 12 Current Research Goals Studies are being done to identify and distinguish subtypes of depression in an effort to more accurately treat individual disorders. Broader investigations into social and environmental factors in depression are bringing the fields of Psychology and Biology together in a more comprehensive approach. Brain imaging technology is a rapidly expanding field, enabling unprecedented views of brain structure and function and allowing valuable comparisons to be made such as the images below demonstrating decreased prefrontal cortex activity with increased deep limbic system activity in the brain of a woman suffering from post mortem depression. Finally, this brings us to my main interest, finding biomarkers of depression that bring the mental illness into the physical realm Despite the prolific studies being done, there is not much evidence that we will see a blood test for depression any time soon. (what types: CT scan, MRI, fMRI, PET imaging, dye injection and x-ray, etc�) Studies are being done to identify and distinguish subtypes of depression in an effort to more accurately treat individual disorders. Broader investigations into social and environmental factors in depression are bringing the fields of Psychology and Biology together in a more comprehensive approach. Brain imaging technology is a rapidly expanding field, enabling unprecedented views of brain structure and function and allowing valuable comparisons to be made such as the images below demonstrating decreased prefrontal cortex activity with increased deep limbic system activity in the brain of a woman suffering from post mortem depression. Finally, this brings us to my main interest, finding biomarkers of depression that bring the mental illness into the physical realm Despite the prolific studies being done, there is not much evidence that we will see a blood test for depression any time soon. (what types: CT scan, MRI, fMRI, PET imaging, dye injection and x-ray, etc�)

13. 13 Summary The specific cause of depression remains elusive, and while our knowledge of the complexities of the system continue to grow. Depressive symptoms may be a result of a malfunction of one of many complex aspects of neurotransmission The mechanisms of action of treatments for depression are not completely understood. Our main source for understanding depression lies in serendipitous discoveries of psychotropic drugs, and trial and error. Neuroscience is rapidly expanding its capabilities through advances in technology � imaging, and an increasing understanding of neuronal function. While many aspects of depression remain unclear, the dynamic field of neuroscience gives hope to those whose quality of life may very well depend on it. The specific cause of depression remains elusive, and while our knowledge of the complexities of the system continue to grow. Depressive symptoms may be a result of a malfunction of one of many complex aspects of neurotransmission The mechanisms of action of treatments for depression are not completely understood. Our main source for understanding depression lies in serendipitous discoveries of psychotropic drugs, and trial and error. Neuroscience is rapidly expanding its capabilities through advances in technology � imaging, and an increasing understanding of neuronal function. While many aspects of depression remain unclear, the dynamic field of neuroscience gives hope to those whose quality of life may very well depend on it.

14. 14 Acknowledgements:

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16. 16 G-protein receptor action