Major Depressive Disorder - Regis University, PDF

Major Depressive Disorder RHCHP School of Pharmacy Integrated Pharmacotherapy 3 Spring 2025 Facilitators Reading and References Dan Berlau, PhD Requ...

Major Depressive Disorder RHCHP School of Pharmacy Integrated Pharmacotherapy 3 Spring 2025 Facilitators Reading and References Dan Berlau, PhD Required [email protected] Integrated Pharmacotherapy 3 Major Depressive Disorder Student Notes (this document) (303) 964-6178 Optional Katie Tuck, PharmD, BCPP, BCPS Goodman and Gilman’s The Pharmacologic Basis of Therapeutics chapter 17 [email protected] Katzung’s Basic and Clinical Pharmacology: Antidepressant Agents (chapter 30) (303) 964-5327 DiPiro’s Pharmacotherapy: A Pathophysiologic Approach: Major Depressive Disorder (chapter 77) Learning Objectives 1. Describe the epidemiology and complications of major depressive disorder (MDD). 2. Compare and contrast the major functions of the central and peripheral nervous systems. 3. Identify the four major regions of the brain and label each appropriately, given an unlabeled anatomical brain image. 4. Recognize steps in the biosynthesis of catecholamines and serotonin neurotransmitters, including identification of key enzymes. 5. List and describe the major cellular structures that make up a synapse, including recognition of antidepressant sites of action. 6. Explain the process of signal transmission between neurons (neurotransmission), paying special attention to the importance of neurotransmitter reuptake. 7. Describe the role of monoamine oxidase and its importance for normal neurotransmission. 8. Discuss cellular mechanisms of receptor desensitization and down-regulation with reference to concepts from previous units. 9. Describe the physiological function of the mesolimbic dopamine system. 10. Identify three brain sub-regions associated with the limbic system and describe the functions of each. 11. Discuss current theories on the pathophysiology of depression. 12. List and describe the signs, symptoms and physical exam findings related to depression. 13. Identify medications and environmental factors that may cause or contribute to depression. 14. List the target symptoms of depression using the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) criteria for depression. 15. Define the goals of treatment to alleviate the signs and symptoms associated with depression. 16. Given one name for an antidepressant drug (i.e., brand or generic) recall the other name for the drug. 17. Match antidepressants to one of the following pharmacologic classifications: selective serotonin reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), secondary amine tricyclic antidepressant (TCA), tertiary amine TCA, monoamine oxidase inhibitor (MAOI), or atypical antidepressant. 18. Describe clinically important aspects of dosing formulations for fluoxetine and bupropion. 19. List the most common route of antidepressant administration and identify why it is the most common. 20. Describe the drug distribution processes important to antidepressants. 21. Predict the effect of p-glycoprotein (P-gp) inhibition on the distribution in the CNS for an antidepressant that is a P-gp substrate. 22. Identify structural characteristics that improve drug distribution into the CNS. 23. Describe how antidepressant drug action supports the monoamine theory of depression. 24. Describe the neurotransmitter receptor binding profile of antidepressants by drug class or individual drug if in a class of its own. 25. Describe the difference between potency and selectivity of antidepressant medications. 26. Explain what a Ki value measures. 27. When given drug Ki data for monoamine neurotransmitter reuptake inhibition, calculate selectivity and rank drugs by their potency and selectivity. 28. Describe the typical time course of action for antidepressants and provide examples of theories explaining this time course. 29. Compare and contrast the side effect profile of the antidepressant drug classes and how their selectivity relates to these side effects. 30. Describe the effect of antidepressant elimination half-life on the severity of antidepressant discontinuation or withdrawal symptoms.  Learning Objectives 31. Describe the cause and symptoms of discontinuation or withdrawal syndrome for antidepressants. 32. Recognize the chemical structure of a tricyclic antidepressant and classify the structure as tertiary amine or secondary amine. 33. Explain the concept of an enantiomerically pure drug and identify enantiomerically pure antidepressants. 34. Compare the therapeutic index of TCAs with other antidepressants and explain how this affects the overdose potential of TCAs. 35. Identify the autonomic and histaminic receptors blocked by antidepressants and predict the pharmacologic effects, including adverse effects, that are due to blockade of these receptors. 36. Identify common adverse effects of individual antidepressants and apply this knowledge to drug therapy decisions based on a patient case. 37. Identify maximum dosing and absolute contraindications for bupropion. 38. Identify the black box warning associated with all antidepressants. 39. List the half-life of fluoxetine and norfluoxetine and compare these half-lives with the typical half-life of an antidepressant. 40. Identify CYP450 isoforms important to the metabolism of antidepressants and predict interactions with known inhibitors or inducers. 41. Differentiate between phase I oxidation and phase II glucuronidation drug metabolism pathways. 42. Differentiate between hydroxylation and demethylation CYP450 reactions. 43. For antidepressants that act as major CYP450 inhibitors, match the CYP450 isoform that is inhibited to the antidepressant. 44. Predict the effect of a patient’s CYP2D6 genotype on the pharmacologic outcomes of antidepressants. 45. Identify the general types of foods that are prone to interact negatively with MAOIs and the medical outcome of that interaction. 46. **Formulate an evidence-based therapeutic plan that includes non-pharmacologic and pharmacologic therapies to alleviate the signs and symptoms of depression, including special populations (e.g., children, elderly, pregnant women, etc.). 47. Differentiate between response, remission, relapse, and recurrence in a patient with depression. 48. Create a plan to monitor the efficacy and toxicity of the therapeutic agents used to treat depression. 49. Choose an appropriate starting, adjunctive or alternative antidepressant based on patient response, characteristics (comorbid health conditions), side effect profile and potential drug/food interactions. 50. Summarize the findings of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. 51. Counsel a patient on the signs and symptoms of serotonin syndrome, identify medications that can cause serotonin syndrome in addition to antidepressants and recommend a treatment plan for a patient with serotonin syndrome. 52. Assess the usefulness of plasma concentrations for each antidepressant. 53. Recognize the treatments used in treatment-resistant depression (TRD). 54. Identify a patient that would be a good candidate for Electroconvulsive Therapy (ECT), describe the general procedure for ECT and list ECTs side effects. Integrated Pharmacotherapy 3 2 Major Depressive Disorder INTRODUCTION TO MAJOR DEPRESSIVE DISORDER Definitions/Abbreviations The term “depressive disorders” is used to describe a group of mood disorders MDD - Major Depressive Disorder in which patients have sad or irritable moods with other physical or cognitive DSM-5 - Diagnostic and Statistic Manual of Mental Disorders, 5th symptoms that impair daily function. Diagnoses in the depressive disorders edition category include major depressive disorder (MDD), disruptive mood MSE - Mental Status Exam dysregulation disorder, persistent depressive disorder, premenstrual dysphoric CNS - Central Nervous System disorder and a few others. The main difference between the various depressive PNS - Peripheral Nervous System disorders is the nature of onset, duration, and potential etiology. SSRI - Selective Serotonin Reuptake Inhibitor MDD is a common illness affecting more than 264 million people worldwide. SNRI - Serotonin and Norepinephrine Reuptake Inhibitor Although the exact prevalence in the United States is unknown, the National TCA - Tricyclic Antidepressant Comorbidity Survey Replication (NCS-R) estimates that 17.3 million adults aged MAOI - Monoamine Oxidase Inhibitor 18 or older and 2.3 million adolescents aged 12 to 17 have experienced at least 5-HT - 5-hydroxytryptamine (serotonin) one major depressive episode within the past 12 months. NE - Norepinephrine DA - Dopamine MDD can occur at any time throughout a person’s life cycle. The typical age of onset is from the mid 20’s through the 50’s with a peak age of onset in the mid 30’s. Women are twice as likely to suffer from MDD compared to men. Likewise, women experience higher rates of suicidal thinking and suicide attempts. However, men are nearly four times as likely to die by suicide, which is attributed to the fact that men tend to choose more violent (more lethal) suicide methods. MDD is more prevalent in people with a history of MDD in a first-degree relative, (risk increased by 3 to 5 times as compared to the general population). Risk is greater in monozygotic than dizygotic twins. Race, ethnicity, and socioeconomic class have not been found to be predictive factors for MDD. MDD can cause decreases in quality of life and impairment in social and occupational functioning for patients. It is associated with increased health care costs as well as Figure 1. Percentage of persons 20 years of age and older reporting difficulty with their work, higher rates of many chronic medical home, or social activities due to depression symptoms. United States, 2013-2016. conditions. Patients with depression are three times more likely to be non- adherent to treatments for medical conditions. At its worst, MDD can lead to suicide, a tragic fatality resulting in the loss of about 850,000 lives every year. According to the World Health Organization, MDD is the world’s leading cause of disability. The National Health and Nutrition Examination Survey conducted by the CDC from 2013-2016 reported that approximately 80% of adults with MDD reported some level of functional impairment because of their depressive disorder, and 30% reported extreme difficulties in work and home life (Figure 1). Although depression is common in everyday life secondary to life events, it is important to note that the specific criteria for a psychiatric illness must be met for a diagnosis. In addition, the symptoms should cause a change in functionality which can impair personal and professional functioning as evidenced in Figure 1. Integrated Pharmacotherapy 3 3 Major Depressive Disorder PHYSIOLOGY AND BIOCHEMISTRY OF THE BRAIN Introduction The anatomy and physiology of the central nervous system (CNS) is extensive, and the biochemical pathways that regulate communication between nerve cells are complex. Based on our understanding of the mood abnormalities observed in patients with MDD, we can attempt to identify sub-regions of the brain that are the most likely to be involved in depression. In addition, the mechanisms of action of commonly used antidepressant drugs provide guidance to understanding the involvement of neurotransmitter systems in the pathophysiology of MDD. Neural Circuitry of Depression In addition to the abbreviated information provided below, it may be helpful to review the discussion of neurophysiology in IP 2 Hypertension and IP 3 Introduction to Neuroscience. Anatomy of the CNS The nervous system includes all the neural tissue in the body, forming the Peripheral Nervous System organs of the brain and spinal cord, as well as sensory and motor nerves. Opposite the CNS is the peripheral nervous system (PNS) Neural cells are divided into two general classes: neurons and glial cells. Glial which delivers incoming (afferent) sensory information to cells, or neuroglia, separate and protect neurons, and provide a supportive the CNS for processing, and delivers outgoing (efferent) framework for neural tissues and the interstitial fluid. Neurons are responsible motor commands to peripheral muscles and organ systems. for the transmission of nerve impulses or signals through the release of neurotransmitter molecules that alter the electrical membrane potential of adjacent neurons, as you will see below. The CNS is composed of the brain and spinal cord. It is responsible for integrating and processing sensory data and motor commands. The CNS includes an extensive network of neurons in the brain that create higher order functions (such as memory, learning, and emotion) which motivate human behavior. The Brain The adult human brain can be divided into four major regions, based both on anatomical structure and function. The cerebrum is the largest region and is divided into two hemispheres that are characterized by a deeply grooved or folded appearance. These two hemispheres are connected by a massive bundle of nerve fibers known as the corpus callosum. The outer layers of the cerebral hemispheres comprise the cortex, which forms the folds and fissures that increase the surface area of the cerebrum. The cerebrum and the cerebral cortex can be further subdivided into smaller brain regions which are responsible for intellectual functions, memory storage, mood, and emotional affect. Some of these smaller regions will be discussed in more detail below. Buried within the cerebrum is the diencephalon, which includes the thalamus and hypothalamus, and the brain stem, which connects the brain to the spinal cord. At the base of the brain stem is the medulla oblongata, which regulates cardiovascular, respiratory, and digestive system activities. Figure 2. Schematic drawing of the mesolimbic system Beneath and behind the cerebrum is the cerebellum, which coordinates patterns of motor stimulation and controls posture. Similar to the cerebrum, the cerebellum is also covered by cortical layers. While many regions of the brain are implicated in regulating mood or emotional states, we have an incomplete understanding of the neural networks that underlie the abnormalities in mood that are the hallmarks of depression. For the purposes of this unit, we will focus on the limbic system that utilizes the neurotransmitters dopamine, norepinephrine, and serotonin (among others). This network is believed to regulate emotional responses under normal circumstances and is very likely to be involved in the pathophysiology of MDD. The Limbic System The limbic system (also referred to as the mesolimbic system) is a collection of brain structures that includes portions of the prefrontal cortex, the temporal lobe of the cerebrum, as well as the thalamus and hypothalamus (Figure 2). Projections of the limbic system originate in the midbrain at Structures within the limbic system are associated with learning, emotional the base of the brainstem and end in the region of the nucleus accumbens and the prefrontal cortex. Limbic projections also experience and behavior, and a wide variety of endocrine functions. pass through the regions of the amygdala and hippocampus. (Modified from Vander, Sherman, and Luciano, 1998.) Integrated Pharmacotherapy 3 4 Major Depressive Disorder The amygdala is central to most, if not all, emotional states. It is located at the front (anterior) edge of the temporal lobe. Neurons in the amygdala are connected to sensory areas of the cortex, from which they receive information about the outside world, and project to parts of the brain involved in emotional response behaviors. The hippocampus is a curved structure in the middle of the temporal lobe with connections to the frontal cortex. The hippocampus is associated with many forms of learning and memory consolidation. The nucleus accumbens (also commonly referred to as the ventral striatum) is located in close proximity to the amygdala and below the hippocampus. It is strongly associated with reinforcement of behaviors. Experiences that are considered pleasurable will increase the activity of the nucleus accumbens. Synaptic Neurotransmission Before delving further into the neurophysiology of MDD, it will be necessary to provide some general information on the mechanisms of communication between neural networks, and more specifically, between adjacent neurons. Communication between neurons requires small molecules called neurotransmitters. As you will see below, antidepressant drugs such as reuptake inhibitors and monoamine oxidase inhibitors exert actions on the metabolism and signaling of monoamine neurotransmitters. Monoamine Neurotransmitters Previously described in IP 3 Introduction to Neuroscience, the class of monoamine neurotransmitters includes epinephrine, norepinephrine (NE), dopamine (DA), histamine, and serotonin (5-hydroxytryptamine, 5-HT). Note that NE and DA are also classified as catecholamine neurotransmitters. These are synthesized in the pre-synaptic neuron from the amino acid tyrosine (Figure 3). Serotonin is synthesized from the amino acid tryptophan. Monoamine neurotransmitters are stored in membrane-bound vesicles beneath the pre-synaptic membrane of the axon terminal. Depolarization of the membrane during neuronal activation promotes an increase in intracellular Ca2+ ions. Depolarization triggers exocytosis and the contents of the vesicle are released into the synaptic cleft. Figure 3. Synthesis of NE, DA and 5-HT A) Tyrosine is converted to norepinephrine in synaptic vesicles of NE neurons. The enzymes involved are shown in blue; essential cofactors in italics. Tyrosine hydroxylase (TH) oxidizes tyrosine to dihydrophenylalanine (DOPA), which is decarboxylated by aromatic L-amino acid decarboxylase (AAD) to generate dopamine. DA is stored in vesicles and may be oxidized to NE by dopamine β-hydroxylase (DβH). Alternatively, in dopaminergic neurons, DA is released into the synaptic cleft. The final step converting NE to epinephrine occurs only in the adrenal medulla and in a few epinephrine-containing neuronal pathways in the brainstem. B) Tryptophan is converted to 5-hydroxytryptophan by tryptophan hydroxylase (TPH), which is subsequently converted to serotonin by amino acid decarboxylase (AAD). Receptor Activation Monoamine neurotransmitters bind to receptors on the adjacent, postsynaptic cell (as well as binding to “peri-synaptic” auto-receptors at the edge of the presynaptic axon terminal) and initiate signal transmission. NE binds to postsynaptic adrenergic receptors (α1- adrenergic receptors and β-adrenergic receptors) and pre-synaptic α2-adrenergic receptors; DA binds to dopamine receptors (D1 – D5); and serotonin binds to 5-HT receptors, of which there are several isoforms. All of these receptors are seven-transmembrane receptors coupled to G protein activation and do not directly stimulate action potentials. However, the effects of receptor activation are different, dependent upon which isoform of G protein is activated and the type of postsynaptic neuron that is present. The monoamine neurotransmitters NE, DA, and 5-HT can influence excitatory or inhibitory postsynaptic potentials by binding to different Integrated Pharmacotherapy 3 5 Major Depressive Disorder isoforms of their respective receptors. In general, receptors that couple to stimulatory G proteins either increase the second-messenger cyclic adenosine monophosphate (cAMP) or increase intracellular calcium concentrations [Ca2+] and promote excitatory potentials. Receptors that couple to inhibitory G proteins decrease cAMP and promote inhibitory potentials through the movement of potassium ions. Neurotransmitter Reuptake Synaptic signaling is terminated by active transport of monoamines (reuptake) into the pre-synaptic terminal, thereby preventing further receptor activation. Following reuptake, the neurotransmitters may be degraded by mitochondrial monoamine oxidase (MAO). As neurotransmitters are removed from the synaptic cleft and receptors are deactivated, the neuron returns to the negative, polarized resting potential. Receptor Desensitization Receptor desensitization and down-regulation are cellular responses to repeated (or prolonged) receptor activation. Desensitization can occur in the presence of endogenous agonists or drugs that activate a receptor. In most cases, the signaling pathways that are initiated by receptor activation mediate receptor desensitization through a feed-back inhibition loop. In the case of monoamine receptors, activation of specific kinase enzymes can increase phosphorylation of adrenergic or serotonergic receptors and cause the receptor to become unable to activate G proteins. This mechanism of desensitization is called “G protein uncoupling”. Receptors may also be removed from the plasma membrane or be associated with proteins that inhibit the receptors’ capacity to become activated by binding to an agonist. When receptors are removed from the surface of the cell, through a process called receptor endocytosis, there are two possible outcomes. The receptor may be eventually returned to the surface, or “recycled”. Or it may be translocated to an intracellular organelle called the lysosome where it is degraded by proteolytic enzymes. This latter outcome is referred to as receptor down-regulation. Recycling results in a short-term inhibition of the signaling pathways that are initiated by the receptor, whereas down-regulation can result in long-term inhibition of those pathways. PATHOPHYSIOLOGY Pathogenesis of Depression Postmortem studies and functional studies conclude that there are small differences in some cortical regions and loss of tissue volume in the hippocampus in individuals with MDD. These pathophysiological changes suggest that loss of particular brain functions or disturbance of network activity can induce the mood disturbances associated with MDD. Underlying the differences in brain tissue are genetic and environmental factors that contribute to the onset of disease. Monoamine Hypothesis One prominent theory for the pathogenesis of MDD has been developed based upon our understanding of the mechanism of action of antidepressant drugs. As most antidepressants increase the levels of NE and 5-HT in the synaptic cleft, the monoamine hypothesis suggests that an imbalance in normal monoamine neurotransmission may be responsible for the onset of MDD. Long-term deficits in adrenergic and serotonergic signaling may prompt a reorganization of neuron pathways that leads to damage in specific brain areas. This concept will be discussed further below. Although this has been the prevailing theory of depression for decades, there is increasing evidence that monoamines are not a critical aspect of depression, and other mechanisms are likely responsible. Additional Explanations for Major Depressive Disorder While the monoamine hypothesis has historically dominated discussions on the pathophysiology of depression, numerous alternative theories have emerged, offering a more comprehensive understanding of the disorder. These theories move beyond serotonin, norepinephrine, and dopamine deficiencies to consider structural, immunological, endocrine, and microbiological factors contributing to depression. Understanding these alternative mechanisms is crucial for the development of novel treatment strategies, particularly for patients with treatment-resistant depression who do not respond adequately to traditional antidepressants. One prominent alternative is the neuroplasticity hypothesis, which posits that depression arises from impaired synaptic plasticity and neuronal atrophy rather than simple neurotransmitter imbalances. Research has shown that individuals with depression often exhibit reduced volumes in brain regions such as the hippocampus and prefrontal cortex, both of which play key roles in mood regulation. Brain-derived neurotrophic factor (BDNF), a protein essential for neuronal growth, synaptic connectivity, and resilience, is often found at lower levels in depressed individuals. Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and ketamine, may exert their therapeutic effects by enhancing BDNF expression and promoting neurogenesis, supporting the idea that structural and functional brain changes are central to depression. Integrated Pharmacotherapy 3 6 Major Depressive Disorder Another compelling explanation is the inflammation hypothesis, which links depression to chronic low-grade inflammation and immune system dysregulation. Studies have shown that individuals with depression often exhibit increased levels of pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). These inflammatory markers can influence neurotransmission, impair neuroplasticity, and disrupt the hypothalamic-pituitary-adrenal (HPA) axis. Additionally, conditions associated with chronic inflammation, such as autoimmune diseases and obesity, have a higher prevalence of comorbid depression. This has led Figure 5. HPA axis dysfunction and depression to growing interest in anti-inflammatory treatments, such as nonsteroidal anti- inflammatory drugs (NSAIDs) and cytokine inhibitors, as potential adjunctive therapies for depression. Closely related to the inflammation hypothesis is the HPA axis dysfunction hypothesis, which emphasizes the role of chronic stress and cortisol dysregulation in depression. The HPA axis controls the body’s stress response, and in many depressed individuals, this system is hyperactive, leading to excessive cortisol release. Prolonged exposure to high cortisol levels can damage the hippocampus, impair synaptic function, and exacerbate depressive symptoms (Figure 5). Furthermore, glucocorticoid receptor resistance may develop, disrupting negative feedback mechanisms that typically regulate cortisol production. This dysregulation contributes to a cycle of stress-induced neuronal damage and inflammation, reinforcing depressive pathology. The glutamate hypothesis provides another perspective, highlighting the role of excitatory neurotransmission in depression. Glutamate, the brain’s primary excitatory neurotransmitter, is involved in synaptic plasticity and cognitive function. Research indicates that depressed individuals often exhibit abnormal glutamate signaling, with excessive glutamate activity leading to excitotoxicity and neuronal damage. The rapid-acting antidepressant effects of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, further support this theory. Stress stimulates the hypothalamus to release CRH, Ketamine’s ability to promote synaptic connectivity and reverse stress-induced which prompts the anterior pituitary to secrete ACTH, neurodegeneration suggests that targeting glutamatergic pathways may be a triggering cortisol release from the adrenal glands. Chronic cortisol elevation due to dysregulation of promising avenue for treating depression. this axis can lead to adverse effects, including insulin An emerging field of research focuses on the gut-brain axis hypothesis, which resistance, neuronal atrophy, cardiovascular disease, and inflammation. explores how gut microbiota influence mood and behavior. The gut microbiome plays a crucial role in regulating neurotransmitter production, immune function, and the HPA axis. Dysbiosis, or an imbalance in gut bacteria, has been linked to Figure 6. The gut brain axis hypothesis increased systemic inflammation, altered serotonin metabolism, and disrupted vagus nerve signaling (Figure 6). Studies have found that individuals with depression often exhibit distinct gut microbiome profiles compared to healthy individuals. Probiotic and prebiotic interventions, as well as dietary modifications, are currently being investigated for their potential to improve mood disorders by restoring gut health. Finally, the mitochondrial dysfunction hypothesis suggests that depression is linked to impaired cellular energy metabolism. Mitochondria are responsible for producing ATP, the primary energy source for neuronal function. Dysfunctional mitochondria can lead to increased oxidative stress, impaired synaptic activity, and neuronal apoptosis, all of which have been observed in depressed individuals. Some research suggests that mitochondrial-targeted treatments, such as coenzyme Q10, creatine, and other metabolic enhancers, may offer benefits for depression. These alternative theories highlight the complexity of depression and emphasize the need for a more holistic approach to treatment. While monoaminergic antidepressants remain the standard of care, a growing body of evidence suggests that targeting neuroplasticity, inflammation, stress response systems, excitatory neurotransmission, gut microbiota, and mitochondrial function may provide new therapeutic avenues. By expanding beyond the monoamine hypothesis, researchers and clinicians can develop more personalized and effective interventions for individuals suffering from depression. Integrated Pharmacotherapy 3 7 Major Depressive Disorder CLINICAL PRESENTATION Depression will typically present as a combination of emotional, physical, cognitive, and other symptoms (Figure 7). It is important to consider age differences in presenting symptoms of depression. Children will often have new behavioral problems and have increased somatic symptoms, adolescents will display more anhedonia (loss of interest) and adults typically present with depressed mood, changes in sleep and eating habits, and rejection sensitivity. Geriatric depression is characterized by neurovegetative symptoms, such as decreased sleep, diminished interest, decreased appetite, and loss of energy. Figure 7. DSM- 5 associated features of depression Patients presenting with depressive symptoms should be fully evaluated by a trained healthcare provider. Once a patient reports depressive symptoms, a full mental status exam (MSE) should be administered. The MSE is a key patient assessment tool in psychiatry. This tool is similar to the physical examination in medicine, however it focuses on behavior and mood. A MSE is completed through a direct patient interview that is designed to assess current behavior, thoughts, perceptions, and functioning (You will receive instruction on how to conduct an MSE in IL 2 Psychiatric Rating Scales and the Mental Status Exam). Additionally, every patient should have a complete physical examination, medication review, and basic laboratory workup, including a complete blood count with differential, thyroid function and electrolyte tests. These additional evaluations are critical in diagnosing and treating patients because certain medical conditions, substance use disorders, and medications can cause depressive symptoms (Table 2 on page 9). Once a medical condition or concomitant medication has been ruled out as the cause of the depressive symptoms, the patient should be evaluated for a major depressive disorder or other mood disorder. Integrated Pharmacotherapy 3 8 Major Depressive Disorder Table 2. Common medical conditions, substance use disorders, and medications associated with depressive symptoms (Adapted from DiPiro) General Medical Conditions ӽ Endocrine diseases (hypothyroidism, Addison disease, Cushing disease) ӽ Deficiency states (pernicious anemia, Wernicke encephalopathy, severe anemia) ӽ Infections (AIDS, encephalitis, HIV, mononucleosis, STDs, TB) ӽ Collagen disorder ӽ Systemic lupus erythematosus ӽ Metabolic disorders ӽ Electrolyte imbalance (hypokalemia, hyponatremia) ӽ Hepatic encephalopathy ӽ Cardiovascular disease (coronary artery disease, congestive heart failure, myocardial infarction) ӽ Neurologic disorders (Alzheimer disease, epilepsy, Huntington disease, MS, pain, Parkinson disease, poststroke) ӽ Malignant disease Substance Use Disorders (Including intoxication and withdrawal) ӽ Alcohol use disorder ӽ Marijuana use and dependence ӽ Nicotine dependence ӽ Opioid use disorder and dependence (e.g., heroin) ӽ Psychostimulant use disorder and dependence (e.g., cocaine) Drug Therapy ӽ Antihypertensives (clonidine, diuretics, hydralazine, methyldopa, propranolol, reserpine) ӽ Hormonal therapy (oral contraceptives, steroids, adrenocorticotropic hormone) ӽ Acne therapy (isotretinoin) ӽ Interferon products (for Hepatitis C Virus, Multiple Sclerosis, etc.) DIAGNOSIS The diagnosis of a major depressive episode is based on a patient’s clinical presentation, self-reported symptoms, and the healthcare provider’s assessment including the MSE. The mnemonic D-SIG-E-CAPS is an easy way to remember the nine symptoms of depression. (Table 3) Table 3. Depression symptom mnemonic The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), published by the D Depressed mood American Psychiatric Association, is the most widely S Sleep changes (insomnia or hypersomnia) accepted and most important diagnostic reference used in caring for mentally ill patients. The DSM-5 includes I Interests (diminished interest or pleasure from activities) criteria for diagnosing major depressive episodes and G Guilt (excessive or inappropriate guilt; feelings of worthlessness) major depressive disorders. According to the diagnostic criteria for a major depressive episode, a patient must E Energy (loss of energy or fatigue) experience 5 or more depressive symptoms (with at least C Concentration (diminished concentration or indecisiveness) one of the five symptoms being depressed mood or loss of interest or pleasure). Symptoms must have been present A Appetite (decrease or increase in appetite; weight loss or gain) nearly every day in the same 2-week period and have P Psychomotor retardation/agitation resulted in a change in that patient’s level of functioning (Table 4 on page 10). The diagnosis of MDD is S Suicide (recurrent thoughts of death, suicidal ideation or attempt) characterized by either a single major depressive episode or recurrent major depressive episodes throughout a person’s lifetime. Integrated Pharmacotherapy 3 9 Major Depressive Disorder Table 4. DSM-5 Criteria for major depressive episode A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. (Note: Do not include symptoms that are clearly caused by a general medical condition or mood-incongruent delusions or hallucinations.) 1. Depressed mood most of the day nearly every day 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day nearly every day 3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day 4. Insomnia or hypersomnia nearly every day 5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) 6. Fatigue or loss of energy nearly every day 7. Feelings of worthlessness or excessive or inappropriate guilt nearly every day 8. Diminished ability to think or concentrate, or indecisiveness, nearly every day 9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The symptoms are not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). *Note: In the DSM-IV, bereavement excluded patients from having a major depressive episode. DSM-5 states that the presence of a major depressive episode with simultaneous bereavement is possible, but that the determination is a clinical judgment that takes into account the individual’s history and cultural norms. GOALS OF THERAPY Treatment is broken up into three phases where the goals are slightly different: (Figure 8) 1. Acute Phase: Resolution of depressive symptoms to complete remission (3 weeks with no sadness or anhedonia and no more than 3 remaining symptoms of depression) 2. Continuation Phase: Prevent a relapse (back into previous episode), alleviate functional impairment, and improve quality of life 3. Maintenance Phase: Prevent a new episode or recurrence of a major depressive episode Figure 8. Phases of treatment J Clin Psychiatry 1991;52(Suppl 5):28-34 *Since the date of this publication (in the 1990’s) less stigmatizing terms have replaced some of the descriptions in this figure. For example, it is no longer common in psychiatric practice to refer to euthymia as “normalcy”, and the technical term is preferred. Integrated Pharmacotherapy 3 10 Major Depressive Disorder  Antidepressants THERAPEUTIC AGENTS FOR DEPRESSIVE DISORDERS* Selective Serotonin Reuptake Inhibitors (SSRIs) Citalopram (Celexa®) Introduction Escitalopram (Lexapro®) Fluoxetine (Prozac®, Prozac Weekly®)(Serafem,® Selfemra®) There are several classes of antidepressant medications approved for treatment Fluvoxamine (Luvox®) of MDD. Nearly all antidepressants have the same general mechanism of action: Paroxetine (Paxil®) they increase the concentration of neurotransmitters in the synaptic cleft, leading Sertraline (Zoloft®) to secondary events that, after several weeks to months of therapy, begin to Vortioxetine (Trintellix®) improve symptoms of depression. The classification of antidepressants is based on Serotonin and Norepinephrine Reuptake Inhibitors which neurotransmitter/s they affect or their chemical structure. Desvenlafaxine (Pristiq®)(Khedezla®) Duloxetine (Cymbalta®) When given at equivalent and target doses, most antidepressants are equally Levomilnacipran (Fetzima®) efficacious in treatment of MDD, but patient response differs. In addition, the side Venlafaxine (Effexor®) effect profiles vary greatly from class to class, and individual patient response to Tricyclic Antidepressants (TCAs) drug therapy varies from class to class. A “response” is considered a reduction Amitriptyline (Elavil®) in symptoms but not complete remission. Therefore, antidepressant therapy is Nortriptyline (Pamelor®) often chosen based on adverse effects and individual response. Imipramine HCl (Tofranil®) Imipramine pamoate (Tofranil-PM®) As you study the pharmacology of antidepressants, pay especially close attention Desipramine (Norpramin®) to their adverse effect profile, as this often dictates therapeutic decisions. In Monoamine Oxidase Inhibitors (MAOIs) addition, it is important to know the classification of individual antidepressants Isocarboxazid (Marplan®) and understand the pharmacologic reasons for their classification. Phenelzine (Nardil®) Selegiline transdermal patch (Emsam®) Tranylcypromine (Parnate®) Drug Formulation, Delivery and Absorption Others Bupropion hydrochloride (Wellbutrin®, Wellbutrin-SR®, Drug Formulation and Delivery Wellbutrin-XL®) With few exceptions, antidepressant therapy is only formulated for oral drug Bupropion hydrobromide (Aplenzin®) delivery. This is because antidepressants take at least a few weeks to begin Dextromethorphan and bupropion (Auvelity®) working for MDD (as explained below) and therefore do not have a need for rapid Mirtazapine (Remeron®) administration (i.e., injectable formulations). Most antidepressants are available Vilazodone (Viibyrd®) in regular-release tablets or capsules, and several are also formulated as extended- Trazodone (Oleptro®)(Desyrel®) release or sustained-release to minimize the frequency of dose administration Nefazodone (Serzone®) and to decrease fluctuation in blood levels throughout the day. Exceptions to oral Brexanolone (Zulresso®) Zuranolone (Zurzuvae®) antidepressant delivery include Emsam®, Spravato®, and Zulresso®. Gepirone (Exxua®) What chemical characteristics make a drug a good candidate for transdermal Ketamine/Esketamine (Spravato®) delivery? Notes All PO except Emsam (transdermal), Spravato (nasal spray), Prozac Weekly® Zulresso (IV) Fluoxetine is available in an oral once-weekly formulation. It is important to Ketamine and esketamine (Spravato®) are reserved for treatment- resistant depression and depression with suicial thoughts/ realize that this dosage formulation does not remain in the body releasing drug behaviors for a whole week (most oral drug formulations have a GI transit time of 12 to *See Table 5 for complete list of antidepressants 24 hours). Rather, fluoxetine may be administered once-weekly due to its active metabolite (see drug action and elimination sections below). Bupropion Bupropion is formulated as several extended-release products (Wellbutrin-SR® and Wellbutrin-XL®) that do not have equivalent drug release profiles and should not be used interchangeably. For example, Wellbutrin-SR® is usually dosed twice daily while Wellbutrin-XL® is dosed once daily. Bupropion extended-release is available in two salt formulations: hydrochloride (Wellbutrin-SR® and Wellbutrin-XL®) and hydrobromide (Aplenzin®). These salt forms are not equivalent to each other on a milligram-to-milligram basis because the molecular weight of each is different (due to the different molecular weight of chlorine and bromine). As a result, the dosage strengths of Aplenzin® are set such that it is convenient to switch patients from one salt formulation to another salt formulation. For example, the amount of bupropion contained in 150 mg of bupropion hydrochloride is equivalent to the amount of bupropion contained in 174 mg of bupropion hydrobromide. Drug Absorption Most antidepressants have an oral bioavailability of 50% or higher. The percent absorbed from the gastrointestinal tract is high for most antidepressants, partly due to their lipophilic chemistry, but bioavailability is decreased for some antidepressants due to first-pass metabolism in the intestinal wall and the liver. Integrated Pharmacotherapy 3 11 Major Depressive Disorder  Table 5. Antidepressants Generic Brand Initial Dose Usual Daily MOA Side Effects Comments Selective Serotonin Reuptake Inhibitors (SSRIs) citalopram (PO) Increased risk of QTc prolongation with doses >40 10, 20, 40 mg tabs Celexa® 10-20 mg/day 20-40 mg mg daily 10 mg/5mL solution escitalopram (PO) 5, 10, 20 mg tabs Lexapro® 5-10 mg/day 10-20 mg 5mg/5mL sollution Integrated Pharmacotherapy 3 Sarafem® is a brand of fluoxetine for PMDD Longest t1/2 of the SSRIs, 5 weeks “washout” before fluoxetine (PO) starting MAOIs or another serotonergic medication 10, 20, 60 mg tabs Prozac® Nausea Most activating of the SSRIs, recommend QAM 10, 20, 40 mg caps 10-20 mg/day 20-80 mg Prozac Weekly® Sexual dysfunction dosing Delayed Release: 90 mg caps Inhibits the presynaptic reuptake of serotonin, Sedation or insomnia In a combination tablet with olanzapine (Symbyax®) 20mg/5mL solution increasing synaptic Initial increase in Patients must be stabilized on IR fluoxetine 20 mg/ serotonin anxiety day prior to switching to Prozac Weekly® 90mg paroxetine (PO) Paxil® Most anticholinergic of the SSRIs, weak muscarinic 10-20 mg/day 20-60 mg 10, 20, 30, 40, mg tabs Pexeva® receptor affinity ER: 12.5, 25, 37.5 mg tabs Higher doses may suppress NO synthesis, possibility 10 mg/5 mL suspension Paxil CR® 12.5 mg/day 25-75 mg for more erectile dysfunction sertraline 25, 50, 100 mg tabs Zoloft® 12.5-50 mg/day 50-200 mg 20 mg/mL concentrate 12 fluvoxamine* Luvox® 50 mg/day 100-300 mg Only indicated for obsessive compulsive disorder 25, 50, 100 mg tabs (OCD) and social anxiety disorder (SAD). Not used CR: 100, 150 mg caps Luvox CR® 100 mg/day 100-300 mg for MDD. SSRI AND 5HT1A agonist vortioxetine Trintellix® 10 mg/day 5-20 mg 5HT3 antagonist Serotonin Norepinephrine Reuptake Inhibitor (SNRI) Phenthylamine Adjust in renal impairment venlafaxine Effexor® Highest risk of HTN with doses >300 mg 25, 37.5, 50, 75, 100 mg tabs 37.5 mg/day 75-375 mg Nausea Effexor XR® Used for neuropathy/ chronic pain conditions (off- XR: 37.5, 75, 150, 225 mg caps Sexual dysfunction label) Inhibits the reuptake Increase BP (dose desvenlafaxine Pristiq® Adjust in renal impairment 50 mg/day 50 mg of serotonin and related) 50, 100 mg tabs Khedezla® Khedezla® is ER form norepinephrine Insomnia Increased Sweating Not recommended in hepatic dysfunction duloxetine Also indicated for neuropathic and chronic pain 20, 30, 60 mg delayed release Cymbalta® 20-30 mg/day 60-120 mg capsules (pellets) Doses higher than 60 mg have not shown additional benefit (although sometimes used) Phenylpiperazine (Serotonin Partial Antagonist/Reuptake Inhibitors- SPARI) Inhibits reuptake of Diarrhea vilazodone Viibryd® 10 mg/day 40 mg serotonin Nausea/Vomiting 10, 20, 40 mg tabs 5HT1A agonist Insomnia Major Depressive Disorder  Generic Brand Initial Dose Usual Daily MOA Side Effects Comments Inhibits reuptake Dizziness nefazodone Serzone (brand of serotonin and Loss os strength, Infrequently used due to black box warning for 200 mg/day 300-600 mg norepinephrine 50, 100, 150, 200, 250 mg tabs discontinued) weakness (asthenia) Hepatic Failure. 5HT2 antagonist Sedation Triazolopyridine (Serotonin Antagonists/Reuptake Inhibitors - SARIs) Desyrel® (brand Inhibits reuptake of 150 mg/day 150-600 mg discontinued) serotonin Oleptro® is the ER version of trazodone Integrated Pharmacotherapy 3 trazodone SEDATION Blocks 5-HT2A and H1 Priapism (1/7000), rare but considered a medical 50, 100, 150, 300 mg tabs receptors Orthostatic hypotension emergency ER: 150, 300 mg tabs Oleptro® 150 mg/day 150-375 mg Priapism Blocks α1-adrenergic Commonly used in lower doses ( 9 mg/24 hours it loses selectivity and requires 6, 9, 12 mg/24 hour patch dietary interventions Major Depressive Disorder DRUG DISTRIBUTION, ACTION, EFFECTS AND THERAPEUTIC CONSIDERATIONS Properties Common to All Antidepressants Drug Distribution Where do the antidepressants need to distribute to in the body to produce their antidepressant effect? While antidepressants produce pharmacologic effects throughout the body, their general site of action for producing an antidepressant effect is in the CNS. This means that antidepressants must cross the blood-brain barrier in order to produce their desired pharmacologic effect. The blood-brain-barrier is a specialized layer of endothelial cells lining the capillaries of intracranial vessels that uses tight junctions and a basement membrane to limit permeability. The rate and amount of antidepressant distribution into the CNS via crossing the blood-brain barrier involves several mechanisms, including: 1. Passive diffusion across the blood-brain barrier due to relatively small molecular size and relatively high lipophilicity. Drugs that passively diffuse well across the blood-brain barrier accumulate well in CNS tissue. 2. Active transport from the blood-brain barrier back into the peripheral blood supply by P-glycoprotein (Pgp). Pgp is an efflux protein located in several places in the body. Pgp works to exclude drug from the body, or from specific areas in the body. For example, in the gastrointestinal tract Pgp pumps some drugs back into the lumen as the drug is being absorbed across the lumen wall. This delays and may decrease oral absorption. At the blood-brain barrier, Pgp pumps many drugs back into the peripheral blood as they try to cross into the CNS. This is a relatively new area of research, and it is not known how many antidepressants undergo Pgp efflux, but it is believed to be common and likely contributes to regulating the rate and amount of antidepressant distribution into the CNS. What would happen if a patient took a drug that inhibited the Pgp efflux protein and also took an antidepressant that was a substrate for Pgp efflux? Effects on Monoamine Neurotransmitters: Evidence for the Monoamine Theory of Depression Most currently marketed antidepressant medications increase the concentration of monoamine neurotransmitters (5-HT, NE, DA) in the synaptic cleft. Some antidepressants are selective for affecting a single neurotransmitter, while others affect multiple neurotransmitters. Most antidepressants produce this effect by inhibiting the transporter that takes up neurotransmitter from the synaptic cleft into the presynaptic neuron (reuptake inhibition), but some work by other mechanisms (Figure 9). At this time, there is no compelling evidence that increasing synaptic concentrations of one neurotransmitter over another neurotransmitter provides additional efficacy for management of MDD. In other words, antidepressants that are selective for increasing 5-HT are not consistently more or less efficacious than those that are selective for NE or not selective at all. As a result, other factors, such as adverse effects and family history, often helps determine which drugs are used first- Figure 9. Antidepressant mechanisms of action line and which drugs are used when first-line Presynaptic Terminal drugs fail to produce adequate effects. Fused vesicle The fact that drugs which produce an releasing NE or 5-HT MAOIs inhibit MAO activity antidepressant effect have this general mechanism in common provides evidence for the “monoamine - NE / 5-HT theory” of depression that was mentioned above in Inactivation of NE or 5-HT the pathophysiology section of these notes. MAO Potency and Selectivity of Monoamine Reuptake Inhibition NE / 5-HT - Reuptake The potency of a drug for inhibition of monoamine Transporter neurotransmitter reuptake is measured by the affinity of a drug to bind with reuptake transport proteins. This affinity is expressed as a Ki which Most antidepressants block reuptake is analogous to a Kd except it refers to a drug that binds to and inhibits a protein or receptor (if you Norepinephrine or Serotonin Receptors do not remember what a Kd is then please review the notes from IP 1 Drug Receptors: Biochemistry and Pharmacology). Postsynaptic Terminal Integrated Pharmacotherapy 3 15 Major Depressive Disorder Figure 10. NE versus 5-HT reuptake inhibition selectivity of antidepressants Amitriptyline Duloxetine Desvenlafaxine Desipramine Imipramine Escitalopram Norepinephrine Serotonin Reuptake Inhibition Reuptake Inhibition = SSRI Nortriptyline Fluoxetine = SNRI Paroxetine Venlafaxine Citalopram = Tertiary Amine TCA = Secondary Amine TCA Note: Not drawn exactly to scale If one drug has a numerically larger Ki for binding to the 5-HT reuptake transporter than another drug, is it more or less potent? The selectivity of a drug for inhibiting the reuptake of one monoamine neurotransmitter relative to another monoamine neurotransmitter is measured by comparing the Ki of the drug for binding to each monoamine transporter. Specifically, the largest Ki is divided by the smallest Ki to give the relative selectivity. This number represents the degree of selectivity for reuptake inhibition of the monoamine neurotransmitter with the smallest Ki relative to the monoamine neurotransmitter with the highest Ki. For example, escitalopram is highly selective for inhibition of 5-HT reuptake relative to NE reuptake. This is determined by comparing the Ki of escitalopram for binding to the 5-HT reuptake transporter (1.1 nM) and the NE reuptake transporter (7840 nM). The relative selectivity is 7840 nM divided by 1.1 nM, or 7127. Of the Table 6. Affinity and Selectivity Data for 5-HT and NE Reuptake Inhibition two escitalopram Ki values, 5-HT is the lowest, meaning Reuptake Transporter Ki (nM) Selectivity that escitalopram binds with higher affinity (potency) to the 5-HT reuptake transporter. The very large relative selectivity Antidepressant Norepinephrine Serotonin for NE or 5-HT number 7127 tells us that escitalopram is highly selective for Amitriptyline 34.5 4.33 7.97 5-HT reuptake inhibition, which is why it is classified as a tertiary amine TCA selective serotonin reuptake inhibitor (SSRI). Imipramine 37 1.41 26.2 tertiary amine TCA Table 6 provides Ki and relative selectivity data for several antidepressants, and Figure 10 expresses the relative Nortriptyline 4.35 18.5 4.25 selectivity in a visual manner. secondary amine TCA Desipramine You are not expected to memorize the data in this table; 0.83 17.5 21.1 secondary amine TCA rather, you should be able to use data like that presented Citalopram in Table 6 to answer questions regarding antidepressant SSRI 5100 1.38 3696 potency and selectivity. For example, consider the following Escitalopram questions: SSRI 7840 1.1 7127 1. Is amitriptyline more or less potent of an inhibitor of Fluoxetine 244 0.810 301 5-HT reuptake than nortriptyline? SSRI Paroxetine 2. Is amitriptyline more or less selective for 5-HT reuptake 40 0.125 320 SSRI inhibition relative to NE reuptake inhibition than Sertraline nortriptyline? 417 0.293 1423 SSRI 3. If the far-right column (NE or 5-HT selectivity) was not Venlafaxine 1060 9.10 116 provided, how would you calculate the selectivity? SNRI Duloxetine Time Course of Drug Action 11.2 1.55 7.23 SNRI (See Approach to Treatment section for more information) Adapted from Goodman & Gilman’s Pharmacologic Basis of Therapeutics, 11th edition, Antidepressants are somewhat pharmacologically unique, table 17-2. in that they produce their effect of increasing synaptic Integrated Pharmacotherapy 3 16 Major Depressive Disorder neurotransmitter concentration immediately (i.e., as soon as the drug Figure 11. Antidepressant time course of action has absorbed and distributed into the CNS), but they do not produce an antidepressant effect in most patients until several (4-6) weeks of drug therapy Administration of Antidepressant have passed. Some recent research suggests that simultaneous reuptake blockade of both NE and 5-HT may result in faster onset of relief of depression Absorption from GI tract Distribution into CNS across blood-brain barrier symptoms, particularly in depression resistant to initial therapy, but more research is needed before this theory can be accepted as fact. This concept ↑ Synaptic Neurotransmitter Concentration (5-HT, NE, DA) of the effect of antidepressants on neurotransmitters relative to onset of antidepressant action is also depicted in Figure 11. Secondary antidepressant effects (2 - 4 weeks for initial response, 4 - 6 weeks for full response) CNS Events Secondary to Increased Synaptic Neurotransmitter Concentration Antidepressant Effects As mentioned, antidepressants cause their effect of increasing synaptic neurotransmitter concentrations immediately (i.e., as soon as the drug has absorbed and distributed to the site of action in the CNS). However, antidepressants do not produce an antidepressant effect (in most patients) until at least 2-4 weeks of continuous therapy have passed (sometimes longer). Based on these observations, it is clear that the mood enhancing effect of antidepressants is more than simply increasing synaptic neurotransmitter concentrations. In other words, after the increase in synaptic neurotransmitter concentration, an additional mechanism is involved in the antidepressant effect. This additional mechanism may be considered secondary antidepressant effects. Over the years, neuropharmacologists have identified many secondary CNS effects of antidepressants. At this time, no one is certain as to which of these effects or which combination of these effects actually results in an improvement of depression symptoms. The following is a selected list of possible secondary CNS antidepressant effects that may improve symptoms of depression: Increased cyclic AMP (cAMP) production in postsynaptic neurons leading to increased neuronal growth and sprouting. Increased expression of neurotrophic factors (proteins that increase neuronal growth) including BDNF. Downregulation of postsynaptic 5-HT and NE (adrenergic) receptors. It must be emphasized that at this time it is simply unclear as to which secondary antidepressant effect(s) contribute to the effects of antidepressants. This is an ongoing area of neuropharmacology research. In summary, antidepressants: 1. increase the concentration of monoamine neurotransmitters in the synaptic cleft, and 2. cause long term CNS effects secondary to their effects of increasing synaptic neurotransmitter concentrations that lead to a decrease in MDD symptoms. Effects at Receptors Most antidepressants are antagonists at one or more receptors in both the CNS and the PNS. Important receptors blocked by antidepressants include autonomic receptors (alpha-adrenergic and cholinergic) and histamine receptors. The degree to which each antidepressant blocks these receptors plays a large part in determining their respective adverse effect profiles. Because antidepressants interact with autonomic receptors, the autonomic receptor and effect table (Appendix A on page 34) that you were introduced to in IP 2 Hypertension is included in these notes. Focusing on the effects of cholinergic and alpha-adrenergic receptors on the tissues and organs listed in Appendix A will be helpful for understanding the adverse effects of antidepressants. Discontinuation / Withdrawal Syndrome Antidepressant therapy gradually results in changes in neurotransmission over the course of weeks of drug therapy. As a result, certain functions in the CNS and PNS become somewhat dependent on antidepressant action. If antidepressant therapy is withdrawn abruptly or the dose is decreased too rapidly then adverse effects may occur. These adverse effects are collectively called discontinuation syndrome or serotonin withdrawal syndrome. The symptoms of serotonin withdrawal syndrome include anxiety, crying spells, insomnia, nausea, vomiting, paresthesias and flu-like symptoms. You may also hear patients describe a shock-like sensation in their head as “brain zaps.” This syndrome is a risk with virtually all antidepressants but is especially common with the SSRIs (especially paroxetine) and the SNRI venlafaxine. Serotonin withdrawal syndrome is unpleasant and uncomfortable and is not associated with causing death like serotonin syndrome which is discussed later. For an easy way to remember the symptoms of serotonin withdrawal syndrome think of the acronym “FINISH”: F = Flu-like symptoms I = Insomnia N = Nausea Integrated Pharmacotherapy 3 17 Major Depressive Disorder  I = Imbalance (gait instability, dizziness) Figure 12. SSRI chemistry S = Sensory disturbances (paresthesias “shock like” sensations/spontaneous crying spells) H N H = Hyperarousal (anxiety, agitation) O Within the SSRI class, the risk and severity of serotonin withdrawal syndrome F F is generally inversely proportional to the elimination half-life of the individual F O antidepressant (Table 8 on page 23). That is, antidepressants with shorter half- O O N lives have a greater risk for causing discontinuation or withdrawal syndrome. A H F drug with a short elimination half-life leaves the body rapidly, and blood levels Fluoxetine Paroxetine can fall quickly upon withdrawal of therapy or a dose decrease. Drugs with a long elimination half-life (fluoxetine) leave the body more slowly, and blood concentrations decrease in a slower manner, resulting in less chance of causing Cl NH adverse effects related to a rapid decrease in drug effect. Cl Sertraline Selective Serotonin Reuptake Inhibitors (SSRIs) The SSRIs are currently the most important and popular antidepressants in terms of first-line use and number of prescriptions filled. Their popularity is not due Figure 13. Citalopram and escitalopram chemistry to better antidepressant efficacy relative to other antidepressants, but rather to an improved safety and adverse effect profile as compared with older antidepressants N N such as the TCAs and MAOIs. O O As their name suggests, SSRIs are highly selective for binding to the 5-HT N N reuptake transporter relative to the NE reuptake transporter, and at normal doses essentially only block the reuptake of 5-HT (see Table 6 on page 16). The most recent addition to this class, vortioxetine (Trintellix®), was approved F F in September 2013. In addition to selectively inhibiting serotonin reuptake (Ki R-Citalopram S-Citalopram for 5-HT transporter is 1.6 nM versus 113 nM for norepinephrine transporter), Celexa® is a racemic mixture of R- and S-citalopram vortioxetine also has significant affinity for several 5-HT receptors. It is a full agonist at presynaptic 5-HT1A receptors, a partial agonist at 5-HT1B receptors, and N an antagonist at 5-HT3, 5-HT7, and 5-HT1D receptors. O N SSRIs are chemically diverse and most lack a common pharmacophore (Figure 12). SSRIs are halogenated, which increases their lipophilicity and therefore increases their penetration across the blood-brain barrier into the CNS. Also of importance is the chemistry of citalopram compared with escitalopram (Figure F 13). Citalopram is formulated as the racemic mixture while escitalopram is an S-Citalopram enantiomerically pure drug containing only S-citalopram, the active enantiomer Lexapro® is an enantiomerically pure preparation (refer to the notes from the IP 1 unit “Principles of Pharmacodynamics and of S-citalopram (escitalopram) SAR” if the term enantiomerically pure is not clear). Escitalopram is the most selective inhibitor of 5-HT reuptake currently marketed. It MAY offer an improvement over citalopram because R-citalopram Figure 14. SNRI chemistry (contained in racemic citalopram) may decrease the efficacy of S-citalopram by allosteric binding to a low-affinity site on the 5-HT transporter. In other words, the inactive enantiomer N N R-citalopram binds to another site on the 5-HT transporter and OH OH decreases the ability of the active enantiomer (S-citalopram) to CYP2D6 inhibit 5-HT reuptake. O HO The improved safety profile of SSRIs relative to other classes of antidepressants is largely due to their lack of antagonist activity Venlafaxine Desvenlafaxine at other receptors, particularly alpha-adrenergic, cholinergic N and histaminic receptors. Table 4 on page 16 compares the H S adverse effects due to blockade of these receptors for various O antidepressants. For example, their lack of antagonist activity at cholinergic receptors results in a lack of anticholinergic adverse effects (dry mouth, constipation, urinary retention) relative to other antidepressants. Duloxetine However, SSRIs are not void of adverse effects. Adverse effects include nausea, diarrhea/constipation, agitation, insomnia Integrated Pharmacotherapy 3 18 Major Depressive Disorder OR sedation, weight gain, and changes in sexual function (e.g., decreased libido, anorgasmia, erectile dysfunction). At higher doses, patients are at a rare risk for serotonin syndrome, especially when combined with other medications that modulate synaptic serotonin levels. Serotonin syndrome is a result of excessive blockade of 5-HT reuptake (see Clinical Monitoring section below for symptoms). An initial increase in anxiety can occur that typically goes away after