Introduction to Psychopharmacology: A Practical Clinician's Guide by John Preston, Psy.D., ABPP 3 Credit hours - $74 Last revised: 02/04/2008 Course content © copyright 2004-2008 by John Preston, Psy.D., ABPP. All rights reserved. ContinuingEdCourses.Net is approved by the American Psychological Association (APA) to sponsor continuing education for psychologists. ContinuingEdCourses.Net maintains responsibility for this program and its content. ContinuingEdCourses.Net is approved by the Association of Social Work Boards (ASWB) to offer continuing education for social workers, through the Approved Continuing Education (ACE) program. ContinuingEdCourses.Net maintains responsibility for its courses. ASWB provider #1107. ContinuingEdCourses.Net is approved by the National Board for Certified Counselors (NBCC) as an NBCC-Approved Continuing Education Provider (ACEP) and may offer NBCC-approved clock hours for events that meet NBCC requirements. ContinuingEdCourses.Net solely is responsible for all aspects of the program. NBCC provider #6323. ContinuingEdCourses.Net is approved by the California Board of Behavioral Sciences (CA-BBS) to offer continuing education for MFCCs (MFTs) and LCSWs. CA-BBS provider #3311. ContinuingEdCourses.Net is approved by the Ohio Counselor, Social Worker, & Marriage and Family Therapist Board (OH-CSWMFT) to offer continuing education for counselors, social workers, and MFTs. OH-CSWMFT provider #RST080501 & #RCX010801. Take the Course Take the Test Buy your Certificate

Learning Objectives

This is a beginning level course. After completing this course, mental health professionals will be able to:

• Discuss ethical and legal considerations in providing information about medications to clients
• Explain medication treatment algorithms for depressive disorders, anxiety disorders, ADHD, and bipolar spectrum disorders
• Troubleshoot treatment resistant cases of depression
• List experimental treatments for these disorders and the data supporting them
• Communicate effectively with patients, primary care physicians and psychiatrists

Introduction

This online continuing education course is designed to teach the basics of clinical psychopharmacology for practicing psychotherapists. The focus will be on three groups of commonly encountered clinical conditions: mood disorders (depression and bipolar spectrum disorders), anxiety disorders and ADHD. An assumption is made that you are very familiar with psychopathology and DSM-IV diagnostic criteria, however there will be supplemental diagnostic information presented in this course as it applies to treatment decision making. Since DSM-IV was published more recent epidemiological studies and new findings in the neurosciences have influenced changes in some diagnostic criteria, and thus these will be addressed in this course. In addition there will be brief mention of neurobiology and pathophysiology associated with certain clinical conditions, although a comprehensive discussion of these topics is beyond the scope of this course (see J. Cooper, et al. 2003 and Preston, et al., 2008 for a more detailed review). The primary focus of this course is to provide a current overview of psychopharmacologic treatment guidelines. Many of these are derived from large-scale empirical studies (often referred to as algorithm studies). Treatment guidelines do not represent personal opinions of the author, but rather are presentations of algorithms that have been developed by NIMH supported programs, guidelines from the American Psychiatric Association, and the Texas Medication Algorithm Project.

All psychotherapists must be familiar with psychopharmacology for three reasons:

1. It is important to know which disorders may respond to medication treatments so that referrals can be made to an appropriate prescriber. It is a part of informed consent to provide clients with information regarding all viable treatment options for their particular disorder so that they can make choices about which treatment to pursue.
2. It is important to be able to communicate clearly with physicians to whom our clients are referred…to share relevant information about the diagnosis and the client’s response to treatment.
3. In these managed care days, increasing numbers of clients are receiving psychiatric medication treatment in primary care medical settings. Here the amount of time spent with the physician is very limited. Thus our clients often want and need additional information regarding their medication treatment that is not readily available from the primary care doctor. Psychotherapists can be very instrumental in providing important information regarding such issues as: side effects, how much time is required for medications to begin working, realistic expectations for treatment outcomes with medications, etc.

I hope that you will find this course to be helpful in your clinical practice. Also please see the appendix that offers a detailed guide to psychiatric medications (doses, side effects, required lab tests, etc.); this reference may be useful to share with clients.

Chapter One

Ethical and Legal Considerations

A review of case law reveals that there are a number of cases in which non-physician health care professionals have been accused of practicing medicine without a license because they gave patients information regarding their medications and medical treatment. Obviously it is important for all therapists to practice within their scope of practice, to do whatever is in the best interests of our patients and to be on solid ethical ground. It is clear from the existing case law that it is unethical and illegal to tell patients either: 1. stop taking a medication or 2. to change the dose of a medication. This is considered practicing medicine. However, in every case (with one exception addressed below) those who provided information regarding medicines and medication treatment and were accused of practicing medicine without a license were found to be not guilty. In half of the cases, further, the judge said that not to provide information to patients may have been acting in a professionally incompetent manner. Here is what this is based on. First and foremost is the right granted by the first amendment (i.e. right to free speech). Secondly, the following are deemed appropriate to share with patients, if and only if the therapist has training and is knowledgeable regarding the facts of medication treatments:

• Once the diagnosis is made, to tell the patient about treatment options. This is a part of “informed consent” in which the therapist must share with patients their available treatment options (mentioning those treatments that are empirically supported). Thus even if a therapist is not especially fond of pharmacological treatments, it behooves them to share information regarding drug treatments. At the heart of informed consent is a respect for our clients in terms of allowing them to be the final judge in opting for certain treatments.
• Discussion about medication side effects
• Discussion regarding the likely or common positive benefits of drug treatments (i.e. what kinds of symptoms are likely to be improved with medications)
• Discussions regarding the length of time that it may take for medications to begin to show clinical effects
• Limitations of medication treatments
• Underscoring the importance of collaborative treatment, e.g. the value in having both the therapist and the prescribing doctor share information about the course of treatment (e.g. improvement, lack of improvement, emergent side effects, etc.).
• There is one case in which a non-medical clinician was found to be unethical and this was due to the fact that this person only recommended an over-the-counter produce but failed to talk about other available treatment options. As will be discussed below, some over-the-counter products do have empirical support for efficacy in treating some psychiatric disorders, and can be mentioned to patients as options. However, this must be done in the context of presenting all available empirically validated treatment options.

Due to the impact of managed care, many patients are receiving prescriptions for psychotropic medications from primary care physicians who have very limited time to spend with the patients both initially (when the diagnosis is made and treatment is initiated) and in follow-up. This is a significant problem and psychotherapists can provide enormous help to patients by monitoring their medication treatment and providing support and information regarding drug treatments, and be able to do so in ethical and legal ways. Ultimately the care of our patients is paramount.

Preliminary Considerations: Drug metabolism and medication dosing

For each psychiatric medication discussed in this text, you will see listed the typical adult daily doses. In many instances the “therapeutic dosage range” is broad. For example, daily dosing with lithium is between 600 and 2400 mg. or for Prozac, 10-80 mg. per day. It is important to know that the amount of medication required to effectively reduce and eliminate symptoms often has little to do with how severe the symptoms are. And what matters is not so much how much drug is ingested but rather, how much of the medication enters the blood stream.

There are three primary factors that influence the amount of drug that finds its way into the blood stream. First is the rate of liver metabolism. Psychotropic medications are absorbed through the walls of the stomach and intestines and go directly to the liver. Here the drug molecules are acted upon by liver enzymes that begin a process generally referred to as biotransformation. Liver enzymes chemically alter the medication in ways that allow the drug to be more readily excreted from the body. The liver’s function is to detoxify the body. Thus in this so-called “first pass effect” through the liver, a good deal of the drug is chemically transformed and then rapidly excreted from the body. However, some of the medication initially escapes this process, makes its way through the liver and into circulation and thus is allowed to begin accumulating in the blood stream. How rapidly the liver metabolizes drugs depends on a number of factors. This resulting blood level is what matters when it comes to reducing symptoms. (Note: two psychotropic medications are not metabolized in the liver: lithium and Neurontin).

Genes play a significant role in this process. A small percentage of people are known as rapid metabolizers. They take certain drugs and then eliminate them very quickly. The result is that even though they may be taking what seems like an adequate dose of the medication, little actually gets into the blood stream. Once it is discovered that someone is a rapid metabolizer, and then usually they are prescribed very high doses of medications and eventually enough gets into the blood stream to be effective. Again, this has nothing to do with how severely ill they are …it’s just a matter of the liver’s metabolic rate. Conversely are hypo-metabolizers. This also small percentage of people (perhaps 5% of the general population), have fewer than average liver enzymes. The effect is that they can take a “typical” starting dose of a medication, and on its trip through the liver, only small amounts are transformed and excreted. The result is often very high blood levels of the medication and severe side effects or toxicity. The ultimate solution for hypo-metabolizers thus is to use very small doses of medications initially and then increase doses gradually. Sometimes when a person is first treated they will experience serious side effects and this may be due to hypo-metabolizing. It is often hard to know ahead of time if this will happen with any one given individual. Thus if your patient has had an experience of encountering very intense side effects with other medications in the past, one may anticipate that they are a hypo-metabolizer, and thus initial dosing should be low and increased dosing should be done gradually.

A second factor determining blood levels of medications is the functioning of the kidney. Sometimes genetic factors play a role here too, but more often problems can occur due to kidney disease. Thus, for some bipolar medications, in particular, pre-treatment labs will include an assessment of kidney functioning (this is especially important for patients being treated with lithium).

Finally, a number of drugs can adversely affect liver metabolism and thus alter blood levels. Here is where drug-drug interactions can cause significant problems. This applies to some prescription drugs, over-the-counter drugs, herbal and dietary supplement products and recreational drugs. The use of prescription drugs must be carefully monitored by the treating prescriber. In addition, even modest amounts of alcohol can have significant affects on the liver. St. John’s Wort, a popular herbal product for the treatment of depression, is well known for causing some very significant changes in liver metabolism.

Chapter Two: Depression

Introduction

The World Health Organization announced findings from a multi-nation study indicating that currently for women major depression is the second most disabling condition (among all medical and psychiatric disorders). And by the year 2020 it will rank as the number one overall disabling condition, world-wide (males and females combined) (Murray and Lopez, 1996). Each year 25 million Americans suffer from serious depression, it has a life-time prevalence rate of 17% (Kessler, McGonagle, Zhao, et al. 1994), and ranks as the second most commonly seen disorder in patients seeking treatment from primary care physicians. Data suggests that the incidence of depression is increasing (Murray and Lopez, 1996). Morbidity and mortality associated with serious mood disorders is enormous. Suicide is the 8^th leading cause of death in the United States, and chronic and recurrent depressions significantly increase risk for coronary heart disease, stroke, and osteoporosis (NIMH, 2003).

It is estimated that only 25-33% of those who suffer seek treatment. Additionally treatment received is often very inadequate. In the United States most drug treatment for depression takes place in primary care medical settings. Seventy percent of prescriptions written in the United States for antidepressants are written by physicians and nurses that do not have specialty training in psychiatry. This is due in large part to managed care’s efforts to cut costs by having the majority of psychiatric treatment take place in primary care settings. Yet, only 11% of those treated for depression in primary care receive adequate treatment (in terms of dosing, time to response, and follow-up) (Akiskal and Cassano, 1997). In addition, 76.1% of patients treated for depression in primary care settings are seen for two or fewer follow-up visits during the year following the start of treatment (Katz, Kessler, Lin and Wells, 1998).

A Changing Treatment Landscape

The 1980s and 1990s saw the proliferation of HMOs and managed care companies that attempted to streamline mental health care in order to achieve cost containment. During this same time psychiatry training programs have increasingly emphasized psychopharmacology as the mainstay of treatment for clinical depression. Additionally, during the past decade the number of medical students choosing psychiatry as a specialty has dropped by 50%. In years to come, there will be increasing unavailability of psychiatrists, likely further contributing to more and more treatment being conducted in primary care settings. Finally, pharmaceutical advances and market-place forces have had a substantial impact on shifting patterns of practice in the mental health arena (see Figure One).

In many settings psychopharmacology has become the primary or sole form of treatment for many suffering from serious mood disorders. Yet, the vast majority of patients treated either do not respond or only experience partial responses.

Treatment Outcomes

How effective are antidepressants? All drugs must go through rigorous trials prior to FDA approval, and must demonstrate clear superiority over placebos. The currently available antidepressants have all passed the test, but the outcome data is often spurious and plagued by methodological flaws. First and foremost in the majority of pre-FDA approval efficacy studies patients selected for medication trials hardly resemble typical outpatient populations. Patient selection excludes those who have had prior suicide attempts, who have psychotic or bipolar symptoms, and who have co-morbid medical illnesses, substance abuse or Axis II disorders. A recent paper by Zimmerman, Posternak and Chelminski (2002) looked at consecutive patients seen in an outpatient setting who were diagnosed with unipolar, major depression. If patient selection criteria as noted above were applied to this typical group of depressed outpatients, 85% of them would be excluded from drug trials. Complex co-morbidity is the rule, not the exception in usual clinical settings. Thus it may not be appropriate to generalize results from efficacy studies to the real world of clinical practice.

Another significant flaw in the reporting of outcome data is the common practice to exclude dropouts due to side effects from percentages of responders (Gitlin, 2002). Thus, for most antidepressants studied, the positive outcomes are inflated (see Figure Two).

A more appropriate picture of outcome is derived from what are termed Intent-To-Treat (ITT) studies. In these studies, dropouts are considered to be failures (non-responders).

Upon closer inspection, the picture is even less positive than these ITT data suggest. In most studies “responders” are those who achieve a 50% or greater decrease in scores on the Hamilton Depression Rating Scale (Ham-D) or a Ham-D score of 7 or less. In most studies only half of the responders reach Ham-D scores below 14, and although they are significantly improved, they still are not fully recovered. Failure to reach full remission is associated with on-going subclinical symptomatology (often patients report just not feeling enthusiastic about life) and with partial responders there is a three-fold increase in acute relapse of major depression (Paykel, Ramana, Cooper, et al., 1995). Finally, even those judged to be in full remission, often continue to experience subtle residual depressive symptoms. In one study only 18% of “fully remitted” patients were truly asymptomatic (Nierenberg, Keefe, Leslie, et al., 1999).

It must be emphasized that this critique of outcome data is not intended to be an indictment of antidepressants. Quite the contrary, these medications have been shown to be highly effective in alleviating many serious mood disorder symptoms (e.g. vegetative symptoms), undoubtedly have saved many lives, and antidepressants may also be neuro-protective (see below). But they are not a panacea. Such is the case with most medications that are used to treat chronic illnesses such as diabetes, hypertension, cancer, chronic pain, etc. Likewise, most studies of psychotherapies for depression (e.g. cognitive-behavioral therapy, interpersonal therapy, etc.) report success rates in the 50-55% range. It is humbling to appreciate the limits of any single treatment modality.

What has become clear is that mood disorders are tremendously complex and heterogeneous disorders involving numerous interacting variables: e.g. genetic predispositions, life stresses, interpersonal relationships, hormonal, neurobiologic, intrapsychic, cultural and existential features. It is the appreciation of such complexity that has lead to increased interest in integrative approaches to treatment (Preston, 2006).

Abnormal Neurobiology: A Compelling Case for the Use of Antidepressants

A comprehensive review of the neurobiology of depression is beyond the scope of this paper. However, let us consider a few important research findings that have emerged during the past decade. Forty to fifty percent of people experiencing a major depressive episode exhibit a hyperactive hypothalamic-pituitary-adrenal (H-P-A) neuroendocrine axis (see Figure Three). In mammals when danger or adversity is perceived in the environment a number of complex events take place in the nervous system, launching adaptive fight-or-flight responses. One of the most important components of this biological response is the activation of the H-P-A axis, which ultimately releases glucocorticoid hormones into general circulation (in humans to principle glucocorticoid is cortisol). Cortisol operates to facilitate the release of glucose into the blood stream and to increase blood pressure (both of which are essential for mounting an effective fight-or-flight response).

Figure Three.
Hypothalamic-Pituitary-Adrenal Neuroendocrine Axis

Cortisol enters circulation and is distributed throughout the body. In the brain the most prominent site for cortisol response is the limbic brain structure, the hippocampus. In adaptive fight-or-flight responses cortisol activates the hippocampus to inhibit the H-P-A axis (operating like a “brake”). Of course if danger persists in the environment, the H-P-A axis is continuously reactivated. However, when stressors subside, the cortisol-mediated feedback loop shuts down the system, and thus plays a role in affect regulation (LeDoux, 1996).

This hyperactivity of the H-P-A axis, seen in many cases of major depression, results in a condition known as hyper-cortisolemia. Here, cortisol levels are significantly elevated and have been shown to be neurotoxic. These high, sustained, toxic levels of cortisol have a marked impact on hippocampal nerve cells (e.g. cause dendrite retraction, cell death, and hippocampal atrophy). Hypercortisol also may damage other neural tissue (e.g. anterior cingulate, amygdala, cerebellum: all of which have been implicated in playing a role in affect regulation). Over time the result is progressive brain damage that likely accounts for the deteriorating course seen in many cases of untreated or poorly treated recurrent and chronic depression and bipolar illness (Sapolsky, 1996). High cortisol levels in depressed pregnant women cross the placental-blood barrier and may adversely affect the fetus’s nervous system.

Additionally, depression reduces the gene expression of brain-derived neurotropic factor (BDNF), which is a neuro-protective molecule known to facilitate the repair of damaged nerve cells and to promote neuron regeneration (i.e. neurogenesis) in the hippocampus.

Antidepressant medications reduce cortisol levels (Heim and Nemeroff, 2002; Nestler, Hyman, and Malenka, 2001) and reactivate the production of BDNF, (note: lithium and regular exercise also increase the levels of BDNF) which can lead not only to clinical improvement, but also to the birth of new nerve cells in the hippocampus (Kempermann and Gage, 1999). Thus antidepressants can play a crucial role in treating symptoms of depression as well as protecting the brain from the effects of toxic levels of stress hormones.

Diagnostic Issues

For many years a distinction was made between so-called “reactive depressions” (by definition, depressions that emerged in the wake of significant psychosocial stressors) and “endogenous depressions” (presumably due to the effects of certain changes in neurobiology…e.g. genetically based mood disorders, secondary to various medical illnesses such as thyroid disease, or due to the impact of substances, e.g. alcohol, antihypertensive drugs). Currently the distinction between endogenous and reactive depressions is less relevant. The critical diagnostic issues (as this relates to the decision to treat with antidepressants) include the following:

1. Marked dysfunction (social, occupational, etc.) that lasts for more than 2 weeks or fails to respond adequately to psychotherapy.
2. Patients, who are of below-average intelligence, are significantly non-psychologically minded (i.e. unable to introspect), who refuse psychotherapy or who are too impaired to productively participate in psychotherapy.
3. The presence of neurovegetative symptoms (if these are sustained; i.e. present most days):
• Sleep disturbances (especially early morning awakening and middle insomnia)
• Loss of libido
• Anhedonia or a non-reactive mood
• Appetite and weight changes (either increased or decreased)
• Marked fatigue
• Psychomotor retardation or agitation
• Diurnal variations in mood and cognitive ability: generally more pronounced in the morning
4. 66% of patients with dysthymia have been shown to be responders to antidepressants and thus should also be considered for such treatment.
5. Depressions caused by a general medical condition or prescription medications. Typically the treatment strategy is to focus treatment on the general medical condition directly and only use antidepressants if such treatment is unable to resolve the depression. Likewise, a change in prescription medications (e.g. changing the type of antihypertensive medication used to treat high blood pressure to a different class of antihypertensive) may be effective in reducing depressive symptoms. However, if not the addition of an antidepressant may be considered.

Psychopharmacology

Antidepressant Medications

Antidepressants and daily adult dose ranges (only the newer generation antidepressants, which are in common use, are listed below. These medications have been developed since the late 1980s and are considerably safer and easier to tolerate than older-generation tricyclic and MAOI antidepressants

Pharmacologic Treatment Guidelines

During recent years large-scaled empirical studies have been designed in order to establish guidelines for what is currently referred to as “evidence-based medicine”. These include the STAR-D (Sequenced Treatment Alternatives for Relieving Depression: a multi-site study sponsored by the National Institute of Mental Health), the Texas Medication Algorithm Project and UCLA’s Targeted Treatment for Depression Program (Metzner, 2000). Treatment guidelines in psychiatry have been influenced by three factors: 1. Market-place variables (e.g. pharmaceutical company advertising; decisions made by HMO’s to adopt cost-effective drug formalities), 2. Consensus (i.e. invite “experts” to convene a panel and discuss pros and cons of various medical treatments and agree upon best treatment strategies), and 3. results from a large amount of research regarding treatment outcomes. The latter of these offer important information, but are also inherently flawed because most psychopharmacology outcome studies are sponsored by drug companies who have a vested interest in producing good outcomes. The major drawback here is that many null studies never make it into the journals. Thus it is difficult to realistically evaluate the effectiveness of certain treatments with primarily positive outcome data available.

The large-scaled studies mentioned above are funded by the NIMH, Texas Department of Mental Health, and a university, respectively, and thus may more accurately reflect realistic outcome data, non-influenced by the profit motives of drug companies. Also, the studies are not ones of consensus opinions, but rather based on empirical outcomes with very large groups of subjects.

What is summarized below are the first of what promises to be a growing body of evidence-based data that can suggest specific strategies for the treatment of major depression.

First-Line Medication Choices: Major Depression

(Metzner, 2000; Shelton and Tomarken, 2001).

Major depression as defined by DSM-IV criteria (APA, 1994) represents a heterogeneous group of mood disorders that vary in terms of severity (mild-to-severe), clinical/symptomatic presentation and presumed etiology. A large body of neuroscience research has strongly implicated that dysregulation of certain central neurotransmitters may be associated with particular psychiatric symptoms. Most individuals that experience a decreased availability of neurotransmitters such as serotonin (abbreviated 5-HT) dopamine (DA) or norepinephrine (NE) do not develop clinical depression (Delgado, Charney, Price, et al., 1990). However, some do, which is likely due to underlying genetic or other vulnerability factors. Among depressed subjects inadequate functioning of 5-HT, DA, or NE can contribute to certain core depressive symptoms such as a depressed mood, pessimistic and negative thinking, guilt, low self-esteem, and fatigue. What has emerged during the past two decades of research are general but consistent findings suggesting that beyond common, core symptoms of depression particular neurotransmitter dysfunctions may be accompanied by or cause specific symptoms:

• Serotonin Dysregulation: irritability, impulsivity, suicidal impulses/behavior, ruminations
• Dopamine and/or Norepinephrine Dysregulation: apathy, anhedonia, low motivation, psychomotor symptoms

Closely paralleling these findings from neuroscience research are data from empirical pharmacologic studies (e.g. Metzner, 2000), which have led to the following guidelines in which particular symptomatic features point toward first-line antidepressant medication choices:

Major Depressive Disorder (MDD) Treatment Algorithm: Choosing a First-Line Antidepressant

• Major Depression with agitation and/or co-morbid anxiety (represents about 50% of cases of major depression). Medications recommended: Selective Serotonin Re-uptake Inhibitors (SSRIs: Prozac, Zoloft, Paxil, Luvox, Celexa, Lexapro). It is likely that SNRIs (serotonin and norepinephrine reuptake inhibitors such as Effexor and Cymbalta) may also be useful in this group of depressed patients, however, this has not been adequately studied as of yet. Additionally, patients that present with irritability, impulsivity, rumination and/or significant suicidal ideations may also preferentially respond to these serotonin-specific antidepressants. Although these agents may prove to be effective in treating agitated/anxious depressions, a significant problem is commonly encountered as treatment begins. This is a side effect referred to as activation; which is experienced as increased energy, anxiety, initial insomnia, and/or agitation typically emerging several hours after taking the first dose. In individuals with this version of MDD, such acute onset side effects often result in abrupt patient-initiated discontinuation (the side effects often scare patients and may make them very reluctant to go through another antidepressant trial). Thus although after 4-6 weeks of treatment SSRIs often begin to significantly reduce both depression and anxiety symptoms, the initial few weeks of treatment can be very challenging and many patients drop out of treatment. A popular and effective way to address this problem is to initially co-administer a benzodiazepine (i.e. minor tranquilizer, e.g. Ativan), using this drug to rapidly reduce anxiety, agitation, and drug-induced activation. In addition, since benzodiazepines begin to reduce anxiety within an hour of taking the medication, the experience for many patients is that they feel noticeably better, quickly. This is an added benefit because it often leads to hopefulness about treatment and enhances compliance. Generally, after one month of treatment the benzodiazepine can be phased out. This is often a very successful strategy, however there is one important warning. Since benzodiazepines can be drugs of abuse, the use of these agents is risky and not indicated if there is a history of alcohol or substance abuse. With an addiction history, many psychiatrists are now using the non-habit-forming anticonvulsant, Neurontin (gabapentin) or the new-generation antipsychotic, Seroquel to target the activation and initial anxiety. Please note: Seroquel may be helpful in reducing anxiety and activation even in individuals who have no psychotic symptoms. It is increasingly being used to help promote sleep and reduce anxiety. These approaches are often successful, but are considered to be experimental and have not as yet been subjected to rigorous research.
• Major Depression with marked anhedonia, apathy, amotivation, and psychomotor retardation (represents about 30-35% of MDDs). The recommended antidepressants are Wellbutrin (that targets DA and NE) and norepinephrine reuptake inhibitors (NRIs) e.g. Strattera (note: new NRIs are likely to be released on the market in the near future).
• Atypical Depression (15-20% of MDDs). Atypical symptoms include: hypersomnia, appetite increase, carbohydrate craving and subsequent weight gain, and severe fatigue. Other symptoms often associated with atypical MDD are: rejection sensitivity and anxiety attacks. Medications of choice are SSRIs, monoamine oxidase inhibitors (MAOIs) and possibly Wellbutrin (APA, 2003). Note that Wellbutrin may increase anxiety; thus, if anxiety symptoms are present, this drug may be contraindicated. It is important to exercise caution when treating atypical MDD because many such individuals may be expressing the depressive phase of bipolar illness, and if treated with antidepressants alone there is a risk of switching (i.e. provoking mania or hypomania) or cycle acceleration (the tendency to cause increasingly severe or more frequent mood episodes). It has been found that 75% of those suffering from atypical depression ultimately are discovered to have bipolar disorder (usually, bipolar II). More will be said about switching and cycle acceleration in the section below on bipolar illness.
• Very Severe and/or Highly Recurrent Cases (symptoms can be anxious, anergic, or atypical) These more severe and recurrent disorders appear to respond best to dual action antidepressants such as Effexor (NE and 5-HT), Cymbalta (NE and 5-HT), Remeron (NE and 5-HT), or the combination of an SSRI and Wellbutrin (this combination actually becomes triple action, i.e. targeting NE, DA, and 5-HT).

Metzner (2000) has demonstrated that targeted treatment for depression (i.e. TTD) where the choice of a first-line antidepressant is based on the presenting clinical picture (as outline above) yields superior outcomes compared to standard (STD) treatment as usual. Positive responses to antidepressants: STD = 65%, TTD = 96%.

Partial and Non-Responder Strategies

Fifty-five to sixty-five percent of patients treated with antidepressants only experience a partial response or no response at all (Paykel, Ramana, Cooper, et al., 1995; Doraiswamy, Kahan, Donahue and Richard, 2001). And as noted earlier, those who do not reach full remission incur an increased risk of relapse (Paykel, Ramana, Cooper, et al., 1995). Empirical studies are beginning to provide databased treatment guidelines for partial or non-responders (see Texas Department of Mental Health, 2003 and NIMH: STAR-D Program, 2003).

It must first be recognized that a number of factors may account for less than adequate antidepressant responses, including the following:

• Poor compliance
• Unreported substance abuse (in particular, alcohol use/abuse which may both exacerbate depressive symptoms and interfere with the metabolism of antidepressant medications)
• Unsuspected medical illnesses (e.g. sleep apnea or thyroid disease)
• Failure to address key psychological conflicts and/or family based psychopathology
• Choice of wrong class of antidepressant medication (e.g. pharmacologically targeting the serotonin system when in fact a particular patient’s depression is associated with dysregulation of norepinephrine)
• Chronic residual brain impairment sustained during previous untreated or inadequately treated depressive episodes (due to hypercortisolemia)

Partial Responder Strategies: (Trivedi and Klieber, 2001): the highest yield next step strategy is to progressively increase the medication dose. This was also born out in the STAR-D program that demonstrated better outcomes for very ill and treatment resistant cases by using high doses of antidepressants. Some patients who are hyper-or rapid metabolizers require higher doses to achieve adequate blood levels. The doses can be progressively increased if tolerated. If this strategy is ineffective or impossible owing to emergent side effects, step two is to augment (i.e. to add an additional medication to the current drug). Augmentation strategies often yield good responses in 35-65% of those treated. The following are common augmentation strategies that often are successful:

• SSRI plus Wellbutrin
• SSRI plus stimulant (e.g. Ritalin) for anergic depressions
• Antidepressant plus Lithium (generally Lithium levels of 0.4 – 0.6 mEq/l)
• Combining Effexor and Remeron (Stahl, 2000)
• SSRI plus atypical antipsychotic (e.g. Zyprexa) (Shelton, Tollefson, Tohen, et al., 2001). Note: this strategy is often successful in treating partial responders who have major depression without psychotic features. Several of the new-generation, atypical antipsychotics appear to have mood stabilizing and antidepressant properties (e.g. Zyprexa, Risperdal, Geodon, Abilify)
• Antidepressant plus T3 (triiodothyronine), 25-50 micrograms per day

Non-Responder Strategies (Trivedi and Klieber 2001): Once again one must evaluate issues involving compliance and possible substance abuse. Should these issues be ruled out, then the highest yield next step strategy is to optimize the dose (dosage increases, if tolerated). Should a high dose be reached and there is still little or no response, then the next step strategy is to change classes of medications (e.g. switch from a serotonin active drug [SSRI], e.g. Zoloft, to an antidepressant that targets norepinephrine [e.g. Strattera] or dopamine [e.g. Wellbutrin]).

Phases of Treatment

There is general agreement among research groups that the treatment of major depression involves three phases (American Psychiatric Association, 2003; Texas Department of Mental Health, 2003):

Acute Phase: Starts with the first dose and extends until the patient is asymptomatic. Since symptoms have abated, many clients will naturally think that they no longer need medications and will discontinue (against medical advice). At this point in treatment should patients discontinue, more than one-half will experience an acute relapse within a few weeks (Stahl, 2000). On-going antidepressant treatment, however, decreases the likelihood of acute relapse, necessitating the next phase:

Continuation Phase: Continue treatment at the same dose for a minimum of 6 months. If during this time period there are no break-through depressive symptoms, then discontinuation can be considered (gradual discontinuation, e.g. over a period of six weeks is strongly recommended to avoid discontinuation withdrawal symptoms).

Maintenance Treatment: Life-long treatment is strongly indicated for patients with highly recurrent major depressions (e.g. those in their 3^rd or subsequent episodes). Chronic treatment attempts to prevent recurrence.

Treatment of Depressive Sub-types

Minor depression: Patients suffering from dysthymia have shown a very positive response to antidepressant medication treatments (33% good response, 33% very good response) (Akiskal and Cassano, 1997).

Seasonal depression: Often responds to high-intensity light therapy, generally provided by the use of a commercially available light box. The typical “dose” of light therapy is 10-30 minutes of exposure to a light source that emits a minimum of 2500 lux. The light has an impact by striking the retina, which activates a specific nerve pathway (the retinal-hypothalamic nerve). In most cases, high-intensity light therapy must be accompanied by the use of antidepressant medications (Blehar and Rosenthal, 1989; Terman, Terman, and Ross, 1998). Note that many seasonal mood disorders are associated with bipolar illness and thus one must exercise caution in using bright light therapy to prevent a shift into mania.

Pre-Menstrual Dysphoric Disorder (PMDD). If mood symptoms are only seen for discrete periods of time prior to menstruation and absent the rest of the month, acute treatment with SSRIs is often successful (while all other mood disorders require 2-6 weeks of treatment prior to the first signs of clinical improvement, many of those suffering from PMDD realize symptomatic relief a few hours after taking the first dose of an SSRI). Often this strategy allows the PMDD patient to avoid chronic medication use (i.e. needing to take the medication only during those days each month when mood symptoms are present). (Nutt, 2002).

Treatment of Psychotic Depressions

Success rates for treating psychotic disorders with single agents are generally poor (American Psychiatric Association, 2003). Thus the combined use of antidepressants and antipsychotics are required.

Phases of treatment for psychotic depression recommend a period of one-year continuation treatment with both antidepressants and antipsychotics before a trial discontinuation. Premature discontinuation is associated with a high risk of acute relapse. And poorly treated psychotic depressions carry a higher risk of suicide than do other forms of MDD. Should pharmacologic treatment fail, ECT (electroconvulsive/shock therapy) is often highly effective.

Highly Treatment Resistant Cases

If despite standard treatments or augmentation strategies there is still little or no response, be sure to re-assess for the presence of:

• Un-reported substance abuse
• Undiagnosed sleep apnea (often causes depressions that fail to respond to standard antidepressant treatments)
• Unsuspected occult illnesses (e.g. endocrine disease, cancer, etc.)
• Undiagnosed bipolar disorder (bipolar depressions are often especially difficult to treat and treatment with antidepressants at times can aggravate the disorder causing switching and/or cycle acceleration)
• Other possible factors:
1. Secondary gain
2. Unaddressed psychological issues (e.g. internal conflicts or unmourned losses)
3. Psychologically toxic interpersonal environment that has not been addressed (e.g. no intimacy, emotional abuse, domestic violence).

Experimental Treatments

A number of experimental treatments have emerged during the past five years, including: repetitive transcranial magnetic stimulation (George, 2003), vagus nerve stimulation, omega-3 fatty acid supplementation (Peet and Horrobin, 2002), exercise therapy (Lawlor, and Hopker, 2002), SAM-e, and St. John’s Wort.

Repetitive Trans-Cranial Magnetic Stimulation (rTMS): is a technology that uses a powerful electro magnet, which is able to stimulate the brain. Treatments generally last from 10-20 minutes during which an electro magnet is placed next to the left frontal part of the skull. During the treatment, approximately 1000 surges of powerful magnetic energy are delivered which penetrates the skull affecting metabolic functioning in the brain tissue in the underlying left frontal lobe. This treatment causes virtually no side effects (the exception is that about 1.5% of people experience a seizure). There is no loss of consciousness. Like ECT, treatments are given three times a week for 3-4 weeks. The literature on rTMS suggests that it is a rapid and effective treatment for some cases of severe depression. As with ECT acute relapses do occur after the rTMS treatments stop and thus people are concurrently treated with mood stabilizers or antidepressants to avoid relapse. This is a promising new approach, but it is still considered to be experimental.

Vagus Nerve Stimulation: is a technique that was initially developed to treat some forms of severe epilepsy. It has been found to be effective in successfully treating about 50-60% of people who suffer from highly treatment-resistant depressions. A pacemaker-like device is implanted in the chest wall (beneath the collar bone) and a wire extends up into the neck where it is wrapped around the vagus nerve. Periodically a mild electrical stimulation is delivered to the vagus nerve, which causes nerve activity that enters the brain. This also appears to be a promising new treatment for some cases of severe depression.

Omega-3 Fatty Acids: are dietary supplements that have some research support as effective agents in reducing the severity of bipolar mood swings and major depression (when added to standard medication treatments (Stoll, et al. 1999). The use of Omega-3 fatty acids is described in more detail in the section below on the treatment of bipolar disorder.

SAM-e (S-adenosylmethionine): is a naturally occurring bio-molecule found in most living cells. It is felt to be necessary for carrying out a number of important intra-cellular chemical reactions. SAM-e has been used in Europe for more than 20 years as a treatment for depression. A number of studies have shown it to be equally effective when compared to prescription antidepressants. Most notable is the virtual lack of side effects. SAM-e may be useful in treating bipolar depression, however one must exercise caution because it has, in fact, been found to switch people with bipolar depression into states of mania. Doses for the treatment of depression range from 400-1600 mg per day, although recent investigations indicate that often the higher doses (1200-1600 mg per day) may be necessary for effectively reducing depressive symptoms. This is available over-the-counter (i.e. not requiring a prescription). It is recommended that if your patient is considering using SAM-e, it should only be taken with close observation by their treating psychiatrist.

St. John’s Wort: is an over-the-counter dietary supplement that has been found to have antidepressant properties. A recent meta-analysis of 22 studies has shown that St. John’s Wort is equally effective to prescription antidepressants in the treatment of mild-to-moderate depression (Whiskey, et al., 2001). This herbal remedy is generally well tolerated with few if any side effects. There are reported cases of possible infertility problems associated with its use, although it is as yet unclear whether this is a common side effect. St. John’s Wort requires daily dosing of 900-1800 mg. per day (taken in three divided doses), and typically the first signs of symptom improvement take about six weeks to emerge. Thus the onset of action is longer than that seen with prescription antidepressants. And as with any other treatment that has antidepressant properties, St. John’s Wort can potentially provoke mania in people with bipolar illness. Caution: although St. John’s Wort, when it is the only medication being taken, appears to be quite safe, it has been found to cause very significant drug-drug interactions. It is strongly advised that patients never take St. John’s Wort without first consulting with their physician or pharmacist.

Combined Psychotherapy and Pharmacotherapy

Aside from its role as a primary treatment for some types of depression, a number of studies have demonstrated that psychotherapy can enhance treatment outcomes when combined with drug treatment (e.g. McCollough, 2000) and may contribute significantly to aiding in relapse prevention (Reynolds, Frank, Perel, et al., 1999; Evans, Hollan, DeRubelis, et al., 1992; Thase, Greenhouse, Frank, et al., 1997). Several authors including MacFarlane (2003) and Whisman & Uebelacker (1999) advocate treatment models that combine couple therapy with individual and pharmacological interventions for a more integrated treatment approach. Additionally, the psychotherapist is in the best position for closely monitoring compliance, side effect problems, and clinical response to medication treatment. This is especially important if the client is being treated in a primary care setting where the therapist can collaborate with the physician in order to optimize treatment outcomes.

Chapter Three: Bipolar Spectrum Disorders

Introduction and Diagnostic Issues

Bipolar disorder is a common type of mood disorder affecting between 3.5-6% of the population (lifetime prevalence: Akiskal, et al. 2000). Previously it was thought that the lifetime prevalence was 1-1.5% of the population, however, more recent epidemiological studies and new, refined diagnostic criteria have revealed the larger prevalence rate. It is now appreciated that there are a number of different types of bipolar disorder and together these are often referred to as bipolar spectrum disorders. Bipolar disorders are a group of genetically transmitted illnesses that result in recurring episodes of depression and mania or hypomania (see below). This is a life-long disorder, which requires on-going medical treatment. Mood-stabilizing medications can effectively reduce episode severity and frequency; however there is currently no cure.

In adolescents and adults, sixty percent of manic episodes are classic manias, 40% are referred to as dysphoric or mixed mania.

Symptoms of Classic Mania

• Euphoria or an inflated sense of self-worth
• Restlessness, agitation, hyperactivity
• High level of energy
• Decreased need for sleep (e.g. sleeping 3-4 hours per night, yet without daytime fatigue)
• Racing thoughts and rapid, pressured speech
• Poor judgment and impulsive behavior, e.g. spending enormous amounts of money, driving fast/recklessly, marked alcohol or drug abuse, promiscuity and engaging in unsafe sex
• Psychotic symptoms can occur

Symptoms of Dysphoric or Mixed Mania

• Symptoms in common with classic mania
• Agitation, restlessness, hyperactivity
• Decreased need for sleep
• Racing thoughts and rapid, pressured speech
• Psychotic symptoms can occur
• Marked irritability
• Negative, pessimistic thinking
• Feelings of worthlessness
• Suicidal ideas

Hypomania is a milder version of mania that typically involves much less intense mood symptoms. The duration of hypomania is often only 1-4 days and is frequently not noticed as being a sign of illness by the person experiencing hypomania (although most times family members are more clearly aware of the mood changes and increased energy). During some hypomanias the person can feel highly motivated and productive, is witty, gregarious and “up beat” (although there is often underlying irritability). One very common sign of hypomania is a decreased need for sleep with no daytime fatigue. DSM IV requires a minimum of 4 days of hypomania to diagnose bipolar II disorder, however the most common presentation of hypomanias is 2-3 days; thus the higher prevalence rates of this disorder (revised diagnostic standards reflecting these new findings are slated to appear in DSM V).

There are five subtypes of bipolar disorder:

• Bipolar I: severe manic (classic or dysphoric) and depressive episodes (often with periods of normal/euthymic mood between episodes).
• Bipolar II: characterized by frequent, severe and prolonged depressions with periodic, brief episodes of hypomania, a normal/euthymic mood can occur between episodes, but often during these in-between times there is a low-grade/mildly depressed mood. Judd, et al. (2003) studied the course of bipolar II disorder for a period of ten years and found that 15% of days were spent in major depressions, 40% in minor depressions and only 1.4% in hypomanias.
• Bipolar III: severe, highly recurrent unipolar depressions with no manias or hypomanias. However if the patient is treated with certain drugs (e.g. stimulants, antidepressants or steroids) there is a likelihood that the medication will provoke a switch into mania or hypomania, and from that point on, manic episodes may begin to occur. A more common outcome is simply that standard antidepressant medications may be ineffective unless combined with a mood stabilizer. This subtype of bipolar is fairly rare, and is also characterized by early onset depressions (in childhood or early adolescence) and a positive family history of bipolar disorder
• Pre-pubertal or early adolescent bipolar disorder: likely to be a more severe variant of bipolar disorder. Manias tend to be non-episodic (i.e. more chronic) and 95% are of the dysphoric variety.
• Cyclothymia: mild depressions and hypomania (note: this less severe version of bipolar can become worse with time and most people with cyclothymia eventually convert to Bipolar I or Bipolar II).

A complication of bipolar disorder affecting about 20% of suffers is called rapid cycling. This represents a time limited worsening of the illness in which episodes occur with greater frequency (i.e. 4 or more episodes of depression, mania or hypomania per year). Most cases of rapid cycling last a few months to a year and a half and then subside. The most common cause for rapid cycling is substance use/abuse. If more frequent episodes are evident it is referred to as ultra-rapid cycling or ultradian cycling bipolar.

Untreated or poorly treated bipolar illness leads to disaster. Careers and marriages are ruined, physical health problems abound, and there is a high rate of suicide (15% lifetime risk). If not treated, most cases of bipolar disorder become progressively worse, likely owing to kindling effects. The sooner this illness can be diagnosed and properly treated, the better.

Treatments for Bipolar Disorder

Although the focus of this course is on psychopharmacology, we will also briefly address adjunctive treatments. Medication treatment alone is never adequate to fully control bipolar disorders. Treatment must have a two-pronged focus: bringing to an end the current manic or depressive episode and relapse prevention. With proper medical treatment most people can experience a marked decrease in episode frequency and severity.

Life-style Management

People with bipolar illness have a very unstable and fragile neurobiologic mechanisms for affect regulation and extreme emotional lability and mood episodes can be triggered by a number of environmental, psychological and physiological stressors. Before a discussion of medication treatment, we will address lifestyle management issues. It is especially important to regulate one's lifestyle closely: without this, medical treatments often are only partially effective (Malkoff-Schwartz, et al. 1998). Most important are:

• Maintain regular bed times and awakening times. Such regularities in sleep patterns are crucial
• Avoid substance abuse and alcohol use/abuse like the plague (substance abuse is very common in bipolar disorder and often significantly aggravates the illness)
• Avoid sleep deprivation, shift work and crossing time zones
• Avoid or greatly minimize caffeine use since it can significantly disrupt the quality of sleep
• Keep the amount of bright light exposure (e.g. sunlight) and the amount of physical exercise stable year round.

Medication Treatments: General Considerations

General references:

1. Hirschfeld, et al. (2002): Bipolar disorder Practice Guidelines
2. Preston, J. et al. (2008)

The choice of medications used to treat bipolar disorder depends on the mood state the patient is currently experiencing (i.e. whether it is mania or depression). In addition, the medication choice always must take into consideration the ultimate goal of preventing recurrences.

Currently there are eleven medications that are approved by the Food and Drug Administration (FDA) for the treatment of bipolar disorder: lithium, Thorazine, Depakote, Lamictal, Symbyax, Risperdal, Seroquel, Equatro, Geodon, Abilify, and Zyprexa. However, a number of other highly effective drugs are in common use. The use of medications not approved by FDA for the treatment of certain conditions is referred to as “off label use”…and it must be emphasized that off label use of medications is very common practice in every branch of medicine.

Recent surveys reveal that in the United States only 11% of people being treated for bipolar disorder are taking just a single drug (i.e. mono-therapy); thus, this is the exception and not the rule. On average, most people being treated are taking 3 or 4 medications simultaneously. The reason for this is simple: medication combinations are often clearly superior to mono-therapy for most people suffering from bipolar disorder.

All medications have side effects and unfortunately the drugs used to treat bipolar disorder are known to produce significant side effects for the majority of people being treated. Side effects, at times, are mild and easy to tolerate. But often they are more noticeable and in rare instances they can be dangerous. In every single case, once the current mood episode has subsided, people with bipolar disorder must continue to take certain medications (mood stabilizers) to help prevent or reduce the likelihood of recurrence. This is absolutely essential! However, some estimates suggest that as many as 90% of people who start medical treatment for bipolar disorder will recover from their first episode, but within weeks or several months, will stop taking the medications (against medical advice). The most common reasons for doing so are understandable: 1. patients are plagued by unpleasant side effects and/or 2. they conclude that the episode they experienced is not really bipolar disorder, but was just a single episode and that there will not be recurrences. This conclusion is borne of hopefulness that this is not really going to be a recurring illness (Pope and Scott, 2003). These reasons for discontinuing the medication are entirely understandable, but they almost invariably lead to the emergence of another episode (this may occur within a few months following the initial episode, but more commonly occurs several years later).

For many patients, taking medications when you feel well, is counter-intuitive. However, the picture is clear that bipolar disorder is always recurring, and over a period of time there is a tendency for episodes to become increasingly severe and harder to treat. There is also research that reveals that untreated or poorly treated bipolar illness can ultimately result in lasting damage to the nervous system. During mood episodes there are often toxic levels of certain neurotransmitters (e.g. glutamate) and stress hormones (e.g. cortisol) that are released that can damage nerve cells. Fortunately, studies also reveal that on-going treatment with some bipolar medications may prevent this from happening (Dreven, et al. 2002). In a very real sense, some of these drugs (e.g. lithium and Depakote) appear to be “neuro-protective”.

Many side effects can be managed by dosage adjustments or by switching to other medications. This is one reason that most times people will need to go through systematic trials on a variety of medications to determine which ones are the most effective and also which drugs are best tolerated for any given individual. Every effort should be made to find the right medication or medication combinations in an attempt to minimize side effects. And this is often something that can be accomplished. However, it is often the case that it takes a year of trials on various medications to finally discover the specific medication or medication combinations that will be effective and that will be best tolerated. This is the rule and not the exception…it is very important for patients to not feel too discouraged if the first medications used are less than optimally effective or if they have problematic side effects. A sign of a competent and compassionate psychiatrist is his or her willingness to be persistent in carrying out systematic medication trials until the best treatment is finally identified. Sometimes side effects can be minimized, however, many people end up having to find ways to tolerate some side effects. Obviously, this is not pleasant, but is ultimately necessary to reduce or eliminate severe mood swings. And unfortunately, a very small number of people are simply unable to tolerate any bipolar medications.

Medication Treatments: What are Realistic Outcomes?

Bipolar disorder is like a number of other chronic medical conditions (such as diabetes, asthma, arthritis, etc.). It is not a condition that can be cured by currently available medications. However, the medications discussed below are effective in relieving many of the more serious symptoms of bipolar illness and often can reduce the frequency of mood episodes for most people, if patients receive appropriate treatment and stick with it. Good news and not so good news: with aggressive, appropriate, and on-going medication treatment, and if the treatment is started during the first or second mood episode, about 30% of people will not experience major recurrences. That is, in about one out of three people the medications are successful in preventing relapses (please note: if the first appropriate medical treatments begin after the second episode, typically treatment becomes somewhat more challenging and the outcomes are not quite as robust). However, for the majority of other people receiving treatment, the recurrence rates for severe episodes can be reduced by about 75% and hospitalizations can often be avoided. Subsequent episodes that do occur tend to be mild depressions and hypomanias (Gitlin, 2002).

Medication treatments are far from perfect, but it is the kind of effectiveness that can substantially reduce suffering, keep families together, avoid catastrophes and save lives.

Bipolar Medications

There are six major classes of psychiatric medications that have been found to be effective in treating various symptoms of bipolar disorder. Generic and brand names (registered trademarks) and typical adult daily doses are listed below.

Lithium:

Therapeutic blood levels

Anticonvulsants mood stabilizers:

Therapeutic blood levels

Atypical Antipsychotics

(the name commonly used for a class of newly developed antipsychotic medications that treat psychotic symptoms and also appear to have anti manic effects as well).

Antidepressants

(listed above in the section on the treatment of depression)

Note: Symbyax, a combination of Prozac and Zyprexa, was approved by the FDA in 2004 for the treatment of bipolar depression. It comes in the following formulations: (Zyprexa dose/Prozac dose): 6/25 mg., 6/50 mg., 12/25 mg., 12/50 mg.

Calcium Channel Blockers

Benzodiazepines

(also referred to as minor tranquilizers or anti-anxiety drugs; only listed are those in most common use)

Benzodiazepine Sleeping Pills:

In addition there are a number of other medications that are occasionally used, including some experimental drugs (e.g. Omega-3 fatty acids). This CE course will provide a brief overview of standard treatment guidelines that have been developed primarily by the American Psychiatric Association (Hirschfeld, et al.,2002).

Targets for Medication Treatment

There are three primary goals in medication treatment of bipolar disorder: dealing with potentially dangerous emergency issues (e.g. extremely severe agitation or suicidal impulses), resolving the current episode (whether mania or depression), and relapse prevention. The choice of medications used always will be influenced by these goals. In addition, and obviously the medication choice will also be dictated by the need to minimize side effects.

Getting Started with Medication Treatment: Emergency Medication Treatments and Laboratory Tests

Sometimes there is a need for emergency treatment; for example if a person is experiencing a sudden onset of severe manic agitation (which may include extreme restlessness, impulsivity, severely impaired judgment and/or aggression) or serious suicidal impulses during a depression. At such times acute medical treatment may be necessary.

When there is such a crisis, hospitalization is almost always necessary. Emergency medical treatments for agitation include the use of either benzodiazepines (anti-anxiety tranquilizers, such as Ativan, Klonopin, and Valium) or antipsychotic medications (such as Zyprexa, Risperdal, or Haldol). These two classes of drugs are often very effective in rapidly reducing agitation. On occasion there is a need for emergency medical treatment for very severe depression (where there is either a grave suicide risk or refusal to eat accompanied by severe weight loss). In such cases ECT (electro-convulsive therapy; “shock” treatments) can be successfully used. ECT is also very effective for the emergency treatment of severe mania.

If the situation is not extremely urgent, then it is commonplace to order some pre-treatment laboratory tests. This is done for two purposes. The first is to rule out the possibility that the mood symptoms may be caused by a primary medical illness (such as thyroid disease). The other reason has to do with the tendency for many of the bipolar medications to cause significant changes in a variety of bodily functions. Mood stabilizers in particular are known to affect a broad range of organs and glands especially when they are taken for prolonged periods of time. Thus typically, pre-treatment labs include measures of cardiac, kidney, liver and thyroid functioning as well as a complete blood count. Laboratory monitoring of blood levels of certain medications may also be required. This is routinely done for the following mood stabilizing medications: lithium, Tegretol, Trileptal, and Depakote.

Treatment Guidelines: Mania

Several classes of psychiatric medications have been found to be effective in treating acute manic episodes:

• Lithium
• Anticonvulsants: Depakote, Tegretol, Equatro, Trileptal, Topamax
• Antipsychotic medications: Zyprexa, Risperdal, Abilify, Geodon, Seroquel, Haldol (an older generation antipsychotic that is still sometimes used)
• Calcium Channel Blockers: Verapamil (generally only used for treating mania in pregnant women because it is the safest mood stabilizer for use during pregnancy)
• Benzodiazepines (minor tranquilizers):

Benzodiazepines and antipsychotic medications are given initially to reduce agitation, which can often be achieved within a few hours (note: for reasons that are not well understood, the tranquilizer, Xanax can sometimes aggravate mania, and thus is generally not used to treat acute mania). The anti-manic medications (e.g. lithium and anticonvulsants) require 7-10 days of treatment before you see an onset of action and symptom reduction. Once symptoms begin to be reduced, continued treatment for several weeks will often be necessary to eliminate acute manic symptoms. As noted earlier, most people will ultimately be treated with 3 or 4 medications simultaneously to achieve the best outcomes.

There are three stages in the medical treatment of mania:

1. Reduce extreme agitation (the goal is to get agitation under control within a few hours). Severe agitation can be dangerous to the patient as well as to others around them and this must be addressed as soon as possible.
2. Reduce core manic symptoms such as restlessness, sleeplessness, rapid speech, paranoid ideas, etc.
3. Begin treatment for relapse prevention.

Stage One

As mentioned above, antipsychotic medications and benzodiazepines are the best medications for treating acute agitation; they quickly produce substantial sedation, calming, or sleep. It is important to note that although antipsychotic medications do successfully treat psychotic symptoms (such as hallucinations) the more recently developed drugs (i.e., atypical antipsychotics) have been found to be effective mood stabilizers and are also commonly used to treat mania. Most mood stabilizers require the 7-10 day period of time before symptom reduction, but with one notable exception: the anticonvulsant mood stabilizer, Depakote, when given in large doses, can begin to show anti-manic effects in about 4 days. Once severe agitation has subsided, often benzodiazepines are gradually reduced and then within a few days are discontinued. This may also be true for antipsychotic medications. However, there are times when antipsychotic drugs may continue to be used for a more prolonged period of time.

During stage one of treatment, as mentioned above, a number of lab tests are often done to monitor the early effects of the drugs.

Stage Two

The choice of medications used to treat core symptoms of mania is important and often complex. As noted above, there are several different types of mania and a considerable amount of research has been done to discover which medications are best suited for treating particular subtypes of mania. Dozens of large-scale research studies have been conducted in recent years and specific treatment guidelines have been developed that are very useful in helping physicians to decide on initial medication choices (see below). However, the fact is that each person will have a number of factors unique to her or him that will influence the choice of medications, such as age, gender, body weight, history of allergies to medications, liver metabolism rate, the presence or absence of other medical conditions and other medicines being used to treat such conditions. Your patients must anticipate that it is extremely common for psychiatrists to make initial medication choices, begin treatment and then during the following weeks or months make what are often frequent changes in the doses or medications prescribed. There is an important reason for emphasizing this. Many times people being treated for bipolar illness or their family members become worried as they begin to encounter side effects, or they must go through what seems like an endless number of lab tests or changes in medications or medication doses. Many people become concerned that these medication changes suggest that their doctor may not be competent or that their case of bipolar is especially treatment-resistant. This then can lead to discouragement and feelings of pessimism. Here is the truth: the pathway to recovery and good outcomes, more often than not, is complicated. The rule, not the exception is that people will be tried on several if not many medications in the search for the right drug or medication combinations. It is so important to help patients understand this and not conclude that the frequent changes in medications are necessarily a reason for concern. The fact is that bipolar disorder is challenging to treat and often requires a considerable amount of time systematically trying various medications before the right medications combinations are found.

“Classic Mania” (with euphoria, expansiveness, up-beat mood, irritability, etc.) has been found to respond best to treatment with lithium or Depakote (other anticonvulsant mood stabilizers or atypical antipsychotic medications often can treat classic mania, but in head-to-head comparisons, lithium and Depakote appear to be the best first-line medications for this type of mania). Generally during stage two of treatment, especially if this is a person’s first episode of mania, just one of these medications will be prescribed. Assuming that the medication is tolerated (i.e. that side effects are mild or manageable) treatment will continue for a period of several weeks. As mentioned earlier, 70% of people being treated for bipolar disorder ultimately must take two or more medications at the same time to adequately treat mania. Thus it is possible that the one medicine initially prescribed may be tolerated and may eventually be effective. Decisions to increase the dose or to change or add another medication in the ensuing weeks will depend on tolerability and effectiveness. Since there are always possible drug-drug interactions, then generally the recommended approach is to first optimize treatment with one medication (which means to progressively increase the dose while always being watchful for the emergence of side effects). What is hoped for is that the first signs of symptomatic change will occur during the first 7-10 days and that symptomatic improvement will continue to unfold over the next few weeks. Just how long it takes to fully resolve a manic episode varies from one individual to another.

Should side effects be significant, typically there will be either a dosage adjustment or possibly a change to another medication. If side effects are mild to moderate and tolerable, but there is only partial improvement in symptoms after several weeks of treatment, then a decision will be made to either change to a different medication or to add another medication (the addition of medications is commonly referred to as augmentation). Medications typically used for augmentation include anticonvulsant mood stabilizers and/or antipsychotic medications.

Dysphoric or Mixed Mania: (agitation, decreased need for sleep, rapid speech, feelings of despair, hopelessness, etc.). There is some controversy regarding the treatment of dysphoric mania. However, most experts agree that the best first-line medication is Depakote. Many people experiencing dysphoric mania do have positive responses to lithium as a mono-therapy. The use of just one medication again, initially is the typical strategy and again, before adding or changing medications, the drug used will be optimized. As in the treatment of classic mania, we are looking for the first signs of improvement within the first 7-10 days.

If after several weeks of treatment and if increased doses of the medication yield only partial symptomatic improvement then augmentation can be used. Often the first augmentation strategy is to combine Depakote and lithium. If other medications are required then the addition of the following are commonly prescribed: anticonvulsants: Lamictal, Tegretol, Topamax, or Trileptal. The anticonvulsant, Neurontin has been found to be ineffective as a mono-therapy, but it is often used as an augmenting agent, especially helpful in reducing anxiety (50% of bipolar patients have comorbid anxiety disorders). Other choices include atypical antipsychotics.

The treatment of childhood-onset bipolar disorder is beyond the scope of this CE course, however a few brief comments will be made. When mania occurs in pre-pubertal children, it almost always presents as a form of dysphoric mania with rapid cycling and marked irritability. With adults the general strategy is to begin treatment with one mood stabilizer and only later add additional medicines if they are needed. This is done with the intention of avoiding unnecessary side effects that occur when multiple drugs are prescribed. Obviously there are compelling reasons for wanting to minimize side effects in children, as well. However, preliminary research has rather strongly indicated that most children suffering from mania ultimately end up taking two or more mood stabilizers (this is required for most to effectively eliminate manic symptoms). Thus there currently is a trend to begin treatment with children using two mood stabilizers (often this combination is Depakote and lithium). It is generally felt that the much higher success rate with two mood stabilizers outweighs the added side effects of using two drugs. Also, it is felt that the earlier you can put a lid on mania and arrest its development, the better…to do so matters not only regarding the current episode but may also have a positive effect on reducing the severity of future episodes.

Rapid Cycling

As mentioned above, rapid cycling generally is a period of time lasting anywhere from a few weeks to a year or year and a half where there is a significant increase in the frequency (and often) severity of mood episodes. In only about 2% of people is rapid cycling continuous for very prolonged periods of time. Three factors account for the majority of cases of rapid cycling: substance abuse (including alcohol), the use of certain prescription medications (e.g. antidepressants, steroids, stimulants), or disorders of the thyroid gland. Thus it is very important to determine whether or not any of these factors are present and take appropriate action to ameliorate them. Beyond this, special attention must be taken to stabilize the patient’s lifestyle, especially making sure that there is regularity to one’s sleep patterns and making every attempt to reduce or avoid sleep deprivation (e.g. establishing regular bed and awakening times, completely avoiding sleep destroying substances such as caffeine, alcohol and decongestants, no pulling all-nighter cramming for exams or late night partying).

Beyond these strategies, the following medication strategies have been found to be helpful. Preferred mood stabilizers include: Depakote, Tegretol, and Lamictal. Atypical antipsychotic medications are frequently also prescribed. An experimental treatment that has been found to be helpful for some people is the use of omega-3 fatty acids (this is an over-the-counter dietary supplement that has some research support in the treatment of bipolar disorder. Discussed below). Finally, the most common mood symptoms seen in rapid cycling are depression or a combination of depression and irritability. However, antidepressants can, unfortunately, contribute to cycle acceleration and rapid switches in mood. Thus the use of antidepressants in rapid cycling is generally not indicated.

Treatment-Resistant Mania

For people who experience very severe mania that does not respond to more traditional treatments there are a number of options.

The antipsychotic medication clozapine (brand name Clozaril) has been found to be effective in some cases of treatment resistant mania. This drug has antipsychotic effects (e.g. for treating hallucinations, delusions, etc.). It is proving to be effective for treating not only mania but relapse prevention. Unfortunately Clozaril is plagued by numerous, significant side effects, some of which are potentially dangerous. ECT (electro-convulsive therapy) is a safe and highly effective treatment for severe mania.

Stage Three: Relapse Prevention

Once the current manic episode is completely controlled it is common practice to continue medications, even though there are no obvious symptoms. This is necessary because it is clear that once symptoms subside, if one discontinues then, the acute relapse rate can be as high as 85%. Thus for a period of several months, typically, medication treatment is continued and often at the same doses used during treatment of the acute phase of the episode. This phase of treatment appropriately is called continuation treatment. After several months, assuming there have been no “breakthrough” symptoms, then the next stage of treatment, maintenance treatment begins. Here the focus of treatment is on the prevention of recurrent episodes. Often if a person has been receiving lithium, the dose is gradually reduced (which often results in fewer side effects). The doses of other medications may also be reduced, however such a decision is highly individual and is influenced by a number of factors including a person’s clinical history and the presence of particular side effects.

In general, the medications used to treat mania are considered to be very effective for most people experiencing a manic episode (Note: this is true for bipolar mania seen in patients who have a late adolescent or adult-onset illness. Mania in pre-pubertal children is significantly more difficult to treat). However the more long-term goal of preventing recurrences is more challenging. Despite the fact that there have been decades of experience in treating bipolar illness, there are no good long-term studies on relapse prevention (the longest studies available only extend to about a year). Yet this is a life-long illness and all experts agree that life-long treatment is required. It is important to know that most medications used to treat bipolar disorder do have side effects that may emerge with very long-term use, thus necessitating periodic lab tests to monitor blood and various glands and organ system functioning. What is clear is that failure to treat (or to adequately treat) bipolar disorder almost always leads to disasters.

The medications for which the best data exist for long-term maintenance treatment are the following mood-stabilizers: lithium (the best data), Lamictal, Depakote, and Zyprexa. Most people on maintenance treatment will continue to take several medications. However, longer-term treatments generally do not include treatment with benzodiazepines or antidepressants. These medications may destabilize bipolar patients.

Treatment Guidelines: Bipolar Depression

Several classes of psychiatric medications are often used to treat bipolar depression:

• Lithium
• Symbyax (a combination of Zyprexa and Prozac…FDA approved to treat bipolar depression)

Some anticonvulsant mood stabilizers may have antidepressant actions:

• Depakote (mixed findings), Lamictal (robust positive effects)

Atypical antipsychotic medications may have antidepressant properties:

• Seroquel has been shown to have antidepressant effects in bipolar depression (however, not in unipolar depression); other antipsychotics may treat bipolar depression: Zyprexa, Risperdal, Invega, Abilify, Geodon (older generation antipsychotics e.g., Haldol, generally do not effectively treat depression).

It is important to underscore that many treatments ordinarily effective in reducing unipolar depression (e.g., antidepressants) carry a risk of provoking manic episodes (a phenomenon referred to as switching) or causing cycle acceleration (this refers to a gradual, over-all worsening of bipolar disorder in which, over time, there is an increased frequency of episodes and episodes tend to become more severe and more difficult to treat). Switching and cycle acceleration have been clearly documented with the use of first-generation tricyclic antidepressants and thus these drugs are almost never used in the treatment of bipolar depression (Ghoemi, et al. 2001; Post, et al. 2001). Excessive bright light exposure (which can treat some types of seasonal depression) has also been associated provoking manias. Additionally, two popular over-the-counter products that have antidepressant properties may, likewise, cause switching or cycle acceleration: St. John’s Wort and SAM-e.

There are two small studies that suggest that the antidepressants Wellbutrin and Paxil have slightly less propensity for provoking manias. However, most experts agree that all of the newer antidepressants are about equal in terms of risks for switching and cycle acceleration (the risk is significantly lower than that seen with tricyclics, but is not zero). Recent findings have suggested that the addition of antidepressants generally is ineffective in treating bipolar depression and because of risks (noted above) should not be used in most cases.

The general strategy in treating bipolar depression is to first “do no harm”…do not use antidepressants.

There are also three stages in the treatment of bipolar depression.

Stage One

In the event of life threatening symptoms such as strong suicidal impulses or refusal to eat, ECT is a highly effective treatment. The treatment approach is much the same as used to treat acute mania. The other emergency treatment is hospitalization. Unfortunately aside from ECT most approaches to treating depression require several weeks before one is likely to see symptomatic improvement.

Stage Two

The choice of medication is dictated primarily by whether or not there has been a history of rapid cycling. If there has ever been rapid cycling, then the risks of cycle acceleration and/or switching are much higher, and thus antidepressant medications are generally avoided. Thus, the following are recommended guidelines.

Start with a medication with proven efficacy in treating bipolar depression. The drugs that have the best track record of effectiveness are Seroquel, lithium, Symbyax and Lamictal.Of these medications, Lamictal is likely to be the most effective. There is an important consideration, however, when using Lamictal: as treatment is begun, it is required that Lamictal be given in small doses and that dosage changes are done very gradually during the first 4-6 weeks of treatment. This is done to avoid inducing a potentially dangerous rash, Stevens-Johnson syndrome, that can occur if there is rapid dose escalation). Fortunately, since the use of gradual dosing has been adopted, the risk of Stevens-Johnson is almost nil. Lithium has been shown to have antidepressant effects when administered as a monotherapy in bipolar depression (although not in unipolar depression); however, it appears that a blood level of lithium of at least 0.8 is required to combat depression effectively. Just how urgent the need is for antidepressant action, will be a critical factor in choosing Lamictal, Seroquel, lithium or Symbyax (i.e. due to the need to slowly increase the dose of Lamictal, it may take somewhat longer to have an effect where with lithium, Seroquel, or Symbyax doses can be titrated up more rapidly). If there is any history of rapid cycling, switching or a recent manic episode, it is best to start with one of the following medications since each also have anti-manic properties: lithium, Seroquel, or Symbyax. There have been a few case reports of Lamictal inducing mania.

If treatment with the first-line medication is not successful or there is a partial response then there are several options:

1. Combine two of these medications
2. Add an antidepressant (Wellbutrin, Paxil, or Cymbalta). It should be noted that evidence from large scale studies does not support this strategy, but there may be certain individuals where the addition of an antidepressant may be effective. Note: if there is a history of rapid cycling, antidepressants should only be used with great caution.
3. ECT

Stage Three

This is much the same as stage three treatments for mania. Among the mood stabilizers that have the best record of effectiveness in the prevention of depressive episodes, Lamictal and lithium appear to be the front-runners.

Adjunctive Therapies

Bright light therapy (using a commercially available light box which generates 10,000 lux of light intensity for 10-30 minutes a day) has been used for treating bipolar depression, especially for those who routinely have winter depressions or who work the night shift. This treatment is typically combined with medication treatments and like all treatments for depression; it too carries a risk of provoking mania in people with bipolar disorder.

Omega-3 Fatty Acids: Approximately 60% of the human brain is composed of lipids (fats) and between 30-35% of brain mass is made up of omega-3 fatty acids. These molecules are important in forming cell membranes, synapses and in facilitating nerve cell actions. The most abundant dietary source of omega-3 fatty acids is fish and shellfish. In cross-cultural studies it has been found that in countries where people eat a lot of fish and other seafood, the severity of mood disorders is less. This interesting finding led researchers to carefully evaluate the impact of diet on mood. During the past five years a number of studies have been conducted with people suffering from bipolar disorder and also major depression. Preliminary findings strongly suggest that adding omega-3 fatty acids to the diet can have a positive effect on reducing the severity of mood episodes in some individuals. In all studies to date, omega-3 fatty acids have been added to traditional medications (i.e. mood stabilizers).

Uses and General Considerations: Omega-3 fatty acids are not effective in treating severe episodes of mania or depression. However their role appears to be in reducing the severity of episodes and possibly having a positive impact on preventing recurrences. Studies have found that people treated with omega-3 fatty acids must take these dietary supplements on a daily basis and over a prolonged period of time (i.e. building this in to one’s ongoing diet). As noted above, the main sources of omega-3 fatty acids are fish and shellfish, and presumably adding more fish to your diet may be a way to enrich levels of these molecules in the brain. However, all of the studies that have had positive results have used dietary supplement capsules (available from health food stores). There are three types of omega-3 fatty acids: LNA (derived from seed and nut oils, primarily from flax seed oil), EPA, and DHA (both from fish oil). Most studies have demonstrated that DHA is the most effective type of omega-3 fatty acids used to treat bipolar. The early studies used mega-doses of DHA (9 grams per day). However, it appears that much lower doses may be effective (for example, 1000 mg. taken twice a day). There are also indications that what may also be involved is achieving a balance between omega-3 and omega-6 fatty acids (the main omega-6 is arachidonic acid). Unfortunately dietary habits in the United States are notoriously poor, and lots of snack and junk foods contain significant amounts of omega-6 fatty acids (this may throw things out of balance). Thus a recommended strategy is to reduce junk foods and add omega-3 fatty acids. Omega-3 fatty acids (especially at lower doses) have few if any side effects and are well tolerated; high doses can cause gastrointestinal discomfort (Stoll, et al., 1999).

Exercise therapy has recently been shown to be effective in treating major depression, however, to date there are no studies of this approach in treating bipolar depression.

Psychotherapy

Although medication treatment is the backbone of successful therapy for bipolar, a number of studies have clearly shown that psychotherapy (especially social rhythm therapy or family-based psychoeducational therapy) can significantly contribute to better treated outcomes.

Chapter Four: Anxiety Disorders

General Considerations

Anxiety disorders affect 25% of people (lifetime prevalence) and many become very chronic conditions. All anxiety disorders discussed in this section have been found to respond well to exposure-based cognitive therapy. In most instances this form of psychotherapy is more effective than drug treatments. Despite this, medication treatments are often useful or necessary owing to the following:

1. In many communities there may not be professionals trained to provide cognitive therapy
2. Some patients refuse cognitive therapy owing to the fact that such treatments require exposure, and people are too afraid to undertake the treatments.
3. Often, symptoms are so debilitating that medication intervention is an important first step to take to reduce suffering and help people re-engage in normal life functioning and then begin psychological treatments.
4. Some patients with marginal ego strength may not be able to tolerate exposure-based treatments.
5. If medications are used and at some point exposure-based treatments are employed, it will be necessary to gradually reduce the dose of medications so that the client will experience some anxiety. This is required since it has been found that exposure therapy and deconditioning is not successful unless the person experiences some amount of anxiety, is able to undergo exposure trials using anxiety management skills, and have the experience of enduring anxiety without catastrophe. This is essential in order to experience mastery.

Diagnostic Issues

The following seven classes of anxiety disorders will be discussed:

• Generalized Anxiety Disorder: chronic, pervasive, low-level anxiety characterized by excessive worry.
• Stress-related Anxiety (i.e. adjustment disorder with anxiety): anxiety symptoms have only emerged in the wake of a recent, significant life stressor.
• Panic Disorder: Characterized by repeated episodes of panic that erupt and rapidly escalate into intense anxiety within 10 minutes or less and then dissipate. Often accompanied by anticipatory anxiety and phobic avoidance (e.g. agoraphobia).
• Social Anxiety: anxiety symptoms are only experienced in social settings, e.g. social gatherings, public speaking, etc.
• Obsessive-Compulsive Disorder: presenting with recurrent, debilitating obsessions and compulsive rituals.
• Acute Stress Disorder (ASD) and Post Traumatic Stress Disorder (PTSD): ASD becomes PTSD if symptoms persist beyond one month. Symptoms include: intrusive symptoms (memories, flashbacks, nightmares, intense emotional responses/reactivity), avoidance, numbing and dissociation, persistent hyperarousal, and often depression. Occasionally transient psychotic symptoms may be present.
• Anxiety due to a general medical condition or substance use or abuse. Of note here is that the use of caffeine can cause or significantly exacerbate anxiety symptoms. In every case presenting with anxiety, it is critical to evaluate the presence of caffeine use. The following questionnaire can be helpful in screening for caffeine use.

If caffeine use exceeds 250 mg. per day, there is a likelihood that it will interfere with slow wave/deep sleep and may play a role in increasing any psychiatric symptom. When anxiety is a prominent feature, then caffeine use should be completely avoided. Many individuals that suffer from anxiety disorders inadvertently consume significant amounts of caffeine and this always complicates psychological or medical treatment. "Energy drinks" should also be avoided.

Psychopharmacology

There are two major classes of medications used to treat anxiety disorders: antidepressants (all mentioned above with the exception of Wellbutrin, which can increase anxiety) and the minor tranquilizers (commonly referred to by their class name: benzodiazepines). We will also consider adjunctive and experimental treatments.

Antidepressants have been addressed in detail above, thus there will be only a few issues presented here. Most of the antidepressants (especially those that target serotonin) have been found to be highly effective in treating most forms of anxiety disorder. However, all have the tendency to produce initial activation. This is a side effect of the drugs that can appear within a few hours after taking the first dose. This is very problematic for those with anxiety disorders. The increase in anxiety that occurs due to activation ranges from mild to marked and typically lasts for 10 days, and then begins to subside. Most patients who encounter this become frightened by the increase in anxiety and stop taking the antidepressant. Thus, a popular and effective way to address this is to co-administer a benzodiazepine. The tranquilizer, if dosed appropriately, begins to reduce anxiety within 30-45 minutes and can also operate to over-ride activation. The goal is to use the benzodiazepine for the first month of treatment and then to phase it out. After one month of treatment, most antidepressants begin to show antianxiety effects. There is one note of caution. Since benzodiazepines can be habit-forming, they should be used with great caution in patients who have a history of alcohol or other substance abuse. In such individuals an alternative to the use of a benzodiazepine is Neurontin (which will be discussed later in the section on adjunctive treatments).

Benzodiazepines

Benzodiazepines:

Benzodiazepines used for sleep:

Special Concerns: If benzodiazepines are being taken on a regular basis the body develops a tolerance for the medication. When this happens, typically the drugs continue to work to reduce anxiety, but the problem is that when there is tolerance, if one abruptly stops the medication there can be withdrawal symptoms. Withdrawal symptoms usually include nervousness, agitation, difficulty falling to sleep, and on occasion can produce seizures. This needs to be taken very seriously. If a patient has been taking a benzodiazepine on a daily basis for more than 6 weeks and especially if the dose is moderate-to-high, withdrawal reactions are a very real risk. One should never abruptly stop taking the medication without first consulting with his or her physician. It is also a good idea to be especially careful to monitor the supply of the medications so that refills can be requested in a timely fashion. Many people find it helpful to keep at least a two-day supply on hand in the event that it takes longer than usual for a prescription to be refilled. Additionally, benzodiazepines can be abused and should not be prescribed to people with a substance abuse history.

The onset of action of benzodiazepines is 30-45 minutes. As noted above, most antidepressants require a minimum of four weeks of treatment before the first signs of clinical improvement are noted.

Generalized Anxiety Disorder

Three classes of medications have been found to be effective in treating GAD: buspirone (BuSpar, a non-habit-forming tranquilizer), benzodiazepines and antidepressants. BuSpar requires ongoing treatment for 2-6 weeks before the onset of clinical improvement and is given in doses of from 10-40 mg per day. The symptomatic improvement is seen to emerge gradually and primarily is experienced by the patient as a decrease in worry and rumination. BuSpar has a very favorable side effect profile and is well tolerated, however, its efficacy is not as robust as that seen with benzodiazepines or antidepressants. Benzodiazepines are effective in treating GAD, although there has been some controversy regarding their use. Clearly they are problematic for three reasons: in patients with a substance abuse history they can be abused, although this rarely occurs in the absence of such a history…(this warning will apply to treatment of all anxiety disorders discussed below), they can cause sedation and impairments in alertness, and finally, as noted above, there is the potential for significant withdrawal effects should there be a rapid discontinuation. Antidepressants (except for Wellbutrin) are generally very effective in treating GAD but require 4-6 weeks of treatment, or longer in some instances, before they begin to show clinical improvement (this is true for all anxiety disorders discussed below, except for OCD which often requires a more prolonged period of treatment before maximal symptomatic improvement is seen). It is generally true for GAD and all of the other anxiety disorders, that when drugs are eventually discontinued at least 50% of patients will have a return of symptoms, and thus drug treatments in most cases target symptoms but do not cure the underlying neurobiologic disorder. Doses used to treat GAD are similar to those used to treat major depression (see above). Such dosing is the case for all anxiety disorders discussed below with one exception: OCD often requires very high doses.

Stress-Related Anxiety

Short-term use of low-to-moderate doses of benzodiazepines can be helpful in reducing both anxiety and stress-related initial insomnia. BuSpar and antidepressants are not indicated since they require a number of weeks to begin working and most acute stressors subside more quickly.

Panic Disorder

Two classes of medications are effective in treating panic disorder: antidepressants and benzodiazepines. The advantage to using benzodiazepines is the quick onset of action. This can be a godsend for patients plagued by frequent and severe panic attacks. The particular drugs used most often are the high-potency benzodiazepines: Xanax, Ativan and Klonopin (other benzos often cause too much sedation). Doses required to contain panic attacks vary considerably and in every case the patient is started on a low dose and gradually increased until symptom control is achieved. It is necessary to have the medication in the body continuously, 24 hours per day to avoid panic attacks (i.e. they cannot be taken only on an “as needed” or PRN basis since panic attacks come on suddenly and the drugs require 30-45 minutes to become active in the central nervous system). Antidepressants, once they have begun to reduce anxiety, are the preferred treatment of choice since they generally require only once a day dosing and usually do not create sedation nor are they habit-forming. Once panic symptoms have been eliminated or greatly reduced, behavioral treatment for phobias is always indicated (the medications are very effective in reducing panic symptoms but not robust in their impact on avoidance and phobias).

Social Anxiety

Social anxiety disorder can be treated with benzodiazepines or antidepressants. The choice of treatments depends largely on how pervasive the symptoms are. If they are only occasional and highly situation specific, benzodiazepines may be preferred (additionally, in such cases the use of Inderal, a beta blocker…taken one hour before exposure to a social situation at doses of 10-40 mg. can reduce some autonomic symptoms of anxiety such as trembling, rapid heart rate and perspiration. This medication is not indicated for chronic use since it has a tendency to cause depression if used continuously, but can be effective used on an “as needed” basis). Antidepressants are effective in the treatment of more s