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Introduction to Psychopharmacology: A Practical Clinician's Guide
by John Preston, Psy.D., ABPP

4 CE Hours - $99

Last revised: 03/01/2018

Course content © copyright 2004-2018 by John Preston, Psy.D., ABPP All rights reserved.


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Learning Objectives

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

The materials in this course are based on the most accurate information available to the author at the time of writing. New developments in the field of psychopharmacology occur each day and new research findings may emerge that supersede these course materials. This course is updated regularly as new practice guidelines are developed. This course will equip clinicians to evaluate the needs for medical treatment for their psychotherapy clients, to assess responses to treatment and to more effectively collaborate with primary care physicians and psychiatrists.

Outline

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 diagnostic criteria, however there will be supplemental diagnostic information presented in this course as it applies to treatment decision making. More recent epidemiological studies and new findings in the neurosciences have influenced changes in some diagnostic criteria in the DSM-5 which 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., 2017 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. 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, which offers a detailed printable guide to psychiatric medications (doses, side effects, required lab tests, etc.); this reference may be useful to share with clients.

Preliminary Considerations

Legal and Ethical Issues

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:

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.

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 it is required that they be prescribed 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. It is important to note that those of Asian and African descent show higher percentages of hypo-metabolism: approximately 33% and thus more caution should be taken with initial dosing in these individuals to avoid significant side effects). 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 may be 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, pretreatment 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 effects 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.

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, worldwide (males and females combined) (Murray and Lopez, 1996). Each year 25 million Americans suffer from serious depression, it has a lifetime 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 8th 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). By 2020 the World Health Organization projects that depression will be the second leading condition leading to decreased life expectancy.

It is estimated that only 50% of those in the United States who suffer from major depression 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. Eighty-five 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. Treatment outcomes in primary care medical settings are poor largely due to the lack of adequate follow-up.

A Changing Treatment Landscape

The 1980’s and 1990’s 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 marketplace forces have had a substantial impact on shifting patterns of practice in the mental health arena (see Figure 1).

Figure 1.
Treatment Received by Patients Diagnosed with Major Depression*

1987

1997

Antidepressants

37%

75%

Psychotherapy

71%

60%

* Olfson, Marcus, Druss, et al. 2002, based on sample size N = 32,000

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 comorbid medical illnesses, substance abuse or personality disorders. A 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 comorbidity 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 2).

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).

Figure 2.
Antidepressant Treatment of Major Depression Outcome Results:
General Results Reported from Drug Efficacy Studies

Commonly Reported Outcomes

ITT Outcomes

Side-effects drop-outs

15%

15%*

Responders

60%

50%

Non-Responders

40%

35%

* Drop-out rates due to side effects vary among new generation antidepressants ranging from Wellbutrin, SR: 9%, to Paxil: 21%

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. Thus, generally, only 25% reach full remission if they are treated with one medication. Failure to reach full remission is associated with ongoing 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 effective in alleviating many serious mood disorder symptoms (e.g. vegetative symptoms), undoubtedly have saved many lives, and antidepressants may also be neuroprotective (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 led 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. Sixty percent of people experiencing a major depressive episode exhibit a hyperactive hypothalamic-pituitary-adrenal (H-P-A) neuroendocrine axis (see Figure 3). 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 3.
Hypothalamic-Pituitary-Adrenal Neuroendocrine Axis
See also, Le Doux (2015)

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, 2017).

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 neuroprotective 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, Depakote, Tegretol, Lamictal, Seroquel, and Equatro, 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). In this way 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” or “psychological 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, where professional treatment is not available, 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):
  4. 66% of patients with dysthymia (Persistent Depressive Disorder: new name introduced in DSM-5) 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

Generic Name

Brand Name

Typical Adult Daily Dose

fluoxetine

Prozac, Sarafem

10-80 mg

bupropion

Wellbutrin

150-400 mg

sertraline

Zoloft

50-200 mg

paroxetine

Paxil

20-50 mg

venlafaxine

Effexor

75-350 mg

nefazodone

Generic only

100-500 mg

mirtazapine

Remeron

15-45 mg

citalopram

Celexa

10-60 mg

escitalopram

Lexapro

5-20 mg

duloxetine

Cymbalta

20-80 mg

atomoxetine

Strattera

60-120 mg

desvenlafaxine Pristiq 50-100 mg
vilazodone Viibryd 10-40 mg
vortioxetine Trintellix 10-20 mg
levomilnacipran Fetzima 40-120 mg

Pharmacologic Treatment Guidelines

During the past 20 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. Marketplace variables (e.g. pharmaceutical company advertising; decisions made by HMOs and managed care companies 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 may be 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 only 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; Goodwin and Jamison, 2007).

Major depression as defined by DSM-5 criteria (APA, 2013) 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:

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:

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

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%. (It is important to note that these figures represent “responders” and not necessarily those reaching full remission).

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 when receiving their first antidepressant trial (Paykel, Ramana, Cooper, et al., 1995; Doraiswamy, Kahan, Donahue and Richard, 2001; NIMH: STAR-D, 2008). 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, 2005 and NIMH: STAR-D Program, 2008).

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

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:

Non-Responder Strategies (Trivedi and Klieber 2001): Once again one must evaluate issues involving adherence 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 and 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, 2013). Ongoing 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 breakthrough 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: Lifelong treatment is strongly indicated for patients with highly recurrent major depressions (e.g. those in their 3rd or subsequent episodes). Chronic treatment attempts to prevent recurrence and can be helpful in this regard.

Treatment of Depressive Sub-types

Minor depression: Patients suffering from Persistent Depressive Disorder (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 or going out-of-doors without sunglasses. The typical “dose” of light therapy is 10-30 minutes of exposure to a light source that emits a minimum of 10,000 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 (Rosenthal,, 2013). Note that some 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). For this reason 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 reassess for the presence of:

Experimental Treatments

A number of experimental treatments have emerged during the past ten 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 and although FDA approved, 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 responses in bipolar patients, however have been disappointingly minimal, while a number of studies do show positive responses when used in unipolar depression. Doses that are used to treat or augment treatment of depression are 1000 to 2000 mg per day (of EPA: the specific type of omega 3 that has an impact on mood). Fish oil sources of omega 3 have greater bioavailability in the brain and are more effective than omega 3 from flax seed or walnut oil. 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 intracellular 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 mental health professional.

St. John’s Wort: is an over-the-counter dietary supplement that has been found to have antidepressant properties. A 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 (Lined, et al. 2008). 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 somewhat 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 some 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 adherence, 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.

Antidepressants and Increased Risk for Suicide

There has been a good deal of media attention regarding potential risks of antidepressants and increased suicidality (especially in children and adolescents). The initial concern came from studies in England that raised concerns about increased suicidality in young patients treated with the antidepressant Paxil. In this study, which included 1300 patients, Paxil was compared to placebo and reports of increased suicidality were seen in 1.2% of placebo and 3.4% of Paxil treated subjects. This difference is statistically significant. It is important to note that there were no actual suicides in this group of youngsters. A problem is that “suicidality” has been very loosely defined in this and other studies. Most times it includes: reports of increased thoughts about suicide, suicide gestures, non-lethal-intent, tension reducing self-harm (as is often seen in borderline personality disorders), and in one instance a report of a child slapping herself. (Brown University, 2004). Of course, actual suicides and lethal attempts are also included under this umbrella of suicidality. The FDA has responded to concerns about increased suicidality by requiring drug companies to issue warnings about the use of these drugs with younger clients. Since the media blitz regarding antidepressants and suicidality in youngsters, prescriptions written for children and teenagers have decreased by 30-40%. There has been a corresponding increase in reported suicidal ideations among depressed youngsters, but not an increase in actual suicides. The FDA has reviewed a number of studies focusing on the use of antidepressants in youth. The total number of subjects in these studies is 4400. The risk of treatment emergent suicidal events is approximately 2% in those treated with either no medications or placebo and 4% of those treated with antidepressants. The most common “suicidal event” is suicidal ideations. In the group of 4400 subjects there were no actual suicides.

What is clear is that untreated major depression carries extreme risks of potential suicide, antidepressants take several weeks of treatment before the first signs of clinical improvement, depression can worsen during this startup period of treatment. This can happen in both drug treatment as well as psychotherapy, and thus therapists must be watchful for treatment emergent suicidality regardless of treatment used. Antidepressants can cause an acute increase in anxiety and agitation during the first 10 days of treatment (i.e., activation: affecting about 10% of adults treated and 10-15% of children and young adolescents treated) which could contribute to increased dysphoria. Maybe more importantly is that among teenagers presenting with major depression, 40% turn out to have bipolar disorder. This is true for 50% of pre-adolescent children with major depression. Antidepressants are known to pose risks for precipitating mania in bipolar patients. In younger people mixed mania is very common in bipolar disorder and dysphoric mania is accompanied by significant suicide risk, Thus, in treating major depression it is very important to make sure the depression is not associated with bipolar disorder before prescribing antidepressants. Finally, it is always important to differentiate between media hype and scientific data.

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 lifelong disorder, which requires ongoing 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 (euphoric mania), 40% are referred to as mixed mania (see description below).

Symptoms of Classic Mania

Symptoms of Mania with Mixed Features (DSM-5; also, often referred to as dysphoric mania)

Hypomania is a milder version of mania that typically involves much less intense mood symptoms. The duration of hypomania is often only 2-4 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 “upbeat” (although there is often underlying irritability). One very common sign of hypomania is a decreased need for sleep with no daytime fatigue. DSM-5 requires a minimum of 4 days of hypomania to diagnose bipolar II disorder, however some epidemiological studies have shown that the most common presentation of hypomanias is 2-3 days (see Goodwin and Jamison, 2007). This finding lead the DSM-5 task force to include a new diagnosis: Depression with short-duration hypomania, requiring 2 or 3 days of hypomania. Among most experts, this is not seen as a separate diagnosis, but simply another version of bipolar II disorder.

There are five subtypes of bipolar disorder:

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 or the use of antidepressants. 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 (19-20% 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.

Lifestyle 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:

Medication Treatments: General Considerations

General references:

  1. Hirschfeld, et al. (2002): Bipolar disorder Practice Guidelines
  2. Goodwin and Jamison Manic Depressive Illness (2007)
  3. Texas Department of Mental Health (1998) Texas Medication Algorithm Project

Obviously, these official practice guidelines listed above are clearly dated. Newer guidelines are in development. Listed below are guidelines drawn from the list above but also include guidelines recommended by individual leaders in the field. 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 and a lot of this ultimately depends on long-term medication tolerability.

Currently there are fourteen 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, Saphris, Latuda, Rexulti, Vraylar, 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 (e.g. Haldol has been used to treat mania for decades, although it has never gotten FDA approval for treating this disorder).

Recent surveys reveal that in the United States only 11% of people being successfully 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; 2. there is the negative stigma regarding mental illness; and/or 3. 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), increases in intracellular calcium and stress hormones (e.g. cortisol) that are released, all of which can damage nerve cells. Fortunately, studies also reveal that ongoing 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, Depakote, Tegretol and Equatro) appear to be “neuroprotective”.

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 emphysema, asthma, arthritis, etc.). It is not a condition that can be cured by currently available medications. However, the medications discussed below can be 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 ongoing medication treatment, and if the treatment is started during the first or second mood episode, about 25% of people will not experience major recurrences. That is, in about one out of four 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 after the first episode, if they stay on medications 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). However, the majority of people being treated for bipolar disorders are frequently non-adherent with medical treatment and recurrent episodes are the rule, not the exception. One of the keys to long-term treatment success rests on medication tolerability. This, however, is a significant challenge since most bipolar medications carry high risks of unpleasant side effects.

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:

Generic Name

Brand Name

Typical Adult Daily Dose

lithium

Lithonate, Eskalith

600-2400 mg

Therapeutic blood levels
Acute mania: 0.8-1.2 mEq/l
Prophylaxis: 0.6-0.8 mEq/l

Anticonvulsants mood stabilizers:

Generic Name

Brand Name

Typical Adult Daily Dose

divalproex

Depakote

750-1500 mg

carbamazepine Tegretol; Equatro 600-1600 mg
oxcarbazepine Trileptal 1200-2400 mg
lamotrigine Lamictal 50-200 mg
Therapeutic blood levels
Depakote blood levels: 50-125 mcg/ml
Tegretol; Equatro blood levels: 4-12 mcg/ml
Trileptal blood levels: not yet established
Lamictal blood levels: not necessary to monitor

Second Generation  Antipsychotics (SGA): also referred to as atypical antipsychotics

(the name commonly used for a class of antipsychotic medications that have been developed since the early 1990s that treat psychotic symptoms and also have anti manic effects as well; two SGAs: Latuda and Seroquel, also treat bipolar depression).

Generic Name

Brand Name

Typical Adult Daily Dose

olanzapine

Zyprexa

5-20 mg

risperidone Risperdal 4-10 mg
ziprasidone Geodon 60-160 mg
aripiprazole Abilify 15-30 mg
quetiapine Seroquel 150-400 mg
paliperidone Invega 3-12 mg
iloperidone Fanapt 12-24 mg
asenapine Saphris 10-20 mg
lurasidone Latuda 40-80 mg
brexpiprazole Rexulti 1-4 mg
cariprazine Vraylar 1.5-6 mg

Antidepressants/Antipsychotic combinations

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

Generic Name

Brand Name

Typical Adult Daily Dose

verapamil

Calan, Isoptin

360-480 mg

Benzodiazepines

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

Generic Name

Brand Name

Typical Adult Daily Dose

diazepam

Valium

4-30 mg

clonazepam Klonopin 0.5-2 mg
lorazepam Ativan 2-6 mg

Note: Alproazolam (Xanax) is the one tranquilizer that can aggravate mania.

Benzodiazepine and benzodiazepine-like Sleeping Pills:

Generic Name

Brand Name

Typical Adult Daily Dose

temazepam

Restoril

15-30 mg

triazolam Halcion 0.25-0.5 mg
zolpidem Ambien 5-10 mg
zaleplon Sonata 5-10 mg
eszopiclone Lunesta 1-3 mg

Non-benzodiazepine sleeping pills:

Generic Name

Brand Name

Typical Adult Daily Dose

ramelteon

Rozerem

4-16 mg

suvorexant Belsomra 15-40 mg

Note: In the past two years the National Sleep Foundation and the National Institute of Health have issues warnings that high dose melatonin (i.e. 2 mg and higher), may destabilize both depression and bipolar disorder.

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. The use of ECT in treating severe mania is very limited.

If the situation is not extremely urgent, then it is commonplace to order some pretreatment 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) or substance abuse (e.g. to see if manic symptoms are being caused by methamphetamine use). 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, pretreatment 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, Equatro and Depakote.

Treatment Guidelines: Mania

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

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, as noted above, the tranquilizer, Xanax can sometimes aggravate mania, and thus should not be used to treat acute mania). The anti-manic medications (e.g. lithium, SGAs, and anticonvulsants) generally 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) they also are effective anti-manic agents. 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, often antipsychotic drugs may continue to be used for a 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, upbeat 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, 90% 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. A trend in treatment is to begin with two anti-manic medications relatively early in treatment (since most times this is ultimately what is required to achieve success) and by administering both drugs (e.g. Depakote and lithium) each at somewhat lower doses, the two medications together often produce fewer side effects than a single agent used at high doses. 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 (i.e., augmentation). Medications typically used for augmentation include anticonvulsant mood stabilizers and/or antipsychotic medications.

Mania with Mixed Features: (agitation, decreased need for sleep, extreme irritability, insomnia, 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 either lithium or an antipsychotic. If other medications are required then the addition of the following are commonly prescribed: anticonvulsants: Tegretol, Equatro 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 (although as noted above sometimes two drugs are started very early in treatment). 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-nighters 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 (SGAs) are frequently also prescribed.  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 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 slightly, 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 lifelong illness and all experts agree that lifelong 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 and Depakote. 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. In the end what matters is the ability to find medication combinations that achieve long-term tolerability.

Treatment Guidelines: Bipolar Depression

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

Atypical antipsychotic medications may have antidepressant properties:

It is important to underscore that many treatments that ordinarily are 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 documented with the use of antidepressants and thus these drugs should only rarely be used in the treatment of bipolar depression (Ghoemi, et al. 2001; Post, et al. 2001). Some recent studies suggest that the addition of an antidepressant to a mood stabilizer may be effective in treating treatment-resistant bipolar II patients, but this approach is not recommended in the treatment of Bipolar I.  Excessive bright light exposure (which can treat some types of seasonal depression) has also been associated provoking manias. Additionally, three popular over-the-counter products that have antidepressant properties may, likewise, cause switching or cycle acceleration: St. John’s Wort, 5-HTP, and SAM-e.

The general strategy in treating bipolar depression is to first “do no harm”…do not use antidepressants. We will see, however, there are some exceptions.

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

Start with a medication with proven efficacy in treating bipolar depression. The drugs that have the best track record of effectiveness, as noted above, are Seroquel, lithium, Symbyax and Lamictal (note: Latuda was approved to treat bipolar depression in late 2013 and it remains to be seen how effective it is after a number of months being used in clinical practice). Of these medications, Seroquel is likely to be the most effective. Lamictal is often also effective in treating bipolar depression (however, there is an important consideration 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; this is the case with older teenagers and adults; Stevens-Johnson can still occur in pre-adolescent children and should generally not be used in this population). Lithium has been shown to have antidepressant effects when administered as a monotherapy in bipolar depression (although not in unipolar depression); however, as noted above, the blood level of lithium that is effective in combating depression appears to require at least a 0.8 level. Just how urgent the need is for antidepressant action, will be a critical factor in choosing Lamictal, Latuda, 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, Latuda, or Symbyax doses can be more rapidly titrated up). 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, Latuda or Seroquel. Although Symbyax contains an antimanic agent (Zyprexa) it also includes an antidepressant (Prozac), which may provoke switching). 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. ECT

Stage Three

This is much the same as stage three treatments for mania. The bipolar medications that have the best record of effectiveness in the prevention of recurrent depressive episodes are Lamictal, Seroquel and lithium.

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 ten years a number of studies have been conducted with people suffering from bipolar disorder and also major depression. Unfortunately, omega-3 fatty acids have not been shown to be effective as an augmenter to standard mood stabilizers. However, people with bipolar disorder suffer from high rates of heart disease and strokes, and thus omega-3, which can afford some protection against vascular disease, may be helpful in that respect.

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

High intensity light therapy (formerly used only to treat seasonal depressions) has been shown to be effective in treating all depressions. Caution: excessive exposure to high intensity light may provoke mania in depressed people who suffer from bipolar disorder.

Psychotherapy

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

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:

Click here for the printable Caffeine Questionnaire

CAFFEINE CONSUMPTION QUESTIONNAIRE
Average number of servings/doses/tablets per day Average total per day
Beverages
Coffee (6 oz.) 125 mg X =
Espresso (one oz.) 50 mg X =
Decaf Coffee (6 oz.) 5 mg X =
Tea (6 oz.) Black 50 mg X =
Green Tea (6 oz.) 35 mg X =
Energy Drinks 200 mg (equivalent*)    
Cocoa (6 oz.) 15 mg X =
Caffeinated Soft Drinks (12 oz.) 40-60 mg X =
Chocolate Candy Bar 20 mg X =
Over-the-Counter Medications
Anacin 32 mg X =
Appetite-Control Pills 100-200 mg X =
Dristan 16 mg X =
Excedrine 65 mg X =
Midol 132 mg X =
NoDoz 200 mg X =
Triaminicin 30 mg X =
Vanquish 33 mg X =
Vivarin 200 mg X =
Prescription Medications
Cafergot 100 mg X =
Fiorinal 40 mg X =
TOTAL MG. CAFFEINE PER DAY

*Caffeine content of energy drinks vary. They also include a number of stimulating herbs.
> 250 milligrams a day, if taken after noon, may interfere with deep sleep

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 (affecting 10-20% of people starting these medications). 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 (although in some cases it may persist for a longer period of time). 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 override 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 hydroxyzine (brand names: Atarax; Vistaril). This is an antihistamine that has significant antianxiety properties. Benadryl can also be used to treat initial insomnia.

Benzodiazepines

Benzodiazepines:

Generic Name

Brand Name

Typical Adult Daily Dose

diazepam

Valium

4-30 mg

clonazepam Klonopin 0.5-2.0 mg
lorazepam Ativan 2-6 mg
alprazolam Xanax 1-4 mg

Medications used to treat anxiety-related initial insomnia:
(See also, my course Bipolar Spectrum Disorders: Diagnosis and Pharmacologic Treatment.)

Generic Name

Brand Name

Typical Adult Nighttime Dose

temazepam

Restoril

15-30 mg

triazolam Halcion 0.25-0.5 mg
estazolam Prosom 1-2 mg
zolpidem Ambien 5-10 mg
zaleplon Sonata 5-10 mg
eszopiclone Lunesta 1-3 mg
diphenhydramine Benadryl

25-50 mg

ramelteon Rozerem

4-16 mg

survorexant Belsomra

15-40 mg

doxepin Silenor 3-6 mg

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.

An experimental treatment is consuming 6 ounces of chamomile tea once a day. There is no acute decrease in anxiety, but after several weeks of treatment, a gradual decreased level of generalized anxiety may be experienced. Subsequent studies show even more robust results using 1220-1500 mg at bed time (must be obtained in capsule form from health food stores).

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 severe or pervasive forms of social anxiety.

Obsessive Compulsive Disorder

OCD may respond to treatment with SSRIs or the tricyclic antidepressant Anafranil (clomipramine. Daily doses: 150-250 mg.). As noted above, the treatment of OCD often requires using antidepressant doses that are higher than that used to treat depression (i.e. the high end of dosage ranges listed in the section on depression, e.g. 60-80 mg of Prozac daily). And it has been found that ongoing treatment will often yield gradual improvement during the first 12 months of treatment. That is, initially reaching a high but tolerable dose and staying with that dose for 12 months may continue to yield ever-increasing improvement with a plateau being reached by 12 months. Anafranil has significant side effects and thus is generally a second line treatment, although it has the most robust efficacy of all antidepressants in the treatment of OCD. A common practice is to start with an SSRI and if there is only partial improvement, augment with low doses of Anafranil (e.g. 25-50 mg.). This strategy is often effective in providing additional symptomatic improvement. Unfortunately, when medications are discontinued for OCD 90%+ individuals experience a full recurrence of symptoms and thus the medications are only suppressing symptoms.

Post-Traumatic Stress Disorder

Acute treatment of PTSD (or Acute Stress Disorder) is best accomplished by the use of clonidine or beta blockers which rapidly decrease anxiety symptoms. Traditionally benzodiazepines have been used, but several studies have actually shown that chronic treatment with tranquilizers can produce poor outcomes. Thus, use of benzodiazepines should be limited to very brief treatment (one or two days). PTSD has also been successfully treated with SSRIs. The down side of SSRI use is that it requires 3-4 weeks of treatment before symptom reduction is noticed and can, in some individuals cause initial activation (i.e. anxiety), as noted above, which can of course be very problematic. These medications reduce intrusive symptoms, hyperarousal and, interestingly, dissociation and numbing symptoms. As with OCD, sometimes relatively low doses may be effective, but more often the dose of antidepressants needed to provide symptomatic relief needs to be high. Case reports suggest that partial responders may benefit by adding BuSpar to the SSRI. Although anxiety can be pronounced with PTSD, generally benzodiazepines are not recommended for longer-term treatment and may in fact complicate recovery. If transient psychotic symptoms are evident, low doses of atypical antipsychotics may be helpful (e.g. 2 mg Risperdal or 7.5 mg. Zyprexa). Generally, the use of antipsychotics can be of relatively short duration. Experimental drugs that may be effective in treating PTSD-related anxiety are beta blockers (e.g. Inderal), clonidine (Catapres; Kapvay), guanfacine (Tenex; Intuniv) and for treatment of nightmares, prazosin (Minipress). Prazosin is also being used to treat daytime anxiety in those suffering with PTSD.

Anxiety related to a general medical condition or substance use / abuse

In most cases the best strategy is to treat the medical disorder or resolve substance use and not use psychiatric drugs to treat these conditions. However, in some instances the use of antidepressants or benzodiazepines may be indicated.

Adjunctive Treatments

The anticonvulsant, Neurontin (gabapentin, daily doses: 300-2400 mg.) has significant antianxiety effects and has been found to be useful in the treatment of generalized and social anxiety disorder. It has the further benefit of being non-habit-forming and effective in relieving some types of chronic pain (especially neuropathic pain). Additionally, antidepressants may exacerbate bipolar disorder. Rates of co-occurring bipolar and anxiety disorders are high. Therefor gabapentin may be an alternative. Finally, the drug Lyrica is approved to treat anxiety in Great Britain, and is sometimes used in the USA to treat anxiety, off- label. The over-the-counter product, Kava Kava has antianxiety properties however it has been associated with cases of liver toxicity and is not recommended for safety reasons. Transcranial magnetic stimulation (with low frequency stimulation over the right frontal lobe) has been used experimentally to treat PTSD and may be an option for other types of anxiety disorders. Finally, exercise therapy has a proven track record of effectiveness in treating most forms of anxiety disorder.

Attention Deficit/Hyperactivity Disorder (ADHD)

Introduction

ADHD affects approximately 7% of children and 4% of adults. With neurological maturation, most teenagers with ADHD will experience a noticeable reduction in motoric restlessness/hyperactivity, but the core symptoms of ADHD (e.g. impulsivity, impaired attention and lack of intrinsic motivation) continue through adolescence and on into adulthood. Most experts agree that about one-third of ADHD children completely outgrow the disorder by early adulthood (likely due to the ongoing maturation of the prefrontal lobes which may continue until the late 20’s or early 30’s). Two thirds experience ongoing symptoms throughout life.

Diagnostic Issues

It is very important to emphasize that most psychiatric disorders in childhood present with some degree of motoric restlessness and inattention. These outwardly observable behaviors absolutely do not automatically lead to a diagnosis of ADHD. The box below lists those disorders that must be considered in any comprehensive evaluation of children or adolescents with hyperactivity and inattention.

Differential Diagnosis of Childhood Onset Psychiatric Disorders Presenting with Hyperactivity and Inattention

  • Diffuse brain damage (e.g. commonly seen in fetal alcohol syndrome or fetal exposure to other drugs of abuse)
  • Post-Traumatic brain injuries
  • Reactive attachment disorders
  • Anxiety disorders (e.g. separation anxiety)
  • Post-traumatic stress disorder
  • Agitated depression
  • Situational stress
  • Bipolar mania
  • Pre-psychotic conditions
  • Impaired affect regulation associated with severe early abuse or neglect
  • Boredom (especially likely in bright children who are academically under-stimulated)

The diagnosis of ADHD is based largely on three sources of data: family history (since ADHD is considered to be a genetically transmitted disorder and thus often runs in families), a very careful history detailing the nature and onset of behavioral symptoms, and a description of current symptoms (especially as they vary across situations). It is also a diagnosis of exclusion (one must always first rule out those disorders listed above).

The most common presentation for ADHD is an early onset (often present in infancy) of restlessness, unstable sleep patterns, affective lability (especially, crying a lot and difficulty in being soothed). Most true ADHD children are identified in preschool when they have their first sustained contact with other children and encounter social standards (expectations to control behavior, follow rules, and stay on task in age appropriate ways). There is some controversy among experts, but general agreement that this very early onset of significant behavioral problems is very characteristic of ADHD. However, there is emerging data to suggest that some children destined to have bipolar disorder may show early-onset behaviors that are ADHD-like (i.e. prodromal symptoms of bipolar).

During childhood the following symptoms predominate: hyperactivity, impulsivity, impaired self-control, difficulties staying on-task and limited ability for intrinsic motivation (e.g. motivation to stay focused, especially on mundane, non-exciting or low stimulus-value tasks). Such symptoms are often highly context-dependent; that is: most noticeable in situations requiring that the child remain still and quiet (e.g. in the classroom), yet may not be as noticeable when in an environment that is inherently exciting, novel or stimulating (e.g. playing video games).

With adolescence, as noted above, motoric hyperactivity often is reduced, but core symptoms remain. Disorganization (manifest by messy lockers, notebooks and bedrooms) often is pronounced in the adolescent ADHD client (also true with adults suffering with ADHD), as are increasing problems adapting to society’s and school’s demands for independent task performance and self-control.

It is important to note that the so-called “inattentive type” of ADHD (in DSM-5: ADHD with inattentive specifier) in many respects is a totally unrelated neurologic disorder (children with this disorder do show impaired attention; however, they are not hyperactive nor impulsive). This fundamental difference is also underscored by the failure of stimulants to effectively treat the inattentive subtype (it should be noted that most people without ADHD when given stimulants do show a degree of enhanced abilities to maintain attention…this can occur to a limited degree when used with children with the inattentive specifier, but the results are nowhere near as robust as seen in typical ADHD).). Currently there are no effective medication treatments for those suffering with the inattentive version of ADHD.

Neurobiology

Numerous studies suggest impaired frontal lobe functioning in people suffering from ADHD (evident in studies of metabolic functioning: e.g. SPECT and PET scans). In addition, abnormalities have been shown in the dopamine neurotransmitter system. Likewise, dopamine agonists (e.g. stimulants or bupropion) [Wellbutrin] are effective medications for reducing ADHD symptoms. Minor structural abnormalities have also been found in the brains of ADHD subjects (e.g. smaller cerebellar volumes, smaller volumes of frontal and temporal areas and a smaller caudate nucleus).

Appropriate treatment with stimulants may not only reduce symptoms, but also may also normalize the chemical microenvironment of the developing brain, and ensure more normal brain maturation. Castellanos, et al. (2002) demonstrated that ADHD children have smaller cerebral and cerebellar volumes than age-matched controls. The degree of reduction in frontal, temporal, cerebellar, and white matter volumes correlated significantly with parent and teacher ratings of ADHD symptom severity. Unmedicated ADHD subjects exhibited strikingly smaller white matter volumes compared to both controls and medicated ADHD children (treated with stimulants). This suggests that appropriate treatment may be neuroprotective.

Psychopharmacology of ADHD

There are three classes of medications with empirical support of efficacy in the treatment of ADHD: stimulants, certain antidepressants and a-2 adrenergic agonists.

Stimulants

The mechanism of action of stimulants is inhibition of dopamine reuptake (additionally, amphetamines promote increased release of dopamine from vesicles). Listed below are the currently available stimulants. There are different ways to categorize stimulants, either by the onset of action or duration of action. In general, most of these agents have a moderately rapid onset, with symptom reduction occurring 30-45 minutes after ingestion, and a duration of action ranging from 4-12 hours. Depending on the formulation, dosing is two to three times daily, with some long acting products providing once daily dosing. What is most important is to find the best possible dose and dosing schedule for a given patient.

In the past few years there has been an explosion of various drugs that have received FDA approval, most of which are versions of methylphenidate. Listed below are those in most commonly in use.

Stimulants

Immediate Release

Typical Daily Doses

  • Methylphenidate
    • Ritalin
    • Metadate
    • Methylin
    • Dexmethylphenidate (Focalin)


10-60 mg
10-60 mg
10-60 mg
5-20 mg

  • Dextroamphetamine
    • Dexedrine


5-40 mg

  • Methylphenidate Patch
    • Daytrana


15-30 mg

  • Amphetamines
    • Amphetamine mixed salts (Adderall)
    • Methamphetamine (Desoxyn)
    • Amphetamine salts (Mydayis)
    • Amphetamine sulfate (Adzenys)
    Amphetamine salts (Evekeo)


5-40 mg

5-25 mg
12.5-50 mg
3.1-18.8 mg

5-40 mg

  • Lisdexamphetamine
    • Vyvanase

30-70 mg

Extended Release

Typical Daily Doses

  • Methylphenidate
    • Ritalin SR
    • Ritalin LA
    • Metadate ER
    • Metadate CD
    • Methylin ER
    • Concerta
    • Quillivant XR (liquid)


20-60 mg
20-60 mg
10-60 mg
20-60 mg
20-60 mg
18-54 mg
10-60 mg

  • Dextroamphetamine
    • Dexedrine spansules


5-40 mg

  • Amphetamine
    • Adderall XR


5-40 mg

There are over 200 well-controlled studies of stimulant use and outcomes are significantly positive. Assuming an accurate diagnosis, any one stimulant taken results in approximately 70% response rate (good to very good response). Although the stimulants are similar, there are differences. Thus, if a trial with one stimulant (e.g. methylphenidate) is less than optimal, then it is advisable to conduct a trial on another stimulant (e.g. dextroamphetamine). If systematic trials are conducted on each of the three classes of stimulants, good outcomes are seen in about 90% of patients treated (Barkley, 2000). Across studies effect sizes are quite high, ranging from 0.8 to 1.0.

The following briefly highlight important issues regarding stimulant treatment:

Failure to accurately diagnose and then to mistreat with stimulants can have very adverse consequences (see table below).

Consequences of Misdiagnosis and Stimulant Treatment

Diagnosis

Consequences

Anxiety disorder

Increased anxiety

Agitated depression

Increased agitation

Pre-schizophrenic

Psychosis

Bipolar disorder

Increased manic symptoms
May cause cycle acceleration

Situational stress

Failure to address psychological issues

Alpha-2 Adrenergic Agonists

Clonidine (Catapres; Kapvay) and guanfacine (Tenex; Intuniv) may be used to treat core ADHD symptoms (see figure below), however they are most effective in reducing irritability, aggression, and impulsivity, and promoting sedation (to treat initial insomnia). Alpha-2 agonists are also the treatment of choice for comorbid tics.

Alpha-2 Adrenergic Agonists

Generic Name

Brand Names

Typical Doses

clonidine

Catapres; Kapray

0.15-0.4 mg (1)

guanfacine

Tenex; Intuniv

0.25-1.0 mg (2)

(1) Three to four times a day
(2) Two to three times a day

There have been 25 reported cases of death in children taking clonidine in conjunction with a stimulant (USA and Canadian data combined). However, the FDA has conducted an investigation and failed to find any significant cause for concern in co-administering these drugs. The deaths seen, as determined upon autopsy, occurred in children who had evidence of pre-existing, yet un-diagnosed significant cardiac disease. It is prudent to do cardiac screening on all subjects prior to administering the medications, including a family history of early heart disease, sudden infant death syndrome, a history of fetal alcohol exposure, or any of the following symptoms: sudden, unexplained loss of consciousness; dizziness; tachycardia; or, chest pain. Should any of these exist it is recommended that the child be given a pre-treatment EKG. Combined use of Alpha-2 agonists and stimulants is a common practice (both for treating ADHD and comorbid ADHD and tics) (Walkup, 2003).

Antidepressants

20% of ADHD children will experience co-occurring depression. Antidepressants certainly may be helpful in reducing mood symptoms. However, beyond this use of antidepressants, certain classes of antidepressants have been shown to have positive effects on core ADHD symptoms. Not all antidepressants treat ADHD; only those that increase the availability of dopamine or norepinephrine (thus SSRIs, although often a good adjunct for treating anxiety or depression, are not effective in treating core ADHD symptoms). Antidepressants that have evidence of efficacy in treating ADHD are listed below.

Antidepressants Used to Treat ADHD

Generic Name

Brand Name

Typical Daily Dosage

bupropion

Wellbutrin SR/LA

150-300 mg

atomoxetine

Strattera

1.2-1.8 mg/kg

Treatment outcomes with antidepressants are not as robust as that seen with stimulants, however they afford several advantages:

Appendix

Psychiatric Medications: Quick Reference Guide

To keep up-to-date with new medications, click on my website www.Psyd-Fx.com for a free download of the Psychiatric Medications Quick Reference Chart.

This appendix may be copied and given to patients who desire detailed information regarding their medications.

Note: To the best of our knowledge doses and side effects listed in the Quick Reference Guide, linked to below, are accurate. However, this is meant as a general reference only and should not serve as a guideline for prescribing medications. Please check the manufacturer’s product information sheet or the P.D.R. for any changes in dosage schedule or contraindications. (Brand names are registered trademarks.)

Mood Stabilizers/Anti-manic agents

Lithium

Lithium Facts:

Brand Names:

Lithium carbonate: Lithotabs, Eskalith, Lithonate, Lithane, Carbolith, Lithobid, Duralith

Lithium citrate: Cibalith

Uses: Treats mania, bipolar depression and is used to reduce recurrences of mania and depression. Used to augment antidepressants in treating major depression

Typical Adult Daily Doses (Eskalith or Lithonate: most commonly prescribed): 600-2400 mg. per day. Note: what matters with lithium treatment is not the dose, per se, but the blood level (which is carefully monitored). A lithium level between 0.8 and 1.2 mEq/l (mEq/l is the technical designation for what is commonly called the lithium level) is generally felt to be in the therapeutic range for treating mania. Once the manic episode is resolved, then it is common practice to lower the dose to establish a blood level somewhere between 0.6 and 0.8 mEq/l. Blood levels above 1.2 are associated with significant side effects, and levels above 2.0 can be dangerous.

Onset of effects (how long it takes to start working): generally, 7-10 days

Laboratory Tests:

Prior to starting treatment with some medications, laboratory tests are required to establish baseline measures of the functioning of certain bodily systems. The following are typically required prior to starting treatment (and those with an * will need to be monitored periodically during treatment).

ECG (EKG)*, electrolytes, complete blood count, kidney function tests* (BUN, creatinine, urinalysis), thyroid tests*, calcium*, pregnancy test (optional).

Laboratory Tests routinely done in an ongoing basis:

Those tests above flagged with an asterisk are repeated periodically. In addition, it is necessary to periodically check lithium blood levels. This is done frequently during the first weeks of treatment and when there are significant changes in dosage. Once a person is stabilized on lithium for several months, lithium levels will then be checked less often (e.g. 3-4 times a year).

Common Side Effects:

Less Common Side Effects

Rare or potentially dangerous (require emergency medical treatment)

Habit-Forming / Addiction Potential: none

Interactions with other medications:

Here we will list only the most common medications with which the drug may cause adverse interactions.

Safety during pregnancy: lithium is generally considered to be safe for use during pregnancy, however there is a slight risk for a rare birth defect (Ebstein’s anomaly, a heart defect) if taken during the first trimester. This occurs 0.1-0.2% of fetuses exposed to lithium.

Breast feeding: not recommended when taking lithium

Special Concerns

Lithium is a very dangerous drug if taken in an accidental or intentional overdose. In the event of an overdose the patient must seek immediate medical attention. Also, lithium blood levels can become dangerously high if one experiences marked dehydration (e.g. commonly seen if there is an illness that causes severe vomiting and diarrhea).

Anticonvulsant Mood Stabilizers

Anticonvulsant Facts

Anticonvulsants are medications originally developed to treat epilepsy. It was only by accident that it was discovered that some anticonvulsants also have the ability to treat mania. In addition the anticonvulsant Lamictal has antidepressant actions and can be used to treat bipolar depressive episodes.

Anticonvulsant Mood Stabilizers:

Generic Name

Brand Name

Typical Adult Daily Dose

divalproex

Depakote

750-1500 mg

carbamazepine Tegretol; Equatro 600-1600 mg
oxcarbazepine Trileptal 1200-2400 mg
lamotrigine Lamictal 50-200 mg

An additional anticonvulsant, tiagabine (brand name Gabitril) is considered to be an experimental treatment. There are positive case reports of the use of Gabitril for the treatment of mania, but to date no well-controlled research studies.

Uses: Treat mania. Lamictal is used to treat bipolar depression. Research evaluating the ability for anticonvulsants to help prevent recurrences of mania and bipolar depression is not yet conclusive. Depakote, Trileptal and Tegretol likely help to prevent recurrences of mania and Lamictal likely reduces the recurrence of bipolar depression.

Therapeutic blood levels: two of the anticonvulsant mood stabilizers must be periodically monitored to check the levels of medication present in blood.

Depakote blood levels: 50-125 mcg/ml
Tegretol or Equatro blood levels: 4-12 mcg/ml
Trileptal blood levels: not yet established
Lamictal blood levels: not necessary to monitor

Onset of effects: generally, 7-10 days (one exception: if high doses of Depakote are administered, effects can be seen in four days)

Laboratory Tests:

Required for: Depakote, Tegretol, Equatro and Trileptal. Specific tests depend on which drug is used, but often include the following:

Complete blood count, platelets, electrolytes, cholesterol, triglycerides, sonogram of ovaries (optional: for females under the age of 20 treated with Depakote), liver function tests, ECG (EKG), pregnancy test. For Topamax: kidney function tests (BUN and creatinine).

Pretreatment labs are generally not required for Lamictal

Laboratory Tests routinely done on an ongoing basis:

Tegretol, Equatro, Depakote and Trileptal blood levels must be monitored (especially during the initial weeks of treatment). Generally, once a person is stabilized on Depakote or Trileptal, blood level monitoring is not necessary. However, those treated with Tegretol or Equatro must have periodic and ongoing monitoring of blood levels.

Ongoing lab test are generally not required for Topamax or Lamictal

Common Side Effects (each medication has specific side effects, however listed here are side effects that can be seen in most of the anticonvulsants).

Less Common Side Effects

Rare or potentially dangerous (if these occur patient should seek emergency medical care)

Habit-Forming / Addiction Potential: none

Interactions with other medicines (varies depending on the specific drug):

Safety during pregnancy: there is a risk of birth defects when taking anticonvulsant mood stabilizers during pregnancy (especially the first trimester). Among the anticonvulsants Depakote is the most dangerous drug to use during pregnancy. Most psychiatrists do not prescribe these medications during pregnancy.

Breast feeding: not recommended when taking anticonvulsants

Antipsychotic Medications

Antipsychotic Medication Facts

Antipsychotic medications were first developed to treat psychotic symptoms such as hallucinations. The first such drugs were found to be effective in reducing psychotic symptoms, but they were notoriously “dirty” drugs, causing significant side effects. Since the mid-1990s new and improved antipsychotics have been developed and marketed. These newer generation medications are not side effect-free, but they are considerably safer and better tolerated. The newer drugs are commonly referred to as atypical antipsychotics.

Although atypical antipsychotic medications are highly effective in treating psychotic symptoms it has been found that they are also good treatments for mania, to augment treatments for depression, to treat aggression and possibly for mood stabilization in general.

Atypical (SGA: second generation) Antipsychotic Medications:

Generic Name

Brand Name

Typical Adult Daily Dose

olanzapine

Zyprexa

5-20 mg

risperidone Risperdal 4-10 mg
paliperidone Invega 4-12 mg
ziprasidone Geodon 60-160 mg
aripiprazole Abilify 15-30 mg
quetiapine Seroquel 150-400 mg
asenapine Saphris 10-20 mg
iloperidone Fanapt 12-24 mg
lurasidone Latuda 40-80 mg
brexpiprazole Rexulti 1-4 mg
cariprazine Vraylar 1.5-6 mg

Another antipsychotic medication that is used occasionally is clozapine (generic), Clozaril (brand name). This older-generation antipsychotic medication has significant side effects (e.g. dry mouth, constipation, sedation, seizures, excessive salivation, blurred vision, nausea, heartburn and weight gain) and has been associated with a serious blood disorder (agranulocytosis: which causes soreness of the mouth, throat and gums and a high fever). For this reason, it is never considered to be a first line medication choice. However, despite the problematic side effects, Clozaril is an important medication that can often successfully treat those rare people who have not responded to more traditional mood stabilizers, antipsychotics or antidepressants. The typical adult daily doses for Clozaril are: 300-900 mg.

Please note that all of the following information regarding antipsychotics pertains to the atypical antipsychotics or SGAs (with the exception of Clozaril).

Uses: Treat mania and agitation; treat psychotic symptoms associated with schizophrenia and both manic and depressive episodes; treat treatment-resistant schizophrenia, bipolar and major depression. The effectiveness of antipsychotic medications in the long-term prevention of recurrences of bipolar illness is as yet inconclusive.

Onset of effects: Antipsychotic medications used to treat mania or acute psychosis and can begin to reduce severe agitation within a few hours to a few days, however, the reduction of more pronounced manic and psychotic symptoms, is similar to that seen with other mood stabilizers such as lithium and anticonvulsants and other antipsychotics (7-10 days or longer).

Laboratory Tests: It is important to monitor triglycerides and cholesterol levels and blood glucose levels because many of these drugs can cause or aggravate type II diabetes. Weight gain must also be monitored. These lab tests are indicated in all new generation / atypical antipsychotics except Abilify and Geodon (it appears that the newest antipsychotics, Saphris, Fanapt and Latuda, may have a low incidence of metabolic side effects). Also frequent blood tests are required for those taking Clozaril to monitor for possible agranulocytosis. The blood monitoring must be done once a week for the first 6 months, during the next 6 months, every other week, and thereafter, once a month.

Common Side Effects for Atypical Antipsychotics (SGAs):

Less Common Side Effects

Rare or Potentially Dangerous Side Effects (if these occur, the patient should seek emergency medical care)

Habit-Forming / Addiction Potential: none

Interactions with other medications (varies depending on the specific drug)

Safety during pregnancy: atypical antipsychotics are generally considered to be safe during pregnancy

Breast-feeding: antipsychotic medications are secreted in breast milk. Since these are recently developed medications, there is inadequate information regarding safety to infants.

Special Concerns:

Antidepressant Medications

New Generation Antidepressants:

Generic Name

Brand Name

Typical Adult Daily Dose

trazodone Desyrel 50-400 mg

fluoxetine

Prozac, Sarafem

20-80 mg

bupropion

Wellbutrin

150-400 mg

sertraline

Zoloft

50-200 mg

paroxetine

Paxil

20-50 mg

venlafaxine

Effexor

75-350 mg

nefazodone

Generic only

100-500 mg

fluvoxamine Luvox 50-300 mg

mirtazapine

Remeron

15-45 mg

citalopram

Celexa

10-60 mg

escitalopram

Lexapro

5-20 mg

duloxetine

Cymbalta

20-80 mg

atomoxetine

Strattera

60-120 mg

desvenlafaxine Pristiq 50-400 mg
vilazodone Viibryd 10-40 mg
vortioxetine Trintellix 10-20 mg
leyomilnacipran Fetzima 40-120 mg

Antidepressants (all except Wellbutrin) are effective in treating severe anxiety, panic attacks and obsessive-compulsive disorder (OCD).

Uses: Treat unipolar major depression, dysthymia, bipolar depression, anxiety disorders, and obsessive-compulsive disorder (OCD), bulimia

Onset of Effects: generally, 2-6 weeks

Laboratory Tests: not required

Common Side Effects:

Rare Side Effects (if these occur, the patient should seek emergency medical care)

Habit-Forming / Addiction Potential: none

Interactions with other medications: (varies depending on the drug)

Safety during pregnancy: most experts agree that some new generation antidepressants are relatively safe for use during pregnancy (e.g. Prozac, Celexa, Lexapro, Zoloft, Effexor, Wellbutrin and Luvox). Paxil is contraindicated during pregnancy. (Note: the following antidepressants have only recently come to market and there is inadequate data to evaluate safety during pregnancy: Cymbalta, Strattera, Lexapro, Celexa, Nefazodone and Remeron). High doses of Desyrel (trazodone) should not be used during pregnancy.

Breast-feeding: antidepressants are secreted in breast milk, but the amounts are extremely low. Most experts agree that it is safe to breast feed while taking new generation antidepressants.

Special Concerns: If a patient has been taking antidepressants for a period of six weeks or more, abruptly stopping the medications, there can be withdrawal symptoms (this can occur with any of the antidepressants with the exception of Prozac). Withdrawal symptoms include: nausea, stomach upset, nervousness, and flu-like symptoms. Withdrawal symptoms are very unlikely if you have been taking the medication for less than six weeks. And withdrawal symptoms can be avoided almost 100% of the time by reducing the dose gradually.

Antianxiety Medications: Benzodiazepines

Benzodiazepine Facts:

Benzodiazepines are also commonly referred to as minor tranquilizers or anti-anxiety medications.

Benzodiazepines:

Generic Name

Brand Name

Typical Adult Daily Dose

diazepam Valium 4-30 mg
clonazepam Klonopin 0.5-2.0 mg
lorazepam Ativan 2-6 mg
oxazepam Serax 30-60 mg
alprazolam Xanax 1-4 mg

Benzodiazepine and benzodiazepine-like medications used for sleep:

Generic Name

Brand Name

Typical Adult Nighttime Dose

temazepam Restoril 15-30 mg
triazolam Halcion 0.25-0.5 mg
estazolam Prosom 1-2 mg
zolpidem Ambien 5-10 mg
zaleplon Sonata 5-10 mg
eszopiclone Lunesta 1-3 mg

Uses: Treats acute anxiety, agitation and insomnia in acute mania, anxiety disorders (such as panic disorder, post-traumatic stress disorder and generalized anxiety disorder).

Onset of Effects: 30-45 minutes

Laboratory Tests: none required

Common Side Effects:

Less Common Side Effects:

Habit-Forming / Addiction Potential: Significant risk for people with a prior personal or family history of alcoholism or other forms of serious drug abuse. Currently, Lunesta has been shown to be non-habit-forming. It is relatively new and as with all new drugs, the final evaluation will unfold as the medication has been on the market for a while.

Interactions with Other Medications: When taking benzodiazepines or any other type of medication that causes drowsiness or impaired alertness and reaction time can be potentially dangerous, especially if one has to drive and automobile. In addition, alcohol should not be consumed when taking benzodiazepines.

Safety During Pregnancy: Benzodiazepines typically are not to be used during pregnancy.

Breast Feeding: Benzodiazepines are secreted in breast milk and should not be used when breast-feeding.

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 abruptly stopped, 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. Never abruptly stop taking the medication except under medical supervision. It is also a good idea for patients to be especially careful to monitor their 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.

Atypical Sleeping Medications

Generic Name

Brand Name

Typical Adult
Nighttime Dose

Description

ramelteon Rozerem 4-16 mg Targets melatonin receptors
doxepin Selenor 3-6 mg A sedating low dose antidepressant marketed as a sleeping pill
suvorexant Belsomra 15-40 mg

Targets orexin receptors: a different mechanism than Benzodiazepines

Note: Over-the-counter Melatonin in doses of 2-10 mg have been used for years to treat initial
insomnia. Recently it has been found that these higher doses may exacerbate depression
and destabilize bipolar disorder. Low dose melatonin (0.5 mg) may enhance the quality
of sleep, but it does not produce sedation. It remains to be seen if a low dose strategy is
helpful and safe for use with mood disorders.

Calcium Channel Blockers

Calcium channel blockers are medications that are often used to treat certain cardiovascular diseases. One of these drugs has been found to be effective in the treatment of mania, and possibly as a treatment to prevent the recurrence of mood episodes.

Generic Name

Brand Name

Typical Adult Daily Dose

verapamil Calan, Isoptin 120 mg. given 3 or 4 times a day
Thus total daily: 360-480 mg

Uses and General Considerations: for people who cannot tolerate lithium, for rapid cycling bipolar, or for use during pregnancy (verapamil is considered to be the safest mood stabilizing medication for the treatment of bipolar disorder during pregnancy). Like most other mood stabilizers, it generally takes 7-10 days to begin reducing symptoms.

One additional calcium channel blocker is used occasionally to treat mania: nimodipine (brand name: Nimotop). This medication looks promising in terms of efficacy; however, it is very expensive and to date although there are positive case reports, there are no well controlled studies.

Miscellaneous

Omega-3 Fatty Acids

During the past ten 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 unipolar depressive symptoms when added to antidepressant medications in some individuals. Results in bipolar disorder have been minimal and disappointing. The best source of omega 3 fatty acids is fish oil because it has better bioavailability in the brain versus omega 3 from nut and seed oil.

Uses and General Considerations: Omega-3 fatty acids: 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 into one's ongoing diet). Doses recommended for treating depression are 1000-2000 mg per day. The version of omega-3 that has effects on mood is EPA.

Older Generation Antipsychotics

As noted above, newer generation antipsychotics have been developed during the past ten years. The newer drugs are considerably safer and have significantly fewer side effects than older-generation antipsychotic medications. We are simply mentioning these medications here just as a point of information since in rare instances some people may be treated with these drugs (brand names): Thorazine, Mellaril, Serentil, Trilafon, Loxitane, Stelazine, Prolixin, Navane, Orap, and Haldol. Of these the most common drugs that are still used these days are Haldol (often useful to initially treat very severe agitation seen in some types of mania or schizophrenia) and Trilafon.

Anticholinergic Medications

This class of medications is used occasionally to combat side effects of some antipsychotic drugs (side effects such as: muscle rigidity or spasms, restlessness, tremor). Again, we will only list these medications (brand names): Cogentin, Akineton, Artane. Anticholinergic drugs have their own set of side effects including: constipation, blurred vision, dry mouth, difficulty beginning urination, and occasionally memory loss, confusion and delirium.

SAM-e

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 intracellular 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. It has not been well supported in studies of the treatment of bipolar disorder, however it may prove to be a viable option for treating bipolar depression. It, however, is not useful for treating mania and 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-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 you are considering using SAM-e, it should only be taken with close observation by your treating psychiatrist.

St. John’s Wort

St. John’s Wort is an over-the-counter dietary supplement that has been found to have antidepressant properties. A meta-analysis (Linde, et al., 2008) has shown that St. John’s Wort is equally effective to prescription antidepressants in the treatment of depression if taken in large doses (e.g. 1800 mg per day). 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 (mild depression) -1800 mg. per day (taken in three divided doses, for major depression), 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. Research on the treatment of bipolar depression is sorely lacking. And as with any other treatment that has antidepressant properties, St. John’s Wort can potentially provoke mania. 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 doctor. Given its tendency to cause multiple and complex interactions with a host of medications, it is recommended that it not be used by people being treated with bipolar medications.

Caffeine Questionnaire

Sleep Disturbances: A high yield treatment intervention often overlooked in the treatment of psychological disorders. www.PsyD-fx.com.

Following is a caffeine questionnaire that allows clinicians to quickly determine caffeine intake in their clients. Even small amounts of caffeine exacerbate anxiety symptoms and the ideal caffeine levels for those with situational stress and anxiety disorders is zero. Small amounts of caffeine taken in the morning may actually be helpful for people suffering from depression (if not otherwise contraindicated due to medical conditions).

Everyone knows that caffeine ingested close to bed time may interfere with the ability to go to sleep (i.e. initial insomnia). However, the more problematic effect of caffeine is its tendency to disrupt deep sleep (also known as slow wave or restorative sleep). High amounts taken in the morning (e.g. 750 mg+) and modest amounts of caffeine taken after noon may interfere with the ability to get adequate deep sleep, even if not causing initial insomnia. Caffeine use among people suffering from almost any type of psychiatric disorder often exceeds levels that are acceptable. Preserving deep sleep is essential for emotional and cognitive functioning. Our patients may not realize or appreciate the negative impact of excessive caffeine use. Sleep is essential for normal brain functioning and needs to be optimized in each and every client we see for treatment.

It is important to tell all clients about the need for good quality sleep and keeping caffeine at acceptable levels is a high yield intervention. Yet, many of our clients may minimize the importance of this, so good patient education is important. Generally speaking, for those with significant psychological disorders, caffeine levels should not exceed 250 mg per day and should not occur after noon (in order to preserve deep sleep). Afternoon fatigue is often easily addressed by a 10-minute brisk walk, which generally results in 60-120 minutes of energy and relief from fatigue. Daily use of caffeine exceeding 750 mg  will require gradual caffeine reduction to avoid caffeine withdrawal (e.g. reducing daily use by 125 mg per day per week).

Please feel free to make copies of the following caffeine questionnaire for use with your clients.

Click here for the printable Caffeine Questionnaire

 

Suggested Readings

Geller, B. and DelBello, M.P. (Eds.) (2003) Bipolar Disorder in Childhood and Early Adolescence. The Guilford Press: New York.

Preston, J.D., O'Neal, J. and Talaga, M. (2017) Handbook of Clinical Psychopharmacology for Therapists: Eighth Edition. New Harbinger: Oakland.

Preston, J.D., O’Neal, J., and Talaga, M. (2015) Childhood and Adolescent Psychopharmacology Made Simple. Third Edition. New Harbinger: Oakland

Preston, J.D., O’Neal, J, and Talaga, M. (2009) Consumer’s Guide to Psychiatric Drugs. Second edition: Penguin Books: New York

References: Psychopharmacology

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Akiskal, HS, Bourgeois, M.L., et al. (2000) Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J. Affective Disorders, 59, Suppl: S5-530.

Alarcon, R.D., et al. (2000) proposing an algorithm for the pharmacological management of PTSD. Annals of Clinical Psychiatry. 12(4): 239-246.

Barkley, R.A. (2000) Taking Charge of ADHD. New York: Guilford Press.

Bauer, M., et al. (2003) Implications of the neuroprotective effects of lithium for the treatment of bipolar and neuro-degenerative disorders. Pharmacopsychiatry. 36 (3): S250-254.

Benes, F.M., et al. (2001) The density of pyramidal and non-pyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects. Biological Psychiatry. 50 (6): 395-406.

Biederman, J. et al. (1999) Pharmacotherapy for ADD reduces risk for substance abuse disorder. Pediatrics. 104(2): e20.

Blehar, M.C. and Rosenthal, N.E. (1989) Seasonal affective disorders and phototherapy. Archives of General Psychiatry. 46 (5): 469-474.

Bowden, C.L., Calabrese, J.R., Sachs, G.S., et al. (2004) A placebo-controlled 18-month study of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. Arch Gen Psychiatry. In press.

Calabrese, J.R., Bowden, C.L., Sachs, G.S., et al. (1999) A double-blind, placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry. 60: 78-88.

Castellanos, F.X., Lee, P.P., et al. (2002) Developmental trajectories of brain volume abnormalities in children and adolescents with ADHD. JAMA. 288(14): 1740-1748.

Cooper, J.R., Bloom, F.E., and Roth, R.H. (2003) The Biochemical Basis of Neuropharmacology. Oxford: Oxford University Press.

Davis, L.L., et al (2001) Pharmacotherapy for PTSD: A comprehensive review. Expert Opinion: Pharmacotherapy. 2(10): 1583-1595.

Dawson, R. et al. (1999) Course of treatment received by depressed patients. Journal of Psychiatric Research. 33: 233-244.

Delgado, P.L., Charney, D.S., Price, L.H., Aghajanian, G.K. Landis, H., and Heninger, G.R. (1990) Serotonin function and the mechanism of antidepressant action: Reversal of antidepressant induced remission by rapid depletion of plasma tryptophan. Archives of General Psychiatry, 47: 411-418.

Delle, C.R., et al. (2002) Efficacy and tolerability of oral and IM SAM-e in the treatment of major depression: comparison with imipramine in 2 multi-center studies. Am. J. of Clinical Nutrition. 76: 1172S-1176S.

Doraiswamy, P. M., Kahn, Z.M., Donahue, R.M., and Richard, N.E., (2001) Quality of life in geriatric depression: A comparison of remitters, partial responders, and nonresponders. American Journal of Geriatric Psychiatry, 9: 4223-428.

Doucherty, J.P. (1997) Barriers to the diagnosis of depression in primary care. J Clin Psychiatry. 58 (suppl 1): 5-10

Dubovsky, S.L. (2001) New concepts in the treatment of mania. U.C. Davis Symposium, Sacramento.

Echols, J., et al. (2000) SAM-e. Harvard Review of Psychiatry: 8, 84-90.

Fava, M. (2000) New approaches to the treatment of refractory depression. J Clin Psychiatry. 61 (suppl 1): 26-32.

Frank, E., Hastada, S., et al. (1997) Insuring lifestyle regularity in recovering bipolar disorder patients. Biological Psychiatry. 41: 1165-1173.

Geller, B. and DelBello, M.P. (Eds.) (2003) Bipolar Disorder in Childhood and Early Adolescence. The Guilford Press: New York

George, M.S. (2003) Stimulating the brain. Scientific American. 289 (3): 66-73.

Ghoemi, S.N., et al. (2001) Effectiveness and safety of long-term antidepressant treatment in bipolar disorder. J Clin Psychiatry. 62(7): 565-569.

Gitlin, M. (2002) Depression Myths and Contrary Realities. Continuing Education Series, UCLA.

Gitlin, M. (2002) Recognition and Resolve: Treatment Resistant Depression. U.S. Psychiatric Congress, Las Vegas.

Goodwin, F.K., Jamison, K.R. (2007) Manic-Depressive Illness. Second Edition New York: Oxford University Press Inc.

Heim, C. and Nemeroff, C.P. (2002) Neurobiology of early life stress. Seminars in Clinical Neuropsychiatry. 7(2): 147-159.

Hirschfeld, R.M.A., et al. (2002) Practice Guidelines for patients with Bipolar Disorder. Washington, D.C. American J. Psychiatry, 159, 1-50.

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