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

4 CE Hours - $99

Last revised: 05/07/2024

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Learning Objectives

This is an intermediate-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 and this course has been updated by Li Liang, MD. 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

Note: “Quick Reference to Psychiatric Medications” is available as a free download on the following website. It is typically updated once or twice a year. It may be helpful to have a copy of this as you read the following material: apadivisions.org/division-55/councils/research/quick-reference.pdf.

Introduction

This 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-5-TR 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-TR 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.

This is the first course in a three-course series. This first course teaches the basics of psychopharmacology. The second course, Bipolar Spectrum Disorders: Diagnosis and Pharmacologic Treatment, focuses on understanding common bipolar spectrum disorders and recognizing symptoms of mania, symptoms of hypomania, and symptoms of depression. The third course, Psychopharmacology for Child and Adolescent Mood Disorders: Problems and Promise, covers mood disorders in youth, including using psychotropic medication to treat youth.

All psychotherapists must be familiar with psychopharmacology for three reasons:

  1. It is important to know which classes of medication we use to treat different disorders 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.
  1. 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.
  1. In the current managed care practice model, increasing numbers of clients are receiving psychiatric medication treatment in their primary care physician’s office. Here the amount of time spent with the physician may be 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.

Preliminary Considerations

Legal and Ethical Issues

A review of case law reveals 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. to 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. Further, in half of the cases, the judge said that to not 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, the 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 practice, as mentioned earlier, many patients are receiving prescriptions for psychotropic medications from primary care physicians who may 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 response to medication and providing support and information regarding drug treatments, and they should 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 2,400 mg. or for Prozac, 10 to 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 either activate the medication or 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 and makes its way through the liver and into circulation, and thus is allowed to begin accumulating in the bloodstream. 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, it is usually required that they be prescribed higher doses of medications and eventually enough gets into the bloodstream 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.

Converse to this are the 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. Thus the ultimate solution for hypo-metabolizers 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 laboratory testing will include an assessment of kidney functioning. This is especially important for patients being treated with lithium; it eliminates without metabolism and is excreted by the kidney.

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.

The Process of Approving a New Drug by the FDA

There are four steps to getting a new drug approved by the FDA. The pharmaceutical company has created a new chemical compound and done the preclinical toxicology studies; then they have to submit an investigation of new drug application (IND) to the FDA, followed by three phases of clinical trials. The FDA will approve the final new drug application (NDA) based on the clinical trial data. The FDA also monitors the post-market drug safety. (Drugs.com)

Depression

Introduction

The World Health Organization (WHO) has launched the comprehensive Mental Health Action Plan 2013-2030. Depression is a common mental illness; it can affect anyone. Globally an estimated 3.8% of the population experience depression, including 5% of adults (4% among men and 6% among women), and 5.7% of adults older than 60 years. Approximately 280 million people in the world have depression.(1) Depression is about 50% more common among women than among men. Worldwide, more than 10% of pregnant women and women who have just given birth experience depression.(2) More than 700,000 people die due to suicide every year. Suicide is the fourth leading cause of death in 15-29 year-olds.

The twelve-month prevalence of major depressive disorder in the United States is approximately 7%, with marked differences by age group such that the prevalence in 18-29 year-old individuals is three times higher than the prevalence among individuals age 60 years or older. Depression is the leading cause of disability in the United States for individuals age 15-44 (DSM-5-TR), and ranks as the second most commonly seen disorder in patients seeking treatment from primary care physicians. Data shows the prevalence increased in the United States from 2005 to 2015 with steeper rates of increase for youth compared with older groups. Non-hispanic whites showed a significant increase. Morbidity and mortality associated with serious mood disorders is enormous. Chronic and recurrent depressions significantly increase risk for coronary heart disease, stroke, and osteoporosis (NIMH, 2003).

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 nurse practitioners and physician assistants who 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. In addition, there are shortages of psychiatrists. Treatment outcomes in primary care medical settings may have poor response largely due to the lack of adequate follow-up.

A Changing Treatment Landscape

The 1980s and 1990s saw the proliferation of HMOs and managed care companies that attempted to streamline mental health care in order to achieve cost containment. During this same time psychiatry training programs have increasingly emphasized psychopharmacology as the mainstay of treatment for clinical depression. Finally, pharmaceutical advances and marketplace forces have had a substantial impact on shifting patterns of practice in the mental health arena away from psychotherapy.

In many settings, psychotropics have 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, or substance use 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 of excluding dropouts due to side effects from percentages of responders (Gitlin, 2002). Thus, for most antidepressants studied, the positive outcomes are inflated (see Table 1).

Table 1.
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%

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

A large-scale clinical trial funded by the National Institutes of Health aims to address whether antidepressants work or not. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study is the largest prospective clinical trial of major depressive disorders ever conducted. It was a multicenter, nationwide association of 14 university-based regional centers, which oversaw a total of 23 participating psychiatric clinics and 18 primary care clinics. Enrollment began in 2000, with follow-up completed in 2004. All enrolled patients began on a single selective serotonin reuptake inhibitor (SSRI) (citalopram) and were managed by clinic physicians who followed an algorithm-guided acute phase treatment through five visits over a 12-week course. Dosing was aggressive and focused on maximizing the tolerable dose; if patients who were tolerating a medication had not achieved remission (that is, complete recovery from the depressive episode) by any of the critical decision points (weeks 4, 6, and 9), the algorithm recommended increasing the dose. Patients whose depression did not remit after this initial treatment were able to participate in a sequence of up to three randomized clinical trials or levels. The results do show antidepressants work, but with limitations, and it requires a combination of medications along with cognitive therapy to achieve better clinical outcome. (Rush, et al., 2006)

What has become clear is that mood disorders are tremendously complex and heterogeneous disorders that involve numerous interacting variables, such as, genetic predisposition, underlying medical and neurobiological changes, life stressors, interpersonal relationships, and 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 (HPA) neuroendocrine axis (see Figure 1). 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 HPA axis, which ultimately releases glucocorticoid hormones into general circulation. In humans, the principal 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 1.
Hypothalamic-Pituitary-Adrenal Neuroendocrine Axis
See also, Le Doux (2015)

Hypo: Hypothalamus, CRF: corticotropin releasing factor, PIT: pituitary gland, ACTH: Adrenocorticotropic hormone.

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 HPA axis, operating like a “brake”. Of course, if danger persists in the environment, the HPA 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 HPA axis, seen in many cases of major depression, results in a condition known as hypercortisolemia. 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., causing dendrite retraction, cell death, and hippocampal atrophy). Hypercortisolism also may damage other neural tissue including the anterior cingulate, amygdala, and 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, that is neurogenesis, in the hippocampus. Molecular studies have also implicated peripheral factors, including genetic variants in neurotrophic factors and pro-inflammatory cytokines. Additionally, volumetric and functional magnetic resonance imaging studies provide evidence for abnormalities in specific neural systems supporting emotion processing, reward seeking, and emotion regulation in adults with major depression (APA, 2022).

Antidepressant medications reduce cortisol levels (Heim & Nemeroff, 2002; Nestler, Hyman, & Malenka, 2001) and reactivate the production of BDNF, which can lead not only to clinical improvement, but also to the birth of new nerve cells in the hippocampus (Kempermann & Gage, 1999) (note: lithium, Depakote, Tegretol, Lamictal, Seroquel, and Equatro, and regular exercise also increase the levels of BDNF). 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, such as, genetically based mood disorders, secondary to various medical illnesses such as thyroid disease, or due to the impact of substances(e.g., alcohol or 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 two weeks or fails to respond adequately to psychotherapy.

2.    Depressed/sad mood and/or loss of interest in life. Feeling hopeless, helpless, and/or worthless most days or every day for at least two weeks.

3.    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.

4.    The presence of neurovegetative symptoms (if these are sustained, i.e., present most days):

5.    66% of patients with Persistent Depressive Disorder (previously called dysthymia) have been shown to be responders to antidepressants and thus should also be considered for such treatment.

6.    Depression is 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.

7.    Substance/Medication-induced depression disorder. The essential character of substance/medication-induced depression is directly due to physiological effects of a substance (e.g., a drug of abuse, a medication, or a toxin exposure). We can do laboratory testing (blood test and/or urine test) to detect a substance. The treatment goal is absence from substance use or stopping the medication that can cause depression. We can use an antidepressant to treat depression as well.

Psychopharmacology of Depression

Antidepressant Medications

Antidepressants and their daily adult dose ranges are listed below. These medications have been developed since the late1980s and are considerably safer and easier to tolerate than older-generation tricyclic and MAOI antidepressants. The following table lists the commonly used antidepressants from the different classes.

Classes of Antidepressants

Generic Name

Brand Name

Typical Adult Daily Dose

SSRIs (selective serotonin reuptake inhibitors)

fluoxetine

Prozac, Sarafem

10-80 mg
 

paroxetine

Paxil/Paxil CR

20-50 mg
 

citalopram

Celexa

20-40 mg
 

escitalopram

Lexapro

10-20 mg
 

sertraline

Zoloft

50-200 mg
 

fluvoxamine

Luvox

50-300 mg

SNRIs (serotonin norepinephrine
reuptake inhibitors)

venlafaxine

Effexor/Effexor XR

37.5-225 mg
 

duloxetine

Cymbalta

20-120 mg
 

desvenlafaxine

Pristiq

50-100 mg
 

levomilnacipran

Fetzima

20-120 mg

TCAs (tricyclic antidepressants)

amitriptyline

Elavil

25-300 mg
 

nortriptyline

Pamelor

25-150 mg
 

clomipramine

Anafranil

25-250 mg
 

sinequan

Doxepin

25-300 mg
 

impramine

Tofranil

25-100 mg

MAOIs (monoamine oxidase inhibitors)

phenelzine

Nardil

45-90 mg
 

selegiline

Emsam (patch)

6-12 mg/24h
 

tranylcypromine

Parnate

30-60 mg

Atypical antidepressants

bupropion

Wellbutrin (SR/XL)

150-450 mg
 

mirtazapine

Remeron

15-45 mg
 

trazodone

Desyrel

100-300 mg
 

vilazodone

Viibryd

10-20 mg
 

vortioxetine

Trintellix

5-20 mg
 

dextromethorphan/bupropion

Auvelity

45/105 mg (two tabs daily)

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, such as pharmaceutical company advertising and decisions made by HMOs and managed care companies to adopt cost-effective drug formalities).

2. Consensus, that is, inviting “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, not 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 & Tomarken, 2001; Goodwin & Jamison, 2007).

Major depression as defined by DSM-5-TR criteria 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 who experience a decreased availability of neurotransmitters such as serotonin (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.

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

In general, medications recommended for major depressive disorder include Selective Serotonin Reuptake Inhibitors, which are used as the first-line treatment (SSRIs: Prozac, Zoloft, Paxil, Luvox, Celexa, Lexapro). SNRIs can be used as the second-line choice (serotonin and norepinephrine reuptake inhibitors such as Effexor, Pristiq, Fetzima, and Cymbalta).

Antidepressants may have a side effect referred to as activation (affecting approximately 10% of patients), which is experienced as increased energy, anxiety, initial insomnia, and/or agitation, typically emerging several hours after taking the first dose (also this can occur shortly after dose escalations). In individuals with this acute onset, side effects often result in abrupt patient-initiated discontinuation (the side effects often scare patients and may make them very reluctant to go through another antidepressant trial).Thus although after 4-6 weeks of treatment SSRIs often begin to significantly reduce both depression and anxiety symptoms, the initial few weeks of treatment can be very challenging and many patients drop out of treatment. A popular and effective way to address this problem is to initially co-administer an anti-anxiolytic agent, such as abenzodiazepine (e.g. Ativan, a minor tranquilizer) to rapidly reduce anxiety, agitation, and drug-induced activation. In addition, since benzodiazepines begin to reduce anxiety within an hour of taking the medication, the experience for many patients is that they feel noticeably better, quickly. This is an added benefit because it often leads to hopefulness about treatment and enhances compliance. Generally, after one month of treatment the benzodiazepine can be phased out. This is often a very successful strategy, however there is one important warning. Since benzodiazepines can be drugs of abuse, the use of these agents is risky and not indicated if there is a history of alcohol or substance abuse. With an addiction history, some psychiatrists are now using the non-habit-forming antihistamine, hydroxyzine (Atarax; Vistaril), to target the activation, or low doses of trazodone (25-50 mg), or low-dose Remeron (7.5-15 mg) for initial insomnia. We can combine the dual-action antidepressants such as SSRIs with Wellbutrin or SNRIs with Wellbutrin to target different neurotransmitters, i.e., targeting 5-HT, DA and NE, and DA and 5-HT respectively. If the patient has only a partial response to an antidepressant, we can use an augmentation strategy to achieve a better result.

If a patient has major depressive disorder with psychotic features, we can add an antipsychotic medication as an adjunctive treatment to manage psychotic symptoms.

If a patient’s depression is very severe – the patient is unable to eat, sleep, or function – the ECT treatment can result in up to 80% symptom reduction.

For patients who have atypical depression, symptoms include: hypersomnia, appetite increase, carbohydrate craving with subsequent weight gain, and severe fatigue. Other symptoms often associated with atypical MDD are rejection sensitivity and anxiety attacks. Medications of choice are SSRIs, monoamine oxidase inhibitors (MAOIs) and possibly Wellbutrin (APA, 2003).

It is important to exercise caution when treating atypical MDD because many such individuals may be expressing the depressive phase of bipolar illness and if treated with antidepressants alone there is a risk of switching (i.e., provoking mania or hypomania) or cycle acceleration (the tendency to cause increasingly severe or more frequent mood episodes). It has been found that 80% of those suffering from atypical depression ultimately are discovered to have bipolar disorder (usually, bipolar II). More will be said about switching and cycle acceleration in the section below on bipolar illness.

Partial and Non-Responder Strategies

Clinically, 55% to 65% 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). STAR*D has shown that 50% of patients will achieve remission if they stay in the treatment after two treatment steps (Rush et al., 2006). 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 The highest yield next step strategy is to progressively increase the medication dose (Trivedi & Klieber, 2001). 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 (that is, 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 Once again, one must evaluate issues involving adherence and possible substance abuse. Another consideration is to make sure the diagnosis is major depressive disorder. 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], such as Zoloft, to a different class of antidepressants. (Trivedi & Klieber 2001).

Phases of Treatment for Major Depressive Disorder

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 patients 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 six months. If during this time period there are no breakthrough depressive symptoms, then discontinuation can be considered. Gradual discontinuation 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, those in their third or subsequent episodes. Chronic treatment in an attempt to prevent recurrence can be helpful in this regard as we manage other chronic illnesses such as hypertension and diabetes. The maintenance of treatment is essential to prevent recurrence of depression.

Treatment for Other Types of Depression

Seasonal Depression: This 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.

Premenstrual Dysphoric Disorder (PMDD): This disorder is characterized by repetitive cyclical, physical, and behavioral symptoms occurring in the luteal phase of the normal menstrual cycle. Symptoms may extend into the first few days of menses. Mood symptoms are only seen for discrete periods of time prior to menstruation and absent the rest of the month. The low-dose SSRI or SNRI is often helpful if the oral contraceptive or other alternative therapies, exercise or change of diet fail to control the symptoms. A higher dose may be prescribed if there is no response.

Postpartum Depression: Clinically, one in eight women experience symptoms of postpartum depression, and the rate of depression diagnoses at delivery is increasing. Technically, this can occur during pregnancy but more commonly occurs after the birth of the infant. Especially if there is a pre-existing depression, the onset can follow rapidly after delivery. However, more commonly, the average onset is within four weeks following delivery. Postpartum depression is distinct from what is often referred to as “the baby blues”. Such a condition is not pathological but rather reflects increased emotional sensitivity in general, for the full range of emotions, including happiness as well as bouts of sadness or tearfulness. It is thought that this phenomenon, common to most new mothers, occurs in 30% to 80% of women following childbirth, with symptoms developing within two to three days after delivery, peaking on the fifth day, and resolving within two weeks.

Postpartum depression, however, is quite different, with a prolonged course and more severe symptoms. It often presents with symptoms of depressed mood, anhedonia, weight changes, sleep disturbance, psychomotor problems, low energy, excessive guilt, loss of confidence or self-esteem, poor concentration or suicidal ideation. Many women tend to experience a severe episode and are completely unable to hold or are disinterested in holding their babies. This can profoundly interfere with critical early child-mother bonding (consequences that may have a life-long impact). The greatest risk is postpartum psychosis. Here, mothers do not interact at all with their children and in many cases, they include the child in their delusional thinking. Estimates show that each year in the United States 150 babies are killed by their mothers in the midst of florid psychotic thinking and behavior. All women with postpartum psychosis should be strongly considered for hospitalization.

The treatment is psychotherapy and/or medication. Antidepressants are recommended for more severe episodes.. Response rates are slow and such depressive and psychotic symptoms,if untreated, last longer than most unipolar depressive episodes. They may continue for one and a half or more years before spontaneous remission. Standard treatment requires at least two to four weeks to begin to cause a response. It is good that the FDA has approved two new medications (Zulresso and Zurzuvae) for treating postpartum depression.

Brexanolone (brand name Zulresso) is a drug approved by the FDA in 2019 with unique actions. It requires gradual intravenous infusion over a period of 60 hours and must be administered in the hospital. This is the first FDA-approved drug for postpartum depression. It is presumed to have actions on allopregnanolone, a neuro-steroid that has actions on the GABA system. With premenstrual depression and postpartum depressions, allopregnanolone levels drop precipitously. Progesterone may be targeted by the drug but the precise mechanism of action is unknown at the time of this course update. Typically, 30% of women experience a significant and rapid reduction in psychiatric symptoms. The drug may have enduring positive effects for at least a month, but longer-term follow-up studies have not been done to date. The cost of the medication alone is currently $34,000, which does not include the cost of the hospital stay and the clinicians involved. The most common side effects are sedation, dizziness, dry mouth, loss of consciousness, and flushing.

Zuranolone (brand name Zurzuvae) is the first oral pill to treat postpartum depression. It has been approved by the FDA since August, 2023. It can be given with fat-containing food for 14 days. It works fast, in three days, and remission is about 60% at six weeks. It improves anxiety symptoms as well. It has a similar action as brexanolone. The common side effects are sedation, dizziness, dry mouth, loss of consciousness, and flushing. However, the medication trials haven’t included breastfeeding women.

New Treatments and Interventional Treatment for Major Depressive Disorder

While the most common treatment for major depression is to use a traditional treatment, that is, an antidepressant, , a better understanding of the pathophysiology underlying many mental illnesses has led to the recent increased use of treatments that require specialized administration and the creation of a subspecialty called interventional psychiatry. For example, we have mentioned Brexanolone (brand name Zulresso), an intravenousdrug for postpartum depression. We have esketamine, a nasal spray for refractory depression treatment as well. Other interventional treatments for depression are rTMS, vagus nerve stimulation, and ECT.

Esketamine (Brand name: Spravato) The drug ketamine has been used in medicine and veterinary medicine for years as an anesthetic. It also has been abused as a street drug because of its dissociative and hallucinogenic properties (on the street it is often referred to as Special K). It is also widely used in psychiatry mainly in ketamine clinics to treat severe, treatment-refractory depression and especially acute, severe suicide risk. In psychiatry, it is used off label and administered typically twice a week in the clinic, because it requires IV dosing and a period of two to three hours of patient observation afterward. This is because dissociative and some psychotic symptoms exist for a period of several hours after dosing. Some severely affected patients respond rapidly to the antidepressant effects. Also, there is often a rapid decrease in suicidal ideation and impulses. It has also been used successfully to treat patients with psychotic depressive episodes.

Recently, the active S isomer of Ketamine (esketamine; brand name Spravato) has been approved by the FDA (March, 2019), to treat refractory depression and/or acute suicidal risk. It is available in a nasal spray. Because of its abuse potential, it is tightly regulated by both pharmacies and treatment facilities. It must be administered in a treatment facility that has been certificated in Spravato Risk Evaluation and Mitigation Strategy (REMS). The duration of effects and even the frequency of dosing is largely unknown. S-Ketamine is a glutamate NMDA antagonist, although its specific mechanism of action is largely unknown. In many individuals, however, the effects are seen within minutes to hours. The success of S-Ketamine opens the door for future drug development because its action on glutamate is clearly different than other, standard antidepressants.

Transcranial Magnetic Stimulation (TMS) In TMS, a series of magnetic pulses are administered via the scalp to stimulate neurons in areas of the brain associated with major depressive disorder (MDD). It is considered a non-invasive treatment for MDD. The initial recommended course of treatment is six weeks, but most improvement is seen in the first two to three weeks. After six weeks of treatment, many patients require ongoing maintenance treatment, which can be weekly or monthly based on response. The repetitive transcranial magnetic stimulation (rTMS) is the first one approved by the FDA, in 2008. As TMS technique has improved, we can do deep TMS, intermittent Theta burst stimulants, navigated TMS, and accelerated TMS to improve symptoms quickly.

Vagus Nerve Stimulation is a technique that was initially developed to treat severe epilepsy. It has been found to be effective in successfully treating about 50% to 60% of people who suffer from highly treatment-resistant depressions. The FDA approved it to treat chronic Treatment Resistant Depression (TRD) in 2005. A pacemaker-like device is implanted in the anterior chest wall (beneath the collar bone) and a wire extends up into the neck where it is wrapped around the left vagus nerve. Periodically, a mild electrical stimulation is delivered to the vagus nerve, which causes nerve activity that enters the brain. Due to the cost of the procedure and risks related to surgery, it has not been used widely in psychiatry.

Electroconvulsive therapy (ECT) Although ECT is used to treat psychiatric illnesses ranging from mood disorders to psychotic disorders and catatonia, it is mainly employed to treat people with severe treatment-resistant depression (TRD). It is one of the most effective treatments for major depressive disorder, and can significantly improve patients’ quality of life. During ECT treatment, the patient can continue to be on antidepressants.

Herbs and Supplements for Major Depressive Disorder

A number of experimental treatments are widely used by people who have experienced depression, especially people who try over-the-counter supplements and herbs. To help symptoms of depression, people have tried omega-3 fatty acid supplementation (Peet and Horrobin, 2002), SAM-e, and St. John’s Wort. It is recommended that if your patient is considering using them, the efficacy and safety may not be established. It should only be taken with close observation by their treating mental health professional.

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 (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. If you want to know more about omega 3, please see NIH omega-3 fatty acids: health professional fact sheet.

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. Some studies have shown it to be equally effective when compared to prescription antidepressants, while others do not show any benefits or only minimal effectiveness. Most notable is the virtual lack of side effects. 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. 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.

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. (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.

Oxytocin is a hormone normally produced in the hypothalamus and released by the posterior pituitary. Oxytocin may influence depressive disorders by modifying stressor reactions. Oxytocin interacts with the HPA axis, monoamines, and inflammatory factors. Social sensitivity might be modulated by oxytocin thereby affecting negative affect (Mcquaid, 2014).

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 (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 1,300 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 4,400. 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 4,400 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, and 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 ten 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, 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.

In 2004, the FDA required a black box warning related to increased risk of suicidality in pediatric patients for all antidepressant drugs, and in 2007 extended the warning to include patients up to age 24.

 

Bipolar Spectrum Disorders

Introduction and Diagnostic Issues

Bipolar disorder is a common type of mood disorder that is a recurrent and often chronic mental illness marked by episodes of hypomania or mania and depression, associated with a change or impairment in function. It includes bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance/medication induced bipolar and related disorder, bipolar and related disorder due to another medical condition and other specified bipolar disorder, and unspecified bipolar disorder. The lifetime prevalence of bipolar disorder type I in the US is estimated to be between 0.5% and 1.0%, affecting men and women equally. The lifetime prevalence of bipolar II disorder in the US is estimated to be between 0.5% and 1.1%, with women more likely than men to be affected.

This is an introductory course on bipolar spectrum disorder. If you want to learn more, please see the course on this website called Bipolar Spectrum Disorders: Diagnosis and Pharmacologic Treatment.

Symptoms of Classic Mania

Symptoms of Hypomania

Hypomania is a milder version of mania that typically involves much less intense mood symptoms. The duration of hypomania is at least four days and is frequently not noticed as being a sign of illness by the person experiencing it (although most times family members are more clearly aware of the mood changes and increased energy). During the hypomanic episode, 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.

Symptoms of Mania or Hypomania with Mixed Features

There are five main subtypes of bipolar disorder:

If the patient’s symptoms do not fully meet the criteria for mania, hypomania, or depression, however, and their symptoms still cause clinically significant distress or impairment in social, occupational, or other important areas of functioning, we call them “Other Specified Bipolar and Related Disorder and Unspecified Bipolar and Related Disorder”.

“Rapid cycling” is one of the specifiers we commonly hear about. It requires at least four mood episodes in 12 months and the mood episodes have met the criteria for manic, hypomanic, or major depressive episodes. These episodes can occur in any combination and order.

Untreated or poorly treated bipolar illness leads to disaster. Careers and marriages can be 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 very unstable and fragile neurobiological mechanisms for affect-regulation. 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, because 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
  4. National Institute of Mental Health (2006) STEP-BD Program
  5. American Psychiatric Association: (2002) Bipolar Disorder Practice Guidelines: Second Edition.

Currently, there are many medications that are approved by the FDA for the treatment of bipolar disorder: Lithium, Depakote, Equetro, Lamictal, Symbyax, Zyprexa, Risperdal, Seroquel, Geodon, Abilify, Latuda, Saphris, Vraylar, and Caplyta. However, a number of other effective drugs are in common use. The use of medications not approved by the FDA for the treatment of certain conditions is referred to as “off-label use.” It is important to note that off-label use of medications is a very common practice in every branch of medicine. Commonly used as off-label medications for bipolar disorders are antiseizure medications such as Tegretol, and antipsychotic medications such as Thorazine and Haldol.

Bipolar spectrum disorder management also requires a long-term management plan that includes medication treatments, continuation of medical follow-up, and adjunctive psychosocial therapies such as a healthy lifestyle including sleep hygiene, exercise, and stress management.

In addition, the medication choice always must take into consideration the ultimate goal of preventing recurrences, a lot of which ultimately depends on long-term medication tolerability.

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 two or four 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 negative stigma regarding mental illness; and/or

3. they conclude that the episode they experienced is not really bipolar disorder but 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).

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 it 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, or arthritis. It is not a condition that can be cured by currently available medications. It is a recurrent disease. 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). 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). The majority of people being treated for bipolar disorders, however, 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 is a significant challenge since most bipolar medications carry high risks of unpleasant side effects.

For many patients, taking medications when they 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. Medication treatments are far from perfect, but they have the kind of effectiveness that can substantially reduce suffering, keep families together, avoid catastrophes, and save lives.

Bipolar Medications

There are three major classes of psychiatric medications used to treat bipolar disorder. These include Lithium, Anticonvulsants, and Antipsychotics. Other medications have been found to be effective in treating various symptoms of bipolar disorder. Generic and brand names (registered trademarks) are listed below.

Lithium

Generic Name

Brand Name

Typical Adult Daily Dose

lithium

Lithonate, Eskalith

600-1800 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 sodium

Depakote

750-1500 mg

carbamazepine

Tegretol, Equetro

800-1600 mg

Oxcarbazepine (off-label)

Trileptal

600mg-1200mg

lamotrigine

Lamictal

50-200 mg

Therapeutic blood levels

Depakote blood levels

50-125 mcg/ml

Tegretol blood levels

4-12 mcg/ml

Trileptal blood levels

not yet established

Lamictal blood levels

not necessary to monitor

Atypical Antipsychotics, also referred to as second generation antipsychotics

Generic Name

Brand Name

Typical Adult Daily Dose

olanzapine

Zyprexa

5-20 mg

risperidone

Risperdal

2-6 mg

quetiapine

Seroquel

200-800 mg for bipolar I disorder, manic and 300 mg for bipolar depression

ziprasidone

Geodon

40-160 mg with food

aripiprazole

Abilify

15-30 mg

asenapine

Saphris

5-20 mg

lurasidone

Latuda

20-120 mg with food

cariprazine

Vraylar

3-6 mg

Lumateperone

Caplyta

21 mg-42 mg

Other Medications We Can Use to Treat Bipolar Spectrum Disorder

Antidepressant/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): 3 mg/25 mg, 6/25 mg, 6/50 mg, 12/25 mg, 12/50 mg.

Benzodiazepines, also called anxiolytic medications or minor tranquilizers

Benzodiazepines: Generic and Brand Names and Typical Adult Daily Doses:

Generic Name

Brand Name

Typical Adult Daily Dose

diazepam

Valium

5-10 mg

clonazepam

Klonopin

0.5-4.0 mg

lorazepam

Ativan

2-10 mg

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

Targets for Medication Treatment

There are three primary goals in medication treatment for bipolar spectrum 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, 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, agitation, impulsivity, severely impaired judgment and/or aggression), and/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 (anxiolytics such as Ativan, Klonopin, or 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 (electroconvulsive therapy; “shock” treatments) can be successfully used. ECT is also very effective for the emergency treatment of severe mania.

If the situation is not extremely urgent, then it is commonplace to order some 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, and Depakote.

Treatment Guidelines: Mania

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

These medications generally require seven to ten days of treatment before you see an onset of action and symptom-reduction, except for benzodiazepines, which can calm and reduce agitation quickly. Once symptoms begin to be reduced, continued treatment for several weeks will often be necessary to eliminate acute manic symptoms. As noted earlier, 90% of people will ultimately be treated with two or more 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;
  1. Reduce core manic symptoms such as restlessness, sleeplessness, rapid speech, paranoid ideas, etc.; and
  1. Begin treatment for relapse prevention.

Stage One

As mentioned above, patients are usually treated in the hospital, and 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 seven to ten day period of time before symptom reduction, but with one notable exception: the anticonvulsant mood stabilizer Depakote, which when given in loading doses, can begin to show anti-manic effects in about four days. Often, once severe agitation has subsided, benzodiazepines are gradually reduced and then within a few days 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 different symptom presentations of mania which can be classic mania or mania with mixed features. A considerable amount of research has been done to discover which medications are best suited for treating particular patients. 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 decide on initial medication choices (see below). However, the fact is that each person will have a number of factors unique to them 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.

“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.

With Mania with Mixed Features (agitation, decreased need for sleep, extreme irritability, insomnia, feelings of despair, hopelessness, etc.), there is some controversy regarding the treatment of dysphoric mania. Currently, there are no FDA-approved medications to treat mixed features. However, clinically we use different classes of mood stabilizers to manage symptoms.

The treatment of childhood-onset bipolar disorder is beyond the scope of this 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.

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 or delusions). It is proving to be effective not only for treating mania but also for relapse prevention. Unfortunately, Clozaril has more significant side effects, some of which are potentially dangerous, such as agranulocytosis, neutropenia, myocarditis, and cardiomyopathy. ECT (electroconvulsive therapy) is a safe and highly effective treatment for severe mania.

Stage Three: Maintenance Treatment

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 maintenance treatment.

In general, the medications used to treat mania are considered to be very effective for most people experiencing a manic episode. Bipolar disorder is a lifelong illness and all experts agree that a 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 disaster.

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:

It is important to underscore that many treatments that ordinarily are effective in reducing unipolar depression, such as, 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 beneficial in treating bipolar depression, however, there is not clear evidence to support this use. Excessive bright light exposure (which can treat some types of seasonal depression) has also been associated with 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.

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 that 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/Seroquel XR, Symbyax, Latuda, Vraylar, and Caplyta. We also use Lamictal to treat bipolar depression. Lamictal has not been approved for this use, clinically, however, it is often effective in treating bipolar depression with good tolerability from patients. 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 four to six weeks of treatment. This is done to avoid inducing a potentially dangerous rash called Stevens-Johnson syndrome that can occur if there is rapid dose escalation. Fortunately, since the use of gradual dosing has been adopted, the risk of Stevens-Johnson is almost nil. Lithium has been shown to have antidepressant effects when administered as a monotherapy in bipolar depression (although not in unipolar depression).

Stage Three

This is much the same as stage three treatments for mania. We can keep the patient on the medications that work for them on stage two as a maintenance treatment. We need to continue to monitor any side effects and check laboratory results periodically to make sure the patient’s liver function and kidney function are within normal range. If side effects are 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). Augmentation medication usually is chosen from a different class of mood stabilizers.

In conclusion, there is an important reason for emphasizing the process in prescribing these medications. 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 laboratory 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 medication combinations are found.

Adjunctive Therapies for Bipolar Spectrum Disorder

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 30%-35% of brain mass is made up of omega-3 fatty acids. These molecules are important in forming cell membranes and 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.

Psychotherapy

Although medication treatment is the backbone of successful therapy for bipolar disorder, 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 are the most common mental disorders in the U.S. They affect 40 million adults every year, that is about 19.1% of the population age 18 and older. An estimated 31.1% of U.S. adults experience an anxiety disorder at some time in their lives and many become chronic conditions. Clinical studies have shown that the combination of psychotherapy and medication treatment is the most effective treatment. Almost all anxiety disorders discussed in this section have been found to respond well to cognitive behavioral therapy (CBT) and/or acceptance and commitment therapy (ACT), or to exposure-based cognitive therapy. Despite this, medication treatments are often useful and even necessary as the first-line of treatment, owing to the following:

  1. In many communities there may not be professionals trained to provide therapy.
  1. Some patients refuse therapy owing to the fact that such treatments require exposure, and people are too afraid to undertake the treatment.
  1. 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.
  1. Some patients with marginal ego strength may not be able to tolerate therapy well.

One caveat regarding using medication initially is that If at some point exposure-based treatments are employed, it will be necessary to gradually reduce the dose of medication so that the client  experiences some anxiety. This is required since it has been found that exposure therapy and deconditioning are not successful unless the person experiences some amount of anxiety, is able to undergo exposure trials using anxiety-management skills, and has the experience of enduring anxiety without catastrophe. This is essential in order to experience mastery.

Diagnostic Issues

The following disorders have been classified in DSM-5-TR as anxiety disorders:

Psychopharmacology For Anxiety Disorders

There are two major classes of medications used to treat anxiety disorders: antidepressants (all of those mentioned above with the exception of Wellbutrin, which can increase anxiety in some patients) and the anxiolytics (commonly referred to by their class name: benzodiazepines., formerly known as tranquilizers ). We will also consider adjunctive and experimental treatments. We will focus on the medication treatments for generalized anxiety disorder, panic disorder, and social anxiety.

Antidepressants have been addressed in detail above in depression treatment, thus there will be only a few issues presented here. Most of the antidepressants, especially those that target serotonin and norepinephrine, have been found to be highly effective in treating most forms of anxiety disorders. 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 ten 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, we need to start antidepressants at a very low dosage and slowly titrate it up as the patient can tolerate it. Another popular and effective way to address this issue is to co-administer a benzodiazepine. Using a benzodiazepine at the low dosage in short duration is considered to be appropriate treatment as an adjunctive treatment. If it is dosed appropriately, it begins to reduce anxiety within 30-45 minutes and can also operate to override activation. The common consensus is to use a benzodiazepine for the first month of treatment and then to taper it off. After one month of treatment, most antidepressants begin to show anti-anxiety 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. Another option is to use beta-blockers such as propranolol (Inderal) to manage physical symptoms of anxiety.

Benzodiazepines

Generic Name

Brand Name

Typical Adult Daily Dose

Diazepam

Valium

2.5-10 mg

Clonazepam

Klonopin

0.5-4 mg

Lorazepam

Ativan

2-10 mg

Alprazolam

Xanax

0.25-4 mg

Medications used to treat anxiety-related initial insomnia:

(See also, the course Bipolar Spectrum Disorders: Diagnosis and Pharmacologic Treatment.)

Generic Name

Brand Name

Typical Adult Nighttime Dose

Temazepam

Restoril

15-30 mg

Triazolam

Halcion

0.125-0.5 mg

Zolpidem

Ambien

5-10 mg

Zaleplon

Sonata

5-20 mg

eszopiclone

Lunesta

1-3 mg

diphenhydramine

Benadryl

25-50 mg

Ramelteon

Rozerem

8 mg

survorexant

Belsomra

10-20 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 six 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 their 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 history of substance use disorder.

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 (GAD)

Selecting antidepressants to treat GAD is based on the treatment guideline and the individual’s history and conditions. The first-line treatment is selective serotonin-reuptake inhibitor (SSRI), the second-line treatment is serotonin-norepinephrine reuptake inhibitor (SNRI). For the third-line medication we can use buspirone (BuSpar). (Please see Depression treatment on SSRIs and SNRIs.) There are other medications that can be used to treat anxiety disorders, such as mirtazapine (Remeron), gabapentin (Neurontin), and pregabalin (Lyrica).

Antidepressants (SSRIs and SNRIs) are generally very effective in treating GAD. It usually requires four to six weeks of treatment, or longer in some instances, before patients begin to show clinical improvement. We need to inform patients about this so they can understand and not prejudge that the medication does not work. The doses used to treat GAD are similar to those used to treat major depression.

Buspirone (BuSpar) dosage starts with 7.5mg twice daily initially and can gradually increase up to 60 mg/daily. 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, at this time, its efficacy is not as robust as that seen with benzodiazepines or antidepressants.

Pregabalin (Lyrica) dosage is at 75mg twice daily initially and can increase to higher dosages, up to 600 mg/day, and Gabapentin (Neurontin) can take between 300 mg to 2400 mg/day. Both have significant antianxiety effects and have been found to be useful in the treatment of generalized and social anxiety disorder. However, patients can develop tolerance and can have withdrawal symptoms if they stop taking it suddenly. Clinically, it has never been used as the first-line treatment for anxiety disorder.

Panic Disorder

Two classes of medications are effective in treating panic disorder: antidepressants and benzodiazepines. At the initial stage, we can use both classes of medication; when the patient’s panic attack subsides, the patient can continue with an antidepressant.

For antidepressants, we use SSRIs and SNRIs, even TCAs. Please see the Depression section regarding medication selection.

The advantage to using benzodiazepines is the quick onset of action. This can be a godsend for patients suffering frequent and severe panic attacks. The particular drugs used most often are the high-potency benzodiazepines: Xanax, Ativan, and Klonopin (other benzodiazepines 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. These medications have a rapid onset of action and are generally well tolerated. The preference for using benzodiazepines is in its scheduled, longer-acting agents so that medication use is time-dependent rather than response/panic-dependent. 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). Once panic symptoms have been eliminated or greatly reduced with antidepressants, we can taper off benzodiazepine.

Social Anxiety

Antidepressants such as SSRIs and SNRIs can be considered as the first-line treatment. Monoamine oxidase inhibitors (MAOI’s) can be used to treat severe and pervasive forms of social anxiety that have not responded to SSRIs or SNRIs. We still can use benzodiazepineson a short-term basisto manage symptoms. Another treatment choice is to use propranolol (Inderal), a beta blocker, at 30 minutes to one hour before exposure to a social situation at doses of 10mg-40 mg.

Herbs and over-the-counter supplements

There are many herbs and over-the-counter supplements that have shown some anti-anxiety benefits, but the majority of them have insufficient evidence for reducing anxiety symptoms. Some of them can cause liver damage if used excessively, such as Kava Kava. People still use them experimentally to relieve their anxiety symptoms. The commonly used herbs are chamomile tea, passion flower, valerian, lavender, and peppermint. Over-the-counter supplements include 5-HTP, ashwagandha, magnesium, theanine.

Coffee and anxiety

For healthy adults, the FDA has cited 400 milligrams a day(that’sabout four or five cups of coffee a day), as an amount not generally associated with dangerous, negative effects. However, when anxiety is a prominent feature, then caffeine use should be completely avoided. Many individuals who suffer from anxiety disorders inadvertently consume significant amounts of caffeine and this always complicates psychological or medical treatment. “Energy drinks” should also be avoided. Caffeine content of energy drinks vary. There is a report that drinking more than 250 mgs 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 symptoms. Please see Appendix ? for the caffeine questionnaire to know how much caffeine is in various drinks.

 

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

=

Excedrin

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.

Attention Deficit/Hyperactivity Disorder (ADHD)

Introduction

ADHD occurs worldwide in about 7.2% of children and 2.5% of adults in a cross-national meta-analysis (DSM-5-TR). 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 20s or early 30s). 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. Delays in language, motor, or social development are not specific to ADHD, but often co-occur. Emotional dysregulation or emotional impulsivity commonly occurs in children and adults with ADHD (DSM-5-TR). 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/impulsivity and inattention.

Differential Diagnosis of Childhood Onset Psychiatric Disorders Presenting with Hyperactivity/Impulsivity 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
  • Oppositional defiant disorder
  • Intermittent explosive disorder
  • Specific learning disorder
  • Disruptive mood dysregulation disorder
  • Substance use disorder
  • 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. The heritability of ADHD is approximately 74%), a very careful history detailing the nature and onset of behavioral symptoms, and a description of current symptoms (especially as they vary across situations, i.e., home, school). 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 is that this very early onset of significant behavioral problems is very characteristic of ADHD.ADHD cannot be diagnosed in the absence of any symptoms prior to age 12. 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 disorder).

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 (manifested by messy lockers, notebooks, and bedrooms) often is pronounced in the adolescent ADHD patient (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.

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 with dopamine agonists (e.g., stimulants or bupropion). 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).

No biological marker has been found for diagnosing ADHD, although ADHD has been associated with elevated power of slow waves (4-7Hz “theta”) as well as decreased power of fast waves (14-30Hz “beta”). A later review found no differences in theta or beta power in either children or adults with ADHD related to control subjects. (DSM-5-TR)

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 two classes of medications with empirical support of efficacy in the treatment of ADHD: stimulants and non-stimulants. We also use some antidepressants to treat ADHD as an off-label treatment, i.e., Wellbutrin.

Stimulants

There are two types of stimulants. One is amphetamines and the other is called methylphenidates. The mechanism of action of stimulants is inhibition of dopamine reuptake (additionally, amphetamines promote increased release of dopamine from vesicles). Each group has different formulary medications based on the onset of action or duration of action, with symptom reduction occurring 30-45 minutes after ingestion, or a duration of action ranging from 4-12 hours, i.e., short-acting or long-acting. Each stimulant group has a liquid formula, a patch formula, and a chewable tablet as well to fit different needs. Listed below are the currently available stimulants. Depending on the formulation, dosing is generally 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 the patient.

In the past few years there has been an explosion of various drugs that have received FDA approval, both on formulations for amphetamine and methylphenidate. Listed below are those in most commonly in use. The dosage shown is only for adult dosage, not for children or adolescents.

Stimulants

Amphetamine Formulations

Short-Acting

Long-Acting

Evekeo/EvekeoODT (d-& l-amphetamine sulfate)

5-40 mg/day (1-2x/day)

Dyanavel XR (d-&I-amphetamine sulfate)

2.5-20 mg/day

Zenzedi (dextroamphetamine sulfate)

5-40 mg/day (1- 2x/day)

Mydayis (mixed amphetamine salts)

12.5-50 mg/day

Adderall (mixed amphetamine salts)

5-40 mg/day (1- 2x/day)

Adzenys XR-ODT/ER (d-&I-amphetamine)

12.5 mg/day

ProCentra (dextroamphetamine sulfate) in solution

5-40 mg/day (1- 2x/day)

Adderall XR (mixed amphetamine salts)

5-60 mg/day
   

Dexedrine Spansule (d-amphetamine sulfate)

10-60 mg/day (1- 2x/day)
   

Vyvanse (lisdexamfetamine) in capsule and chewable

10-70 mg/day

Methylphenidate Formulations

Short-Acting

Long-Acting

Focalin (dexmethylphenidate)

5-20 mg/day, divided twice a day

Concerta

18-72 mg/day

Ritalin

10-60 mg/day divided BID or TID

Aptensio XR

10-60 mg/day

Methlphenidate chewable

10-60 mg/day divided BID or TID

Focalin XR (dexmethylphenidate)

5-30 mg/day

Methylin Solution

10-60 mg/day divided BID or TID

Quillivant XR (liquid formula)

20-60 mg/day in 25 mg/5mL (5mg/ml)
   

Ritalin LA

20-60 mg/day
   

Metadate ER

20-60 mg/day
   

Daytrana (path)

10-30 mg/day (9h on and 15h off)
   

Azstarys (dexmethylphenidate + serdexmethylphenidate)

39.2/7.8-52.3/10.4 mg/day
   

Jornay PM

20-100 mg/night (dosed in the evening)

There are more than 200 well-controlled studies of stimulant use and the 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 highlights 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

Non-stimulants include four drugs that have been approved by the FDA.

Two of them are Alpha-2 Adrenergic Agonists. They have been approved for ADHD treatment for ages 6-17 years old.

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

Alpha-2 Adrenergic Agonists

Generic Name

Brand Name

Typical Doses

clonidine ER

Kapray

0.1-0.4 mg/day (1)

guanfacine ER

Intuniv

1-7 mg (2)

(1) Take daily or divided twice a day
(2) Daily based on the weight, and the dosage is different

There have been 25 reported cases of death in children taking clonidine in conjunction with a stimulant (U.S. 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). For adults, we also need to ask their medical history and family of history of cardiac disease. ECT may be necessary as well prior to the medication treatment.

Another two non-stimulants are selective norepinephrine reuptake inhibitors

20% of ADHD children will experience co-occurring depression and anxiety. 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). The FDA has approved two selective norepinephrine reuptake inhibitors for ADHD in children and adolescents and adults. See the list below.

Antidepressants Used to Treat ADHD

Generic Name

Brand Name

Typical Daily Dosage

atomoxetine

Strattera

40-100 mg

viloxazine

Qelbree

100-600 mg

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

Appendix I

Psychiatric Medications: Quick Reference Guide

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

Note: To the best of our knowledge doses and side effects listed in the Quick Reference Guide, linked above, 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 PDR (Physician’s Desk Reference) for any changes in dosage schedule or contraindications. (Brand names are registered trademarks.)

Mood Stabilizers/Anti-manic Agents

Lithium

Lithium Facts:

Brand Names:

Uses:

Typical Adult Daily Doses (Eskalith or Lithobid, most commonly prescribed):

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):

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 (for reproductive-age females).

Laboratory Tests Routinely Done On An Ongoing Basis:

Those tests flagged above 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. Initial monitoring: Every one to two weeks until desired serum concentration is achieved, then every two to three months for the first six months. Stable monitoring is every 6 to 12 months.

Lithium can cause weight gain, so we need to monitor body mass index (BMI).

Common Side Effects:

Less Common Side Effects (these should be reported to prescribing physician immediately):

Rare or potentially dangerous side effects (If these occur, immediately contact prescribing physician):

Habit-forming/Addiction Potential:

Interactions with other medications:

Here are only the most common medications with which the drug may cause adverse interactions:

Safety during pregnancy:

Breast-feeding:

Special Concerns:

Appendix II

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.

Generic Name

Brand Name

Typical Adult Daily Dose

Divalproex sodium

Depakote

750- 1500 mg

Carbamazepine

Tegretol, Equetro

800-1600 mg

Oxcarbazepine (off-label)

Trileptal

600mg-1200 mg

Lamotrigine

Lamictal

50-200 mg

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 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, the loading dosage is 50 mg/kg and the effects can be seen in less than five days)

Laboratory Tests:

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

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 Neurontin or Lamictal.

Laboratory Tests routinely done on an ongoing basis:

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

Ongoing lab tests are generally not required for 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 (should be reported to prescribing physician):

Rare or potentially dangerous side effects (if these occur, patient should seek emergency medical care):

Habit-Forming/Addiction Potential:

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 in the first trimester; significant birth defects seen most commonly in treatment with Depakote). Lamictal is a relatively safe medication during the pregnancy.

Breast-feeding:

Not recommended when taking anticonvulsants.

Antipsychotic Medications

Facts:

Antipsychotic medications were first developed to treat psychotic symptoms such as hallucinations and thought distortion, mainly for schizophrenia and schizoaffective disorder. 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 or second-generation antipsychotics (SGAs).

Although atypical antipsychotic medications are highly effective in treating psychotic symptoms, it has been found that they are also good treatments for mania and possibly for mood stabilization in general. They also have a role in treating aggression and agitation. Thus, these medications are currently being widely used to treat bipolar disorder even in individuals who have no psychotic symptoms.

Atypical Antipsychotic Medications: Generic and Brand Names and Typical Adult Daily Doses

Generic Name

Brand Name

Typical Adult Daily Dose

olanzapine

Zyprexa

5-20 mg

risperidone

Risperdal

2-6 mg

quetiapine

Seroquel

200-800 mg for bipolar I disorder, manic and 300 mg for bipolar depression

ziprasidone

Geodon

40-160 mg with food

aripiprazole

Abilify

15-30 mg

asenapine

Saphris

5-20 mg

lurasidone

Latuda

20-120 mg with food

cariprazine

Vraylar

3-6 mg

Lumateperone

Caplyta

21 mg-42 mg

Another antipsychotic medication, Clozaril (brand name) or clozapine (generic) is an important medication that can often successfully treat those people who have not responded to more traditional mood stabilizers and who have persistent suicidal thoughts. The typical adult daily doses for Clozaril are 300-900 mg.

These first-generation antipsychotic medications, such as Haldol and Thorazine, have significant side effects (e.g., dry mouth, constipation, sedation, seizures, excessive salivation, blurred vision, nausea, heartburn, and weight gain) and have been associated with a serious blood disorder (agranulocytosis, which causes soreness of the mouth, throat, and gums and a high fever). Thus, it is never considered a first-line medication choice. However, despite the problematic side effects, we do use them for agitation management.

Please note that all of the following information regarding antipsychotics pertains to the atypical antipsychotics or SGAs (not Clozaril).

Uses:

Treat mania and agitation, mixed features, rapid cycling, hypomania and depression.

Onset of Effects:

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

Laboratory Tests:

All SGAs can cause metabolic syndrome, so we need periodic measures of blood glucose, triglycerides, cholesterol, weight, and body mass index (BMI). These should be done at the beginning of treatment, every three to six months, and yearly afterward.

Common Side Effects for SGAs or Atypical Antipsychotics:

Less Common Side Effects (these should be reported to prescribing physician):

Rare or Potentially Dangerous Side Effects (if these occur, patient should immediately contact prescribing physician):

Habit-forming / Addiction Potential:

None

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

Safety during pregnancy:

SGAs (atypical antipsychotics) are generally considered to be cautiously used during pregnancy.

Breast-Feeding:

Antipsychotic medications are secreted in breast milk. Since these are recently developed medications, there is inadequate information regarding safety for infants.

Special Concerns:

Avoid exposure to extreme heat (e.g., saunas)

Grapefruit juice may interfere with the effects of the drug

Excessive cigarette smoking may interfere with the effects of the drug

Avoid direct exposure to sunlight: antipsychotic medications can increase the likelihood of severe sunburns

Antidepressant Medications

Note: Not recommended in the treatment of bipolar disorder. The following list is offered simply as a general reference. They are selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and dopamine reuptake inhibitors (NDRIs), serotonin antagonist and reuptake inhibitor (SARI), noradnergic and specific serotonergic antidepressant (NaSSA) and serotonin modulators.

New Generation Antidepressants: Generic and Brand Names and Typical Adult Daily Doses

Generic Name

Brand Name

Typical Adult Daily Dose

trazodone

Desyrel

50-400 mg

fluoxetine

Prozac

20-80 mg

bupropion

Wellbutrin XL/SR

100-450 mg

sertraline

Zoloft

50-200 mg

paroxetine

Paxil, Paxil CR

20-50 mg

venlafaxine

Effexor, Effexor XR

75-225 mg

nefazadone

Serzone

100-600 mg

fluvoxamine

Luvox

50-300 mg

mirtazapine

Remeron

15-45 mg

citalopram

Celexa

10-40 mg

escitalopram

Lexapro

5-20 mg

duloxetine

Cymbalta

20-80 mg

desvenlafaxine

Pristiq

50-400 mg

vilazodone

Viibryd

10-40 mg

vortioxetine

Trintellix

5-20 mg

levomilnacipran

Fetzima

40-120 mg

Antidepressants are effective in treating depression, anxiety, panic attacks, and obsessive-compulsive disorder (OCD).

Uses:

Generalized anxiety disorder, panic disorder, obsessive-compulsive disorder (OCD), and major depressive disorder.

Onset of Effects:

Generally two to six weeks.

Laboratory Tests:

Not required.

Common Side Effects:

Rare Side Effects (if these occur, patient should immediately contact prescribing physician):

Habit-forming / Addiction Potential:

None

Interactions with Other Medications (vary depending on the drug):

Do not take with St. John’s Wort, 5-HTP (dietary supplement), or MAOIs, cimetidine (Tagamet) without medical supervision.

Safety During Pregnancy:

Most experts agree that some new generation antidepressants are safe for use during pregnancy (e.g., Prozac, Zoloft, Wellbutrin). Note: the following antidepressants have only recently come to market and there is inadequate data to evaluate safety during pregnancy: Cymbalta, Strattera, Lexapro, Celexa, Serzone, Pristiq, and Remeron. High doses of Desyrel should not be used during pregnancy. In addition, recent data suggests that Paxil is less safe for use 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, however we need to use it with precaution.

Special Concerns:

If someone has been taking antidepressants for a period of six weeks or more and abruptly stops taking the medication, there can be withdrawal symptoms (this can occur with any of the antidepressants with the exception of Prozac due to its long half-life). Withdrawal symptoms include nausea, stomach upset, nervousness, flu-like symptoms, and a peculiar sensation described by patients as electrical shocks going through one’s head or extremities. Withdrawal symptoms are very unlikely if one has been taking the medication for less than six weeks. Moreover, withdrawal symptoms can be avoided almost 100% of the time by reducing the dose gradually over a period of several weeks.

Combination Drug: Symbyax (Prozac and Zyprexa):

FDA-approved for the treatment of bipolar depression. Common side effects are those seen with other SSRIs and Zyprexa (e.g., weight gain, increased risk of type II diabetes, hyperglycemia, and elevations in LDL cholesterol and triglycerides).

Antianxiety Medications: Benzodiazepines

Benzodiazepine Facts:

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

Benzodiazepines: Generic and Brand Names and Typical Adult Daily Doses

Generic Name

Brand Name

Typical Adult Daily Dose

diazepam

Valium

5-10 mg

clonazepam

Klonopin

0.5-4.0 mg

lorazepam

Ativan

2-10 mg

Note: Alprazolam (Xanax) can provoke mania in bipolar patients.

Benzodiazepine-like Z drugs Used for Sleep: Typical Adult Nighttime Doses

Generic Name

Brand Name

Typical Adult Daily Dose

zolpidem

Ambien

5-10 mg

zaleplon

Sonata

5-10 mg

eszopiclone

Lunesta

1-3 mg

Note: There are two non-benzodiazepine prescription sleeping pills, suvorexant (Belsomra, 10 mg-20 mg) and ramelteon (Rozerem, 8 mg).

Uses:

Ttreats acute anxiety and insomnia during episodes of mania. Also used as adjunct treatment to treat anxiety disorders (such as panic disorder, social anxiety, and generalized anxiety disorder). In the treatment of mania, benzodiazepines are generally used only for the first few days of treatment to reduce agitation; only rarely are these drugs used beyond a couple of weeks.

Onset of Effects:

30-60 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. Rozerem has a less habit-forming character.

Interactions with Other Medications:

When taking benzodiazepines, any other type of medication that causes drowsiness or impaired alertness and reaction time can be potentially dangerous, especially if one has to drive an 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, the drugs continue to work to reduce anxiety, but the problem when there is tolerance is that sudden cessation of the medication can lead to 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 person has been taking a benzodiazepine on a daily basis for more than six weeks, and especially if the dose is moderate to high, withdrawal reactions are a very real risk. The patient should never abruptly stop taking the medication without first consulting with his/her doctor.

Appendix III

Miscellaneous

Omega-3 Fatty Acids

During the past decades, 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 40 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 and Artane. Anticholinergic drugs have their own set of side effects including: constipation, blurred vision, dry mouth, difficulty beginning urination, and occasional 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, other studies do not show any antidepression benefits. 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 be used as a viable option for treating bipolar depression. However, it is not useful for treating mania and has, in fact, been found to switch people with bipolar depression into states of mania. Another interesting fact is that SAM-e can help reduce some ADHD symptoms. Doses for the treatment of depression range from 400 mg to 1600 mg per day, although recent investigations indicate that often, higher doses (1000-1600 mg per day) may be necessary for effectively reducing depressive symptoms. SAM-e is available over the counter.If you want to try it, you can discuss it with your physician.

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 600 mg (mild depression) to 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 its use in 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.

Appendix IV

Caffeine Questionnaire

Following is a caffeine questionnaire that allows clinicians to quickly determine caffeine intake for 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 bedtime 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 ten-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 patients. Click here for the printable Caffeine Consumption Questionnaire.

 

Suggested Readings/Resources

Advoka, C, (2018). Julien’s Primer of Drug Actions. Worth Publishers.

American Medical Association website: (https://www.ama-assn.org/system/files/bhi-psychopharmacology-how-to-guide.pdf)

American Psychiatric Association (2022). DSM-5-TR. Washington, DC.

Carlat Psychiatry Reports: a monthly subscription. Reports for adult psychiatry and one for children and adolescents. PO Box 626, Newburyport, MA

Geller, B. & DelBello, M.P. (Eds.) (2008) Treatment of bipolar disorder in Children and Adolescents. The Guilford Press.

NIH omega-3 fatty acids: health professional fact sheet. https://ods.od.nih.gov/pdf/factsheets/Omega3FattyAcids-Consumer.pdf

Preston, J.D., O'Neal, J. and Talaga, M. (2017) Handbook of clinical psychopharmacology for therapists: Eighth Edition. New Harbinger.

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

Preston, J.D., O’Neal, J, and Talaga, M. (2009) Consumer’s guide to psychiatric drugs. Second edition: Penguin Books.

Psychceu.com: (https://www.psychceu.com/quick_reference_bw.pdf)

Stahl, S. (2017). Prescriber’s guide 6th edition, Cambridge University Press.

Texas Health and Human Service: (https://www.hhs.texas.gov/sites/default/files/documents/doing-business-with-hhs/provider-portal/facilities-regulation/psychiatric/psychiatric-drug-formulary.pdf)

DSM-5-TR by American Psychiatric Association, 2022.

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American Medical Association (n.d.). Psychopharmacology How-to Guide. https://www.ama-assn.org/system/files/bhi-psychopharmacology-how-to-guide.pdf

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