Mental Health Pharmacology

3.0 Contact Hours

Syllabus

Please note: This course is not approved by the AANP and therefore not eligible to provide Pharmacology CE credit

At the completion of this activity, the learner should be able to successfully:

  • Briefly define the pathophysiology, and discuss the positives, negatives, adverse effects, controlled substance regulations, and forthcoming developments for drugs used in the treatment of attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD)
  • Briefly define the pathophysiology, and discuss the positives, negatives, adverse effects, controlled substance regulations, and forthcoming developments for drugs used in the treatment of depression
  • Briefly define the pathophysiology, and discuss the positives, negatives, adverse effects, controlled substance regulations, and forthcoming developments for drugs used in the treatment of anxiety disorders, including obsessive compulsive disorder (OCD) and post-traumatic stress disorder (PTSD)
  • Briefly define the pathophysiology, and discuss the positives, negatives, adverse effects, controlled substance regulations, and forthcoming developments for drugs used in the treatment of bipolar disorder
  • Briefly define the pathophysiology, and discuss the positives, negatives, adverse effects, controlled substance regulations, and forthcoming developments for drugs used in the treatment of schizophrenia/psychosis


            According to the World Health Organization (WHO), mental health disorders are characterized by a combination of abnormal thoughts, perceptions, emotions, behavior, and relationships with others. Unfortunately, those suffering from mental disorders are often untreated or at least under-treated. In low- to middle-income countries, around 80% of those with mental disorders receive no treatment, and in high-income countries that number is between 35-50% of folks with mental disorders. Even those who are treated are not treated optimally. The WHO Mental Health Action Plan 2013-2020 aims to use evidence-based technical guidance, tools, and training packages to help improve the amount and quality of mental health care offered worldwide by increasing leadership, providing comprehensive and integrated care in community-based settings, implementing strategies for promotion and prevention, and strengthening evidence and research (WHO, 2018). In an effort to help better educate the entire medical community and all healthcare providers, this module aims to better elucidate the pharmacological treatment of some of the most common mental health disorders.

ADD/ADHD

            Attention deficit disorders (ADD) with or without hyperactivity component are neurodevelopmental disorders that can affect both children and adults as a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with daily life or development. It can affect attention, executive function, and working memory. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) revised some of the diagnostic criteria for ADHD in 2013 making diagnosis of teens and adults easier, changing the previous “subtypes” to “presentations” that can change throughout life, adding a severity scale, and requiring more pervasiveness of symptoms in various settings to qualify. Some examples of characteristics used to diagnose ADHD- Inattentive Presentation include poor attention to detail, difficulty sustaining attention to tasks, poor listening, poor organizational skills and/or poor follow-through on tasks. Characteristics of the hyperactive/impulsive presentation include fidgeting/squirming, running about/climbing excessively (children) or restlessness (adults), excessive talking and/or frequent interrupting. In preschool aged children (4-5), the American Academy of Pediatrics recommends parent or teacher administered behavioral intervention first, with medications considered second line only if behavior therapy proves to be ineffective. Children aged 6-11 should receive dual treatment with behavioral interventions and medication, and adolescents (ages 12-18) should receive approved medications, preferably with behavior therapy. (CHADD, 2018). Medications are also used into adulthood, as up to one-third of children with ADHD continue to have symptoms into adulthood (CDC, 2018). The goal of medication use is not to cure ADHD, but to ease symptoms while the medication is active in the patient’s system (CHADD, 2018). Medications commonly prescribed for the treatment of ADHD include stimulants, which are the most widely used and well-known medications, and nonstimulants, which were approved for the treatment of ADHD in 2003 and can last longer but are slower to take effect (CDC, 2018).

Stimulants have been shown to reduce symptoms in 70-80% of children with ADHD (CDC, 2018). They work primarily by blocking the reuptake and increasing the release of the neurotransmitters dopamine and norepinephrine which affect thinking and attention (NIMH, 2016). Stimulants are all categorized as Schedule II with a high abuse potential and were previously categorized by the FDA as pregnancy category C (risk cannot be ruled out). These medications were first administered to children with behavioral and learning disorders in 1937 and there exist hundreds of controlled studies (of over 6,000 children, adolescents, and adults) to determine the effects of these medications on a short-term basis. That being said, there are no long-term studies (more than a few years) of the effects of these medications as those studies would necessitate the withholding of treatment over many years from patients with significant impairment, which has been deemed unethical. However, many individuals have used these medications for many years without adverse effects. The common stimulants used for ADHD include methylphenidate (Ritalin, Concerta, Metadate, Focalin), dextroamphetamine (Dexedrine, Dextrostat), and mixed salts of single entity amphetamine (Adderall, Adderall XR). They are available as short-acting formulas (last about 4 hours) or long-acting formulas (variable from 6-12 hours). Many prefer long-acting formulas that may reduce the “ups and downs” throughout the course of the day and eliminate the need to dose medication at school or work. There is also a method of adding a “booster” dose of short-acting medication taken in the mid to late afternoon to help with evening activities, meetings, or homework when a long-acting medication taken first thing in the morning would otherwise have worn off, but this method is not well studied. The specific timing and dosage of medication may vary widely from patient to patient, is usually determined by performing a medication trial. This involves starting on a low dose of medication with gradual dose increases every three to seven days until optimal benefits/minimal adverse effects are seen to determine the most beneficial dosage. Before, during, and immediately after the trial the patient should be observant about symptoms and severity. In children, this means observations from parents, teachers as well as coaches or tutors (CHADD, 2018).

The adverse effects of stimulants could include increased blood pressure, increased heart rate, anxiety, decreased appetite, sleep problems, personality changes, tics, stomach pain, or headaches. They should be used with caution in patients with hypertension, seizures, heart disease, glaucoma, liver disease, kidney disease, or anxiety disorders (NIMH, 2016). Most side effects seen with stimulants are mild and short-term and can be eliminated or decreased with a “start low and go slow” medication initiation plan. Some people describe a “stimulant rebound” as the medication is wearing off in which they experience a negative mood, fatigue, or hyperactivity. This can be managed by changing the dose/schedule of short-acting formulas or switching to a long-acting formula if possible. Studies indicate some children may experience an initial effect on height/weight, but these are rarely affected long-term. Studies also indicate children with ADHD reach puberty slightly later than peers, but this is not thought to be related to medication. The tics (facial twitches, eye blinking, shrugging, and throat clearing) seen in ADHD patients on stimulants are not thought to be caused by the medication itself but instead made more noticeable sooner or more prominent than they would be otherwise. These often resolve with time, even if the patient continues on the medication. However, caution should be taken in patients with a family history of Tourette’s syndrome or tics, and if worsening tics are seen a nonstimulant medication could be considered as an alternative (CHADD, 2018).

Nonstimulant medications are also often used as part of the treatment plan for ADHD patients, but these may take longer to start working. They are often used in place of stimulants in patients who had unacceptable adverse effects or inadequate results with stimulants, or in combination with stimulants to enhance effects. They can help improve focus and attention and decrease impulsivity (NIHM, 2016). Atomoxetine (Strattera) alleviates inattention and hyperactivity symptoms of ADHD by selectively inhibiting the reuptake of norepinephrine. It is not a controlled substance, as it is not a stimulant, and is thus determined to have no abuse potential. It was previously categorized as pregnancy category C by the FDA. It is a newer medication, but still has been tested on over 1600 patients. As it is a slower mechanism of action, it may take up to four weeks to feel the full effects of the medication.  Antidepressants that target the neurotransmitter norepinephrine are sometimes used in the treatment of ADHD symptoms, but these are not FDA approved for this indication and are thus considered “off label” (CHADD, 2018). Venlafaxine (Effexor) inhibits the reuptake of norepinephrine, serotonin, and dopamine. Bupropion (Wellbutrin) blocks the reuptake of norepinephrine and dopamine. Duloxetine (Cymbalta) blocks the reuptake of norepinephrine and serotonin. Reboxetine* selectively inhibits the reuptake of norepinephrine. Like atomoxetine, these drugs are not controlled substances, and have no abuse potential, but should be used with caution and extensive patient counseling. They are not recommended for children with depression and should be used with caution in adolescents due to increased risk of suicide (WHO, 2018). Antihypertensives such as clonidine (Catapres, Kapvay) and guanfacine (Tenex, Intuniv) have been approved for ADHD symptoms in children such as hyperactivity and aggression, and may be helpful in adults, but studies are limited at this point. These drugs carry some significant adverse effects, such as hypotension, sedation, and a potential for hypertensive rebound. Clonidine is an alpha-2 noradrenergic agent, and guanfacine is an alpha-2a noradrenergic agent, but both are believed to work by affecting the available levels of norepinephrine, and thus dopamine. These medications are not controlled substances and therefore carry no abuse potential. Guanfacine was a pregnancy category B, while clonidine was category C. Finally, another option in adult ADHD patients is a wake-promoting agent modafinil (Provigil), which is currently approved by the FDA for narcolepsy and extreme fatigue in patients with multiple sclerosis (MS). It does not seem to have an effect on central dopamine or norepinephrine pathways, but instead indirectly activates the frontal cortex. A small study on adults with diagnosed ADHD showed favorable results from modafinil after a two-week trial in 48% of patients. This is limited and preliminary, but warrants further long-term studies and consideration (CHADD, 2018).

Depression

            According to the WHO, as many as 300 million people worldwide are affected by depression, women more than men. It leads to significant amounts of disability in adult patients and is characterized by a period of at least two weeks of sadness, loss of interest or pleasure, guilt, low self-worth, disturbed sleep, poor appetite, tiredness, and/or poor concentration. When it is severe, depression can lead to suicide (WHO, 2018).  Depression has a variety of causes such as genetics, environmental, psychological and biochemical. It can be persistent (also called dysthymia, lasting at least two years), postpartum (extreme sadness, anxiety, and exhaustion after giving birth), psychotic (with delusions or hallucinations), seasonal (symptoms appear during the winter months when there is less natural sunlight and is accompanied by increased sleep, weight gain, and social withdrawal), or bipolar (a separate disorder, but which includes periods of depression). Disruptive mood dysregulation disorder, which can be diagnosed in children and adolescents, and premenstrual dysphoric disorder, seen as a hormonal depression in women, are depressive disorders newly added to the DSM-5. Depression can occur in children and adolescents, but is most common in adults, and often presents as irritability or anxiety in children. Risk factors for depression include personal or family history, major life change/stress/trauma, and certain physical illnesses or medications (such as diabetes, cancer, heart disease, and Parkinson’s) (NIMH, 2018). A previously accepted theory that depression stems from a chemical imbalance in the brain regarding the monoamines serotonin, norepinephrine, and dopamine has shifted in the last 15 to 20 years. Theories regarding alterations in brain architecture and complex circuitry have led researchers to question if the neurotransmitters are not simply a messenger of information or symptom as opposed to the cause itself. Advancements in the fields of genetics and functional neuroimaging have opened new and exciting investigational possibilities and altered the way depression is viewed in the last 20 years, hopefully leading to changes in treatment down the road (Goldberg, 2018). Cannabinoids may be a possibility for future further study, but at this time there exists only very low-quality evidence which suggested no benefit from the use of nabiximols* (a purified natural combination of equal parts Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in an oromucosal spray) in the treatment of depression (Whiting, et al., 2015).

            While mild to moderate depression can often be treated with therapy alone (cognitive behavior therapy (CBT), psychotherapy), moderate to severe cases of depression often require the addition of medication (WHO, 2018). There are numerous additional nonpharmacological treatment options such as acupuncture, mindfulness training, transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT) that are beyond the scope of this particular training, but that are nonetheless valid treatment options that should be explored and discussed with patients that wish to avoid medications or are searching for adjunctive therapy. There are also a few over the counter medication options, such as St John’s wort, omega-3 fatty acids, and s-adenosylmethionine (SAMe). These options have been approved by the FDA for the treatment of depression and remain under study. They can also have significant adverse effects and drug interactions (never take St John’s wort with a prescription antidepressant) despite being sold over the counter with a prescription. In terms of prescription medication, the bulk of medications currently FDA-approved for the treatment of depression target the three neurotransmitters traditionally associated with depression: serotonin, norepinephrine, and dopamine. They usually take 2-4 weeks to work, and symptoms such as sleep, appetite, and concentration often improve before mood. Most need to be tapered up slowly when starting and down when stopping. There exists a current FDA warning that patients, especially those under the age of 25, may experience an increase in suicidal thoughts or behaviors during the first few weeks of taking an antidepressant, and all patients should be monitored for this effect (NIMH, 2018).

Selective serotonin reuptake inhibitors (SSRIs) are usually the safest initial choice and cause the least side effects. This includes medications such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox CR), paroxetine (Paxil), and sertraline (Zoloft). Serotonin-norepinephrine reuptake inhibitors (SNRIs) include duloxetine (Cymbalta), venlafaxine (Effexor), desvenlafaxine (Pristiq), and levomilnacipran (Fetzima) (Mayo Clinic, 2018). Tricyclics (TCA) and tetracyclics, which is an older class of medications including clomipramine, nortriptyline, imipramine and amitriptyline, inhibit norepinephrine and serotonin reuptake but with significantly more adverse effects (sedation, weight gain, anticholinergic effects, hypotension, cardiac effects and even seizures) (Mayo Clinic, 2016). Mirtazapine (Remeron) is an atypical tetracyclic antidepressant that antagonizes alpha-2 adrenergic and serotonin receptors. Monoamine oxidase inhibitors (MAOIs) such as tranylcypromine (Parnate), phenelzine (Nardil), isocarboxazid (Marplan), and selegiline (Emsam) are rarely used except when other medications have failed due to serious adverse effects, drug interactions, and even dangerous food interactions. There are also a few uncategorized atypical antidepressants. Bupropion (Wellbutrin), as previously mentioned, blocks the reuptake of norepinephrine and dopamine and can be used for depression as well as seasonal affective disorder and smoking cessation (NIMH, 2016). Vortioxetine (Trintellix) is also a newer medication for depression which works by inhibiting serotonin reuptake, but also as a mixed antagonist/agonist of specific serotonin receptors. Vilazodone (Viibryd) also acts as a selective serotonin reuptake inhibitor, as well as a partial serotonin receptor agonist. Trazodone antagonizes serotonin and alpha-1 adrenergic receptors and blocks the reuptake of serotonin. Similarly, nefazodone antagonizes serotonin receptors, as well as blocking the reuptake of norepinephrine and serotonin (Mayo Clinic, 2018). In general, antidepressants should not be abruptly stopped as this can cause withdrawal as well as a return of depression symptoms. The most common adverse effects seen with antidepressants include nausea/vomiting, weight gain, diarrhea, sleepiness, and sexual dysfunction. A drug interaction with other medications that increase serotonin levels, such as triptans used to treat migraines, can cause a condition called serotonin syndrome (agitation, hallucinations, high temperature, severe blood pressure changes. In women of childbearing age, they should be warned that most antidepressants were pregnancy category C (risk cannot be ruled out) with the exception of paroxetine (category D) and bupropion (category B), with slight variations between the medications’ safety in lactating mothers (NIMH, 2016).

A published systematic review and network meta-analysis published in Lancet earlier this year reviewed 522 double blind randomized controlled trials, involving 116,477 patients diagnosed with major depressive disorder (MDD) and 21 different antidepressants. Unfortunately, this analysis only recorded outcomes on or around 8 weeks, which is a rather short period of time, especially for such long-acting medications, and included 426 of 522 (81%) trials that were deemed by the authors to be moderate or high risk of bias.  Despite these limitations/shortcomings, the results showed all antidepressants were more effective than placebo. Agomelatine**, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were among the most effective, while fluoxetine, fluvoxamine, reboxetine*, and trazodone were among the least effective. Agomelatine* is a novel antidepressant which acts as a melatonin agonist and serotonin antagonist. It has been marketed in Europe since 2009 and in Australia since 2010. Regarding tolerability, agomelatine*, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine had the lowest dropout rates, while amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine*, trazodone, and venlafaxine had the highest dropout rates. Overall, when evaluating effectiveness as well as tolerability, the best options for the treatment of depression appear to agomelatine* and escitalopram and the worst options appear to be fluvoxamine, reboxetine*, and trazodone (Cipriani et al, 2018).

Anxiety

Anxiety is an umbrella term that encompasses many different disorders, but all linked by the common thread of fear, worry or concern that interferes with daily functioning and/or performance. Variations include:

  • generalized anxiety disorder (GAD- excessive anxiety/worry about a number of various things, most days, for at least six months)
  • social anxiety disorder (SAD- a general intense fear of social or performance situations)
  • panic disorder (characterized by sudden, recurrent and unexpected periods of intense fear called panic attacks)
  • phobia-related disorders (such as agoraphobia, a fear of being out in public, or a fear of heights/flying, injections, blood, certain animals, etc)
  • separation anxiety disorder (a fear of being separated from the person/people to whom they are attached)
  • selective mutism (a condition typically seen in children under 5 who are unable to speak in certain social situations despite having normal language skills) (NIMH, 2018).

Both environmental and genetic influences contribute to anxiety disorders, and risk factors include childhood shyness, stress buildup, certain personality types, exposure to stressful or traumatic life events when young, comorbid psychological condition, drug/alcohol use, and biological relatives with anxiety disorders. Additionally, anxiety may be linked to an ongoing medical/health issue such as diabetes, heart disease, thyroid dysfunction, respiratory disorders, drug misuse, alcohol or drug withdrawal, chronic pain, irritable bowel syndrome (IBS), and rare tumors that produce hormonal imbalances. The gold standard treatment for anxiety, similar to depression, is often a combination of psychotherapy (cognitive or exposure therapy) and medications. Other adjunctive treatments that many patients with anxiety find helpful include support groups/chat rooms, stress management techniques (such as exercise), meditation, and mindfulness (Mayo Clinic, 2018 and NIMH, 2018).

            Regarding medications used to treat anxiety, benzodiazepines are the most commonly used, and include clonazepam (Klonopin), alprazolam (Xanax), and lorazepam (Ativan) among others. They work by enhancing the effects in the brain of gamma-aminobutyric acid (GABA) and can be used as a first line for GAD but are considered second line treatment for panic disorder and SAD behind antidepressants (NIMH, 2016). Benzodiazepines have the advantage of a very fast onset of action, but they are schedule IV controlled substances according to the drug enforcement agency (DEA), and in some states they are classified as a schedule II due to high risk of abuse and dependence. Benzodiazepines also carry a high risk of tolerance, and can cause withdrawal symptoms if abruptly discontinued, so they should be tapered slowly and carefully. Benzodiazepine adverse effects also include drowsiness/tiredness, dizziness, nausea, blurred vision, headache, confusion, and nightmares (NIMH, 2016). Most benzodiazepines were pregnancy category D or X (positive evidence of risk), and women of childbearing age should be counseled extensively on their individual risk prior to starting a benzodiazepine.  For this and other reasons, benzodiazepines are often considered second line for chronic anxiety behind antidepressants or used on an as needed basis for break through symptoms (NIMH, 2018). Buspirone (Buspar) is approved for the treatment of chronic anxiety, but it is not a benzodiazepine and is not a controlled substance. It works by binding to serotonin and dopamine D2 receptors. Unfortunately, it does not work for everyone, and needs to be taken every day as it does not function on an as needed basis. Adverse effects of buspirone include dizziness, headache, nausea, nervousness, lightheadedness, excitement, and trouble sleeping, and was categorized as a pregnancy category B (no evidence of risk). Beta blockers can be given to help alleviate the physical symptoms of anxiety such as sweating, trembling, tachycardia during especially stressful events, such as large social gatherings, weddings, or public speaking engagements. They can be taken as needed, but can cause hypotension, bradycardia, dizziness, weakness, fatigue, and cold hands and are not recommended for diabetics and asthmatics. Antidepressants such as SSRIs and SNRIs (see above) are now more commonly being used as a first line treatment for chronic anxiety conditions (NIMH, 2016).

            In patients suffering from post-traumatic stress disorder (PTSD), trauma focused psychotherapy is considered first line treatment, while the SSRIs sertraline, paroxetine, and fluoxetine, and the SNRI venlafaxine are the most commonly used medications in refractory cases, although only sertraline and paroxetine have been FDA approved for this indication (US Dept of VA, 2018). Obsessive-compulsive disorder (OCD) is a chronic condition characterized by reoccurring and repetitive thoughts (obsessions) and behaviors (compulsions) that interfere with all aspects of their life. It is often treated with a combination of psychotherapy and medications, the most common of which are clomipramine (a TCA), fluoxetine, fluvoxamine, and sertraline. These medications will typically take 8-12 weeks to show improvement in symptoms for OCD patients, and typically need to be dose significantly higher than in depression patients. The results of use of antipsychotics such as risperidone (Risperdal) are mixed (NIMH, 2016).

Regarding the future of anxiety treatments, preclinical evidence supports the use of CBD in the treatment of GAD, panic disorder, SAD, OCD, and PTSD. Human studies support its use at doses between 3-600 mg in healthy adults exposed to acute anxiety/stress without affecting baseline levels. CBD was shown to reduce anxiety in SAD, and acutely enhances fear extinction which may prove useful in PTSD treatment in the future. These studies all used small sample sizes and acute dosing only so further studies would be needed to expand the patients tested, establish independent replication, and assess the safety and effectiveness of chronic use (Blessing, Steenkamp, Manzanares, & Marmar, 2015). Specifically, studies on patients with PTSD showed consistent decrease in frequency of nightmares when treated with nabilone (Cesamet, a synthetic THC capsule) or 5mg THC in oil (Mouhamed, et al., 2018).

Bipolar Disorder

            Formerly manic depression, bipolar disorder is characterized by extreme mood swings between manic periods of elevated or irritable mood, over-activity, racing thoughts, pressure of speech, inflated self-esteem, and decreased need for sleep, usually interspersed with depressed periods.  According to the WHO, bipolar disorder effects around 60 million people worldwide (WHO, 2018). There are currently four classifications:

  • Bipolar I (BDI)- manic episodes lasting at least seven days and often require hospitalization, with depressive episodes usually lasting at least two weeks
  • Bipolar II (BDII)- typically longer-lasting depressive episodes separated by periods of hypomania periods lasting at least four days (similar to manic episodes but less severe, without psychosis or need for hospitalization)
  • Cyclothymic disorder/cyclothymia- numerous periods of hypomanic and depressive symptoms, alternating for at least two years, but not severe enough to meet the above diagnostic criteria for bipolar II
  • Other- bipolar disorder symptoms that do match any of the above three categories, such as symptoms induced by substance abuse or caused by certain medical conditions such as Cushing’s disease, multiple sclerosis (MS), or stroke (Mayo Clinic, 2018)

Symptoms of a depressive episode match the aforementioned symptoms of depression above. Behavior seen in a manic episodes may include the previously mentioned symptoms as well as disorganized or nonlinear patterns of thoughts/speech and risk taking behaviors such as spending frivolously or sexual promiscuity. Hypomanic episodes may present as the individual feeling very good, being highly productive, and functioning well. Hypomania may develop into full mania if untreated. Some patients with bipolar disorder may also suffer from psychotic features, such as delusions or hallucinations. Patients with bipolar disorder are at higher risk for thyroid disease, migraines, heart disease, diabetes, obesity and other physical illnesses as well as anxiety, ADHD, and substance abuse. While the exact cause of bipolar disorder is still unknown, most scientists believe it is some combination of altered brain structure/function, genetics, and environmental factors (NIMH, 2016). Risk factors include a first degree relative with bipolar disorder, a stressful or traumatic life event, and drug or alcohol use. It is most commonly diagnosed in the teenage years or early 20’s, and if left untreated can lead to drug/alcohol abuse, legal or financial problems, damaged relationships, poor work/school performance, or suicide (Mayo Clinic, 2018). Estimates are that 6-7% of bipolar patients die by suicide, and up to 43% of patients with bipolar disorder report suicidal ideations (Yatham et al, 2018). Bipolar disorder is a lifelong illness and requires consistent and regular treatment with psychotherapy and medications to manage symptoms long term. Psychotherapy may consist of CBT, family-focused therapy, interpersonal and social rhythm therapy, and/or psychoeducation and in severe cases may require ECT (NIMH, 2016).

Medications for bipolar disorder may include mood stabilizers, atypical antipsychotics, antidepressants, sleep medications, and/or supplements. Lithium, a commonly prescribed mood stabilizer that works by altering sodium transport across neurons, has been approved for the treatment of acute mania and the maintenance treatment of bipolar disorder (NIMH, 2016). According to the International Society for Bipolar Disorders (ISBD), lithium alone is recommended as first line treatment for acute mania and maintenance therapy of BDI based on level 1 evidence, and based on level 2 evidence it is considered first line treatment for acute depression in BDI, first line for maintenance treatment in BDII, and second line for acute depression treatment in BDII. There is however moderate concern about safety and tolerability with lithium use long term, was previously categorized by the FDA as pregnancy Category D, and is considered possibly hazardous in breastfeeding moms (Yatham et al, 2018). Alternatives for mood stabilization include anticonvulsants such as divalproex sodium (Depakote), valproic acid (Depakene), carbamazepine (Tegretol), and lamotrigine (Lamictal) (NIMH, 2016). Divalproex is currently a first line monotherapy for acute mania and maintenance therapy of BDI based on level 1 evidence, second line for acute depressive episodes in BDI based on level 2 evidence, third line for maintenance treatment in BDII based on level 3 evidence, and third line for acute depression treatment in BDII based on level 4 evidence. Carbamazepine is considered second line treatment in acute mania based on level 1 evidence, and can be used for maintenance treatment, but it is considered second line treatment for BDI based on level 2 evidence, and third line treatment for BDII based on level 3 evidence. Lamotrigine is not recommended for acute mania. It is considered a first line treatment for maintenance therapy of BDI based on level 1 evidence, and based on level 2 evidence it is considered first line treatment for acute depression in BDI, second line for acute depression in BDII, and first line for BDII maintenance treatment. Regarding safety and tolerability for long term use, divalproex has moderate safety and minor tolerability concerns, and carbamazepine has minor safety and moderate tolerability concerns, while lamotrigine has very limited safety or tolerability concerns. Divalproex and carbamazepine should both be used with caution in women of childbearing years due to possible teratogenic effects (previously pregnancy category D), while lamotrigine is considered slightly safer (category C). Divalproex is also considered potentially hazardous in lactation, while carbamazepine and lamotrigine are considered safer in breastfeeding moms. (Yatham et al, 2018). Downsides of most mood stabilizers include their renal toxicity and the need for initial serum drug levels until dosing is stable and then periodically to rule out toxicity (for patients on lithium, divalproex, and carbamazepine). There are significant adverse effects that can be seen from mood stabilizers, such as:

  • Itching, rash
  • Excessive thirst
  • Frequent urination
  • Tremor (shakiness) of the hands
  • Nausea and vomiting
  • Slurred speech
  • Fast, slow, irregular, or pounding heartbeat
  • Blackouts
  • Changes in vision
  • Seizures
  • Hallucinations (seeing things or hearing voices that do not exist)
  • Loss of coordination
  • Swelling of the eyes, face, lips, tongue, throat, hands, feet, ankles, or lower legs (NIMH, 2016).


Atypical antipsychotics help treat the symptoms of agitation, delusions, and hallucinations that are often seen in bipolar disorder. This may include medications such as quetiapine (Seroquel), asenapine (Saphris), aripiprazole (Abilify), paliperidone (Invega), risperidone (Risperdal), olanzapine (Zyprexa), ziprasidone (Geodon), cariprazine (Vraylar), clozapine (Clozaril) and lurasidone (Latuda). These drugs function mostly by antagonizing dopamine D2 and serotonin 5-HT2A receptors in the brain, except for aripiprazole and cariprazine, which function as partial dopamine and serotonin 5-HT1A agonists and 5-HT2A antagonists (NIMH, 2016). Adverse effects for this group of drugs may include:

  • Drowsiness
  • Dizziness
  • Restlessness
  • Weight gain (weight, glucose, and lipid levels should be monitored regularly)
  • Anticholinergic effects, like dry mouth, constipation, blurred vision
  • Nausea/vomiting
  • Hypotension
  • Seizures
  • Leukocytopenia (NIMH, 2016).

According to the ISBD, there is level 1 evidence to support the use quetiapine, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine for the treatment of acute mania. It is estimated that as many as 50% of patients will significantly improve with monotherapy in 3-4 weeks, but combination therapy increases this by about 20% and may be beneficial in patients with a history of partial response to monotherapy, with psychotic mania, or where rapid response is desired. In those cases, there is level 1 evidence supporting the combination of lithium or divalproex with quetiapine or risperidone for acute mania.  There is level 2 evidence supporting lithium or divalproex combined with aripiprazole or asenapine for acute mania. There is level 1 evidence supporting the use of olanzapine (alone or with lithium/divalproex), carbamazepine, or ziprasidone as second line treatments for acute mania. In the treatment of acute depression in BDI, there is level 1 evidence supporting the use of quetiapine or a combination of lurasidone and lithium/divalproex as first line treatments, and level 2 evidence supporting the use of lurasidone alone. Olanzapine also has level 1 evidence as a second-line treatment for acute depression in BDI. Of note, there is also level 1 evidence against the use of aripiprazole or ziprasidone in acute depression in BDI. Regarding maintenance/long term therapy, there is level 1 evidence to support using quetiapine (alone or with lithium/divalproex), and level 2 evidence for the use of asenapine, aripiprazole (alone or combined with lithium or divalproex) as first line treatment options in BDI. There is also level 1 evidence supporting the use of olanzapine or risperidone as second line maintenance treatment options in BDI. In BDII, there is level 1 evidence supporting the use of quetiapine as a first line treatment for acute depression or long-term maintenance therapy. Third line treatment options for long term maintenance treatment of BDII include carbamazepine (based on level 3 evidence) or risperidone (based on level 4 evidence, primarily to prevent hypomania episodes). Regarding safety and tolerability, there are more concerns regarding olanzapine, quetiapine and risperidone than the other atypical antipsychotics discussed here, especially when combined with lithium or divalproex (this treatment combination is reasonably safe for brief periods but should be avoided long-term). The safest and most tolerable options for long term treatment in this category appear to be asenapine and aripiprazole. In women of childbearing age, it should be communicated that most atypicals were pregnancy category C, which means risk cannot be ruled out, with the exception of clozapine (category B). In breastfeeding patients, aripiprazole and clozapine should be avoided (moderately safe), while olanzapine, quetiapine, risperidone, and ziprasidone are considered safer during lactation (Yatham, 2018).

            SSRIs, SNRIs, and bupropion are sometimes used for acute depressive symptom management in bipolar disorder. See previous section on depression for further details regarding the names, mechanisms of actions, and adverse effects of these drugs. According to the ISBD, these drugs should not be used as monotherapy in patients with bipolar disorder I acute depression. However, in patients with BDI there is level 1 evidence supporting their use as second line adjunctive therapy (with lithium, divalproex, or an atypical antipsychotic) for acute depression, and level 4 evidence supporting their long-term use for prevention of depressive episodes. In patients with BDII, there is level 2 evidence suggesting bupropion (as an adjunct), sertraline, or venlafaxine are appropriate second line treatment adjuncts for acute pure (non-mixed) depression, and third line options include agomelatine* (based on level 4 evidence) or fluoxetine (based on level 3 evidence). For long-term maintenance therapy in patients with BDII, there is level 2 evidence supporting the use of venlafaxine as a second line treatment, and level 3 evidence of the use of escitalopram, fluoxetine or other antidepressants as third line treatment options only. Antidepressants should be avoided in patients with a history of antidepressant-induced mania/hypomania, current or predominantly mixed features, or recent rapid cycling. TCAs should be avoided in patients with BDI due to increased risk for mania, but the MAOI tranylcypromine was recommended as a third line treatment option for acute depression in BDII based on level 3 evidence (Yatham, 2018).

            Benzodiazepines have not been shown to provoke mood instability in patients with bipolar disorder, so for comorbid anxiety or difficulty with sleep, lorazepam, clonazepam or similar could be considered as a short-term alternative, although no long-term studies exist to confirm this (Yatham, 2018).


Schizophrenia/Psychosis

            According to the WHO, there are around 23 million people affected by schizophrenia worldwide. This severe mental disorder typically begins in late adolescence or early adulthood and is characterized by psychoses or distortions in thinking, perception, emotions, language, behavior or sense of self (WHO, 2018). Symptoms can be categorized as positive (hallucinations, delusions, disorganized thoughts/speech, movement disorders), negative (flat affect, loss of pleasure in everyday life, difficulty beginning/sustaining activities, reduced speaking) or cognitive (poor executive functioning, decreased focus/attention, poor working memory). Genetic predisposition along with potential environmental triggers such as viruses, prenatal malnutrition, problems during birth, and psychosocial factors likely combine to cause or increase risk for schizophrenia. Alterations in brain structure and chemistry (especially neurotransmitters dopamine and glutamate) also play a role (NIMH, 2016). According to the Mayo Clinic, risk factors for schizophrenia include a family history, increased immune system activation from inflammation or autoimmune disorder, older age of father, prenatal malnutrition or exposure to viruses/toxins, and exposure to psychotropic drugs during adolescence/young adulthood. Common complications of schizophrenia include self-injury, anxiety, depression, OCD, alcohol/substance abuse, social isolation, inability to work/attend school, medical problems, legal/financial problems, homelessness, aggressive behavior (uncommon) and suicide. (Mayo Clinic, 2018). Treatment for schizophrenia usually starts with medication, and once stabilized, then progresses with psychosocial support to learn and use coping skills to help attend work, school. A team approach which includes medication, psychosocial support, case management, family involvement, and supported education/employment services is an ideal approach called coordinated specialty care (CSC) and has been shown to be especially helpful in patients with schizophrenia at reducing symptoms and improving quality of life (NIMH, 2016).

            Regarding medications used to help manage the symptoms of schizophrenia, the primary medications used include antipsychotics. Older generation, first generation, or typical antipsychotics include chlorpromazine (Thorazine), haloperidol (Haldol), perphenazine, or fluphenazine. These work by antagonizing dopamine D2 receptors, and can have additional adverse effects including rigidity, muscle spasms, tremors, restlessness, and tardive dyskinesia (TD), an involuntary movement disorder that may develop with long term use of typical antipsychotics that is oftentimes irreversible. Newer, or atypical antipsychotics, include medications such as quetiapine (Seroquel), asenapine (Saphris), aripiprazole (Abilify), paliperidone (Invega), risperidone (Risperdal), olanzapine (Zyprexa), ziprasidone (Geodon), cariprazine (Vraylar), clozapine (Clozaril) and lurasidone (Latuda). As previously stated, these drugs function mostly by antagonizing dopamine D2 and serotonin 5-HT2A receptors in the brain, except for aripiprazole and cariprazine, which function as partial dopamine and serotonin 5-HT1A agonists and 5-HT2A antagonists. Clozapine also antagonizes alpha adrenergic and cholinergic muscarinic receptors. Please see aforementioned list of antipsychotic adverse effects in previous section on Bipolar Disorder. When starting these medications, agitation and hallucinations typically resolve first (within days) but delusions may take weeks to resolve, and full effects are usually seen by six weeks (NIMH, 2016). In a network meta-analysis of forty blinded randomized clinical trials (RCTs), the efficacy of antipsychotics was compared/contrasted as measured by overall change in symptoms of schizophrenia. The subjects were 5,172 participants with treatment-resistant schizophrenia. The authors concluded that olanzapine was more effective than quetiapine, haloperidol and sertindole* (an atypical antipsychotic). Clozapine was deemed more effective than haloperidol and sertindole*, and finally risperidone was more effective than sertindole*. The authors ranked ziprasidone highly in terms of effectiveness, but due to a limited number of studies regarding ziprasidone (two), these results were not statistically significant. Risperidone seemed the most effective in reducing positive symptoms, while olanzapine performed better with negative symptom relief. In terms of treatment failure (treatment discontinuation for any reason), the only statistically significant finding was that olanzapine proved to be more tolerable than haloperidol and fluphenazine. In terms of extrapyramidal symptoms (EPS), clozapine caused significantly less EPS than risperidone and haloperidol. Ziprasidone, olanzapine, and quetiapine all had statistically less EPS than haloperidol. In terms of sedation, ziprasidone, olanzapine, quetiapine, and risperidone all caused statistically less sedation than clozapine. In evaluating weight gain, olanzapine caused significantly more weight gain than risperidone, quetiapine, ziprasidone, and haloperidol, and clozapine caused significantly more weight gain than risperidone (Samara, et al., 2016). In a systematic review of pharmacological treatment options in first-episode schizophrenia patients, authors point to consideration of side effects as paramount in this group of patients. For example, the long term neurological adverse effects of typical antipsychotics (to limit this, they recommend the less-potent chlorpromazine) and the metabolic adverse effects and weight gain seen in atypical antipsychotics (to limit this they suggest avoiding olanzapine). They failed to identify any antipsychotic with superior efficacy for this patient population (Keating, et al., 2017). In a database retrospective study of over 29,000 patients in Sweden published in JAMA, the risk of treatment failure (defined as rehospitalization, suicide attempt, discontinuation or switch to another medication, or death) was lowest with injectable paliperidone, injectable zuclopenthixol* (a typical antipsychotic), oral clozapine, injectable perphenazine, or injectable olanzapine. Oral flupentixol* (a typical antipsychotic), oral quetiapine, and oral perphenazine had the highest rates of rehospitalization in this study. All injectable medications showed lower rates of treatment failure versus oral formulas (Tiihonen, et al., 2017).

            In looking for possibilities in the future, Schrot & Hubbard identified a 2013-14 Cochrane review which found limited/inconclusive evidence for the use of cannabinoids in the treatment of schizophrenia as well as a systematic review from 2015 using plant-derived CBD in the treatment of psychosis that showed “potential” as an antipsychotic but suggested a large randomized clinical trial in order to support regular clinical use (Schrot & Hubbard, 2016). Others identified only low-quality evidence showing the use of CBD leading to no benefit in psychosis treatment (Whiting, et al., 2015). When the current published evidence was assessed by Mouhamed, et al, their conclusions were that CBD may help in the treatment of schizophrenia, but that THC increased symptoms of psychosis (Mouhamed, et al., 2018).

 

*Please note: Agomelatine, Sertindole, Nabiximols, and Reboxetine are medications not yet available or approved for use in the US

 

 

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