By: Jennifer Tran, PharmD; PGY1 Pharmacy Resident
Mentor: Lisa Sterling, PharmD, BCPS, BCGP; Residency Program Director/Clinical Pharmacy Specialist, Mercy Hospital – Springfield, MO
Program Number: 2020-11-03
Approval Dates: December 1, 2020 to May 1, 2021
Approved Contact Hours: 1 hour
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Psychiatric disorders affect 450 million people across the world.1 According to the World Health Organization (WHO), one in four people will have one or more mental disorders in their lifetime.1 Listed in Table 1 are common risk factors for psychiatric disorders:
Medications used to treat a variety of major psychiatric disorders include antipsychotics, antidepressants, mood stabilizers, and anti-anxiety, however the efficacy of these medications varies and many of them have significant adverse effects. Treatment failure and adverse effects along with significant adherence issues lead to many patients with psychiatric disorders needing adjunctive or alternative therapy. As a result, several nontraditional medications have been investigated in psychiatric disorders with sufficient data for some of these medications to be included in clinical guidelines. This article will discuss medications that have been investigated in the treatment of major depressive disorder, anxiety disorders, schizophrenia, and bipolar disorder.
Patients with major depressive disorder feel persistently depressed or lose interest in activities. Despite the numerous antidepressant medications, remission in depression is difficult to achieve. Failure to respond to antidepressants leads to the diagnosis of treatment resistant depression and may result in treatment with alternative medications. In the landmark Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trials, researchers evaluated the effectiveness of antidepressants in clinical practice. The first study found that only 25-33% of patients achieved remission in the first 14 weeks of therapy.2 The number of patients who fail to achieve remission continues to decrease after consecutive trials of antidepressants in later stages.3 The STAR*D trial shows that patients who progressed through the treatment algorithm were at high risk for relapse during the follow-up phase.3 These trials show how difficult depression may be to treat due to lack of efficacy.
Generalized anxiety disorder is characterized by excessive, uncontrollable, or irrational worry about events or activities. Medications used for depression have also demonstrated efficacy in anxiety and are used as first line agents in anxiety, as serotonin regulates both fear and worry in the amygdala.4 Anxiety can be difficult to treat. In a systematic review, remission of anxiety symptoms varied between antidepressants with fluoxetine having the highest remission rate (60.6%) and escitalopram having the second highest remission rate (26.7%). 5
In schizophrenia, patients are not in touch with reality due to psychotic symptoms such as hallucinations or delusions. This occurs due to increased levels of dopamine in the brain. First line treatment for schizophrenia is antipsychotics. However, these medications have been shown to have high discontinuation rates and adherence is difficult to achieve. In the landmark Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trials, more than 60% of patients discontinued their antipsychotic medication due to lack of efficacy, intolerance, patient’s decision, or other reasons.6 In a systematic review, clinicians estimated that approximately 40% of schizophrenia patients were nonadherent to their medications. Factors that may be associated with nonadherence include poor insight, negative attitudes towards medications, or inadequate discharge planning.7
In bipolar disorder, patients experience extreme mood shifts that can lead to manic symptoms including delusions of grandiosity, extremely easy distractibility, and flight of ideas. Bipolar disorder tends to have a higher risk of relapse in comparison to other psychiatric disorders.8 Nonadherence may be attributed to bipolar patients’ risk of relapse. In this patient population, nonadherence rates are approximately 50%.8 Factors that may influence nonadherence include negative attitudes towards medication, severity of illness, complexity of medication regimen, and side effects.8 Antipsychotics and mood stabilizers are two medication classes used to treat bipolar disorder. Mood stabilizers are used to prevent and treat mania. The purpose of this class is to stabilize a patient’s emotions from intense mood shifts.4
Anticonvulsants affect four main molecules which may have a role in treating bipolar disorder: GABA, excitatory amino acids like glutamate, dopamine, and serotonin.10 Anticonvulsant medications used to treat bipolar disorder represent some of the first alternative agents used in psychiatric disorders. Specifically, anticonvulsants that have shown a high level of efficacy in stabilizing mood in bipolar disorder include carbamazepine, lamotrigine, and divalproex sodium.4 Carbamazepine and valproate were the first anticonvulsant agents to be studied in treating the manic phase of bipolar disorder. This led to the investigation of other anticonvulsant agents in treating bipolar disorder. Not all anticonvulsants have been found to be efficacious, as each anticonvulsant has a different mechanism of action.
Valproic acid’s mechanism of action in bipolar disorder may be due to its diminished flow of sodium through voltage-sensitive sodium channels. The result of less sodium release leads to diminished release of glutamate. Another possible theory could be due to valproate increasing the release of GABA. Carbamazepine acts differently compared to valproic acid, as it works by binding to the alpha subunit of voltage-sensitive sodium channels. This leads to enhancing the inhibitory effects of GABA.4 Another anticonvulsant used in bipolar disorder is lamotrigine, which is specifically indicated for bipolar depression. Lamotrigine, like carbamazepine, blocks the alpha subunit of voltage-sensitive sodium channels. However, the mechanism of action in treating bipolar depression with lamotrigine may be due to its ability to reduce the release of glutamate. Lamotrigine has not been found as effective in treatment of mania as carbamazepine.4
Other anticonvulsants have been investigated in psychiatric disease states. Pregabalin and gabapentin have demonstrated no significant efficacy as a mood stabilizer4 but may have a role in anxiety. The mechanism of action in bipolar disorder of both gabapentin and pregabalin are thought to be due to binding selectively to voltage-sensitive calcium channels, which inhibits the release of excitatory neurotransmitters.4 Pregabalin is a GABA analog and recommended as first-line treatment in Canadian guidelines for social anxiety disorder and generalized anxiety disorder.11 Pregabalin was found to be superior to placebo in two randomized control trials, but the response rate was low at 30-43% compared to 20-22% for placebo.11 The anxiety effects of pregabalin relieved symptoms quickly. Pregabalin is a schedule V medication and should be used with caution in patients with a history of substance use disorder. Gabapentin has been shown to relieve symptoms of social phobia or social anxiety disorder. In a double-blind, placebo-controlled trial, 69 patients were randomized to receive either gabapentin flexibly dosed 900-3600mg/day in three divided doses or placebo for 14 weeks. A significant reduction of symptoms and a higher response rate was shown in the group that received gabapentin (32%) compared to those who received placebo (14%).12 Side effects were more frequently with gabapentin including dizziness and dry mouth. The response rate to gabapentin is low but provides a treatment option for those who are unable to tolerate a SSRI or at risk of dependence with benzodiazepines.
Ketamine has demonstrated anti-depressive effects, which are thought to result from glutaminergic N-methyl-D-aspartate (NMDA) receptor antagonism. In a systematic review of parallel-group or cross-over randomized controlled trials that compared single-dose intravenous ketamine to placebo in patients with unipolar or bipolar depression. The primary outcome was symptoms change measured by Hamilton Depression Rating Scale (HAM-D) or Montgomery-Asberg Depression Rating Scale (MADRS). The review found that ketamine was statistically significant in reducing depression in comparison to placebo at 40 minutes of infusion (p<0.001) and lasting until days 5-8.13 The systematic review showed that ketamine has an ultra-rapid effect on improving depressive symptoms. In a single-site, active placebo control, randomized, double-blind crossover study, forty-one patients suffering from treatment-resistant depression with single infusions of ketamine or midazolam. After patients relapsed with depressive symptoms, they received 6 open-label ketamine infusions three times a week for 2 weeks. Ketamine infusion was found to significantly reduce depressive symptoms with 59% of patients meeting response criteria (>50% decrease MADRS score 24 hours post infusion). This study showed how ketamine infusion can quickly reduce depressive symptoms, as well as maintain cumulative and sustained antidepressant effects with repeated infusions.14 Although the trial showed fast improvement in depressive symptoms there is a possibility of the placebo effect, which is high during the first couple of weeks of treatment. Long-term studies are needed to determine if ketamine infusion should be used as a treatment option. The efficacy of ketamine has led to the development of esketamine (Spravato®) specially for the treatment of major depressive disorder.
Dextromethorphan has been investigated as a treatment for depression and, like ketamine, is a NMDA receptor antagonist. Dextromethorphan also has an effect on serotonin and norepinephrine. Recently, the results of the GEMINI study were released in a press release. This was a Phase III randomized, double-blind, placebo-controlled, multi-center trial completed in the United States. The study randomized 327 patients with moderate to severe major depressive disorder to receive either dextromethorphan/bupropion modulated delivery tablet or placebo once daily for the first 3 days and twice daily thereafter for a total of 6 weeks. The active drug combination was found to be statistically significant in reducing the MADRS score compared to placebo (16.6 vs 11.9, respectively).15 In a phase IIA, open-label clinical trial, the efficacy and tolerability of the combination of dextromethorphan 45 mg and quinidine 10 mg twice daily over a 10-week period in 20 patients with treatment resistant depression was investigated. The researchers found that the treatment group statistically significantly reduced the MADRS score by -13 (p<0.001). Although the results show promise in reducing depression, tolerability may be an issue as 30% of patients discontinued treatment. The treatment was discontinued primarily due to tolerability. 16
Two anti-hypertensive agents’ prazosin and propranolol are frequently used to treat symptoms of psychiatric disorders. Prazosin is used to treat post-traumatic stress disorder (PTSD) induced nightmares. The mechanism of action is due to its alpha-1 adrenergic antagonism that reduces adrenergic response in the central nervous system. Thus, relieving symptoms of PTSD due to overstimulation of adrenergic activity.17 The use of this medication is controversial due to its place in the Veterans Affairs and Department of Defense (VA/DOD) guidelines, which do not include recommendations for or against the use of prazosin in PTSD associated nightmares.18 Smaller trials had shown promising results in reducing nightmares in PTSD patients. A larger, VA multi-site trial with 304 subjects found that prazosin failed to separate from placebo in treatment of global symptoms of PTSD and nightmares. The Prazosin and Combat Trauma PTSD trial (PACT) was a 26-week, multicenter, double-blind, randomized, controlled trial. Investigators found that there was no significant difference between the prazosin and placebo groups in the PTSD scale, sleep quality index, and global impression of change score. 19 In conclusion, they found that prazosin did not reduce symptoms of distressing dreams or improve sleep quality. Although there is conflicting evidence for the use of prazosin PTSD, pharmacists may continue to see it used.
Propranolol is a highly lipophilic beta receptor blocker, a property allowing it to cross into the blood brain barrier. Propranolol is used to treat the physical symptoms of performance anxiety including tremor, tachycardia, and sweating. The medication is dosed initially at 10mg/day as needed to a target of 10-40mg/day.17 Propranolol only reduces the physical symptoms of performance-anxiety but does not treat the underlying anxiety.
Anti-inflammatory and Salicylic Acid Agents
Inflammation has been shown to play a major role in depression, schizophrenia, and bipolar disorders. This is thought to be due to dysregulation of immune response leading to abnormal pro- and anti-inflammatory cytokine findings in patients.20 In depression, the theory of increased inflammation and an altered immune response has led to the investigation of non-steroidal anti-inflammatory agents (NSAIDs) as possible treatment options. Along with inflammation having a role in depression, specifically COX-2 inhibitors have been shown to have direct effects on the serotonergic system by increasing serotonin levels in rats.21 Celecoxib, a selective COX-2 inhibitor, was used to augment the SSRI sertraline over 8 weeks of therapy in female patients experiencing a first episode of major depression. Patients were randomized to receive either sertraline (up to 100mg/day) plus celecoxib 200mg/day or sertraline plus placebo. Both groups showed improvement with the celecoxib group having a greater decrease in HAM-D.21 During week 4, the difference in the change in the HAM-D score was statistically significant and in favor of the treatment group (-13.7 in the treatment group vs -8.8 in placebo, p=0.021). However, the investigators did not provide p values for week 8. Another double-blind, randomized controlled trial with similar findings looked at another selective serotonin reuptake inhibitor (SSRI), fluoxetine 20-40mg/day. Celecoxib was dosed higher in this trial at 400mg/day. Both groups showed a decrease of the HAM-D score, but the celecoxib group showed greater improvement in symptoms (p=0.04).22,23
Aspirin has been studied in the treatment of depression. In a randomized clinical trial, 100 patients with major depressive disorder were assigned to either aspirin plus sertraline (treatment group) or placebo plus sertraline for 8 weeks. Mean Beck Depression Inventory (BDI) scores for depression severity were statistically significantly lower in the aspirin treated group (p=0.001). Both groups were similar in terms of side effect profile with more than half of the aspirin group (64%) not experiencing side effects at all.24 Key points to consider with this trial is that depression in the placebo group was more severe in comparison to the treatment group, which could have influenced results.
Pramipexole is a dopamine agonist at the D2 and D3 receptors and used in the treatment of Parkinson’s disease and restless leg syndrome. It has been demonstrated efficacy as a treatment option in treatment-resistant depression and bipolar depression I. One of the most common symptoms with depression is anhedonia or loss of interest in activities. Anhedonia has been associated with decreased levels of dopamine.25 In 60 patients with treatment-resistant major depressive episode, flexibly dosed pramipexole was added to standard antidepressant treatment in an 8-week, randomized, double-blind, placebo-controlled trial. The standard antidepressant therapy included both SSRI’s and serotonin-norepinephrine reuptake inhibitor (SNRI). The mean dose of pramipexole as augmentation was 1.35 mg/day. The primary outcome was change in MADRS score. Mixed-effects linear regression model was used to determine the change in MADRS. The results found a statistically significant time effect favoring pramipexole (p=0.038). However, response (p=0.27) and remission (p=0.61) comparing pramipexole to placebo was not statistically significant.26
Estrogen and Progesterone Agents
The onset of schizophrenia for women commonly occurs five years later in comparison to men which have an earlier onset at usually in their 20’s. Women with schizophrenia are more vulnerable or at risk for relapse during the postpartum period after pregnancy or during menopause when estrogen levels are down.27 In a dose-finding, double-blind, placebo-controlled study, adjunctive transdermal estradiol 100 mcg compared to placebo was investigated in 102 female child-bearing schizophrenia patients for 28 days. The results showed the addition of estradiol significantly reduced positive and general symptoms on the psychopathological symptom ratings (PANSS subscale scores) compared to women who received antipsychotic medication alone (p<0.05). 27 This trial included primarily a younger subset of patients who may be in the early phases of the disease.
Estrogen has been investigated in the management of depression. Depression risk increases in women who are perimenopausal. One trial examined the efficacy of transdermal estradiol plus intermittent micronized progesterone in preventing depressive symptom onset among euthymic perimenopausal and early postmenopausal women. Patients (n=172) were randomized to receive transdermal estradiol 100 mcg plus progesterone 200 mg/day for 12 days or placebo plus progesterone every 3 months for 12 months. The study found that patients in the treatment group (17.3%) were less likely to score a 16 on the Center for Epidemiological Studies – Depression Scale (CES-D) in comparison to placebo (32.3%) which would indicate a diagnosis of depression (p=0.03).28 This was one of the first studies to look at long-term effects of prophylactic mood benefits of transdermal estrogen and progesterone alone in women during menopause transition and early postmenopausal period.
Other agents used in psychiatric disorders that are mechanistically involved with estrogen are raloxifene and tamoxifen. Both are selective estrogen receptor modulators (SERM) that are used to treat hormone-sensitive breast cancer. Recently, they have been studied as a potential treatment option for schizophrenia and bipolar disorder. There have been some studies that show estrogen’s potential in a protective role in the pathophysiology of schizophrenia due to lowering psychotic and negative symptoms in pre-menopausal women.27,28 A systematic review of nine randomized controlled trials of raloxifene versus placebo for the treatment of schizophrenia in 561 patients showed improvement in total symptom severity (p=0.009), and a reduction in positive (p=0.02) and negative symptoms (p=0.02). Dosing ranged from 60 to 120 mg per day.29
Tamoxifen’s efficacy in bipolar disorder is thought to result from inhibition of protein kinase C (PKC). Studies suggest that excessive PKC activation leads to disruption of the prefrontal cortex in regulating thinking and behavior. A systematic review of five randomized, placebo-controlled trials evaluated tamoxifen as monotherapy or as augmentation therapy with lithium or valproate in the treatment of acute mania in bipolar patients. The results found that tamoxifen had improved mania scale score compared to placebo.30 Although, these results are promising it does not provide information of the effect of tamoxifen with other agents such as antipsychotics.
Dysfunction of the hypothalamic-pituitary-adrenal axis (HPA) is thought to affect psychiatric disorders such as depression and anxiety due to its release of cortisol. In the STAR*D trials, one of the studies compared the effectiveness of lithium to triiodothyronine (T3) augmentation in patients with major depressive disorder. Patients were augmented with T3 up to 50 mcg/day for up to 14 weeks. Remission rates were greater in the T3 group compared to the lithium group (24.7% vs 15.9%, p=0.4258). The difference between groups was not statistically significant.31 As a result, T3 augmentation is recommended by the American Psychiatric Association (APA) in the 2010 Major Depressive Disorder treatment guidelines.
The CANMAT/IBSD guidelines recommend levothyroxine as a third-line option for treatment of acute bipolar I depression.32 In a 6-week, double-blind, randomized, placebo-controlled trial of supratherapeutic levothyroxine (300 mcg/day) dose as augmentation in 62 patients the mean decrease of HAM-D score was greater in the levothyroxine group compared to the placebo group (-5.1 vs -7.8; p=0.198).33 However, the study failed to show statistical significance between the two groups. The trial used the maximum dosing of levothyroxine, which can cause symptoms of hyperthyroidism including nervousness, hair loss, tachycardia, tremors, and fatigue.
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Future Treatments in Psychiatric Disorders and Conclusion
With the limitations of therapies available to treat psychiatric disorders, clinicians are finding value in other medications that may not typically be used in psychiatric disorders. There is an abundance of data to support possible use of some of these agents, but further studies with larger sample sizes are needed for many of the medications. The efficacy of these alternative therapies has given new insight into the pathophysiology of psychiatric disorders through their mechanisms of actions. This has created the opportunity for new therapies to be developed such as esketamine. In addition, clinicians may have available medications to treat psychiatric disorders not previously treatable as our understanding of these conditions expands
The use of non-psychiatric medications in psychiatric disorders provides us a greater understanding about the pathophysiology as well as another option in treating disease states. Overall, many of the trials had small sample sizes and were used primarily as adjunctive therapy. Before considering these treatment options, ensure that patients have adequate trials of psychiatric medications.