Alessandro Serretti, MD, PhD

Psychiatric disorders affect more than 1 billion people globally and are among the leading causes of disability worldwide in all age ranges from 5 to 75 years.

 A careful clinical evaluation is the first step in making an accurate diagnosis and treatment decision. However, the complexity of many cases or the effect of unmeasured biological markers (biomarkers) may make this approach difficult. Various psychotropic medications belonging to different classes are available, which contributes to the difficulty in making treatment decisions. Consequently, multiple drug switches or combinations/augmentations are a frequent practice and months may be required before finding an effective and well-tolerated treatment.

 Approximately 50% of patients with depression do not respond to at least one antidepressant.

 Moreover, poor treatment adherence often due to adverse effects is frequent and may be one of the causes of treatment resistance.

In this scenario, the use of biomarkers, and specifically genetic variants, to tailor treatment to the individual is an option to improve mental health care by increasing remission rates and reducing the incidence of adverse effects. Genetic variants are involved in the inter-individual differences in psychotropic drug pharmacokinetics and pharmacodynamics. Compared with other types of biomarkers such as neuroimaging brain measures or plasma proteins, genotyping has several advantages: it is easy and quick to perform (the patient can collect the sample using a saliva kit at home), it is economically affordable, and the information generated does not change over time and can be used life-long. These facts explain why psychiatric pharmacogenetics has become a central interest for academic and non-academic institutions and of course for patients and caregivers.

The circumstances requiring the prescription and/or interpretation of a pharmacogenetic test are becoming more and more frequent in everyday psychiatric clinical practice. In some cases, a patient may come for the initial visit to a psychiatrist’s office with the results of a pharmacogenetic test. He or she asks for “the right” prescription based on the results. Some key questions arise at this point: is this test the best option to guide treatment choice in this patient? How to translate the information into a prescription?

In other cases, it might be the clinician who wonders if pharmacogenetic testing should be recommended: for example, in a patient with a history of treatment resistance or poor tolerability to several drugs. The answers are not always straightforward.

There is sufficient evidence for the clinical application of pharmacogenetic testing guiding drug choice and dose (

 genes, which code for the human leukocyte antigens involved in the pathogenesis of the Steven-Johnsons Syndrome, all the other reported genetic variants affect both the risk of nonresponse and adverse effects, because they mediate drug hepatic metabolisms and drug plasma levels. Two cytochrome P450 (CYP450) enzymes, CYP2C19 and CYP2D6, metabolize the most antidepressants and antipsychotics, and the corresponding genes are highly polymorphic. Polymorphisms carried by an individual in each of these 

 genes define the patient’s metabolizing status, which can be normal (extensive metabolizer), increased (ultrarapid metabolizer), decreased (intermediate metabolizer), or severely decreased/completely defective (poor metabolizer).

 gene are examples of pharmacogenetic biomarkers supported both by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetic Working Group (DPWG) for several antidepressants and antipsychotics. Recommendations include to avoid drugs mostly metabolized by CYP2D6 (eg, several tricyclic antidepressants, paroxetine, risperidone) in patients with altered function of this enzyme or alternatively they suggest dose adjustments and increased monitoring to avoid adverse effects in poor metabolizers and treatment failure in ultrarapid metabolizers (

Current guidelines provide no advice on when, or to whom, genetic testing should be offered. This is due to the lack of data regarding which patients will garner the most benefit from testing and for whom it will be most cost effective. Large non-sponsored trials are expected to clarify this point in the next few years, but in the meanwhile we must rely on available evidence.

Findings from clinical trials suggest that testing is likely most beneficial for individuals who have experienced an adverse drug reaction or inadequate response to a previous treatment (

 For these patients, testing may be particularly indicated before prescribing a drug with a narrow therapeutic index, such as a tricyclic antidepressant. In these cases, the cost of the test may be refunded by some health insurance companies or the test is provided by some national health care services.

 In patients who experienced poor efficacy/tolerability to a number of different treatments, genetic testing can help to identify effective medications or guide appropriate dose adjustments.

Compared with therapeutic drug monitoring (TDM), which is a broadly available method to guide dose adjustments, pharmacogenetic testing has some advantages. It can save time that would be spent waiting for the drug to reach steady-state concentration, and the results of the test remain the same life-long so there is no need for retesting. The information can be used to guide future prescriptions of psychotropic drugs as well as medications of other classes metabolized through the same enzyme. This is particularly relevant since chronic medical disorders are common in patients with psychiatric disorders. (An average of 3.5 chronic medical disorders was reported in depressed patients.

Choice of the pharmacogenetic test and interpretation of the results

There are a number of direct-to-consumer pharmacogenetic tests for purchase on the Internet or in drug stores. These tests include variants in the genes reported in 

. Most tests also add other variants with a more heterogeneous level of evidence for association with psychotropic drug response/adverse effects (

 The results are usually provided in less than a week, and they distinguish drugs that can be prescribed as directed from those that require increased monitoring or should be avoided based on the genetic profile.

Several commercial tests were evaluated in terms of clinical benefits compared with standard care, mostly in non-randomized studies with other methodological limitations. The strongest evidence is an improvement in symptom remission rate in the tested group compared with standard care, but long-term data are not available.

 Until the additional genes included in commercial tests are endorsed by clinical guidelines such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) their clinical relevance is uncertain.

The need for a cautious interpretation is confirmed by a case report showing that pharmacogenetic testing may be misleading when the scientific evidence is not definitive, and a complete clinical evaluation is not performed. In this case, the patient had treatment-resistant schizophrenia and had been struggling with the disease for years. He had had multiple hospitalizations and lack of response to multiple medications, including haloperidol, olanzapine, ziprasidone, and paliperidone. The clinical team considered the patient’s documented history of antipsychotic resistance and concluded that a trial of clozapine would be the next appropriate step. However, the results of a pharmacogenetic test advised against the prescription of clozapine because of a variant in the 

 (DRD2) gene, which was associated with poor clozapine response. Nonetheless, the clinical team reached a consensus to try clozapine; the patient subsequently had a rapid improvement on 400-mg clozapine daily and gradually returned to the previous level of autonomous functioning.

, other genes that had insufficient levels of evidence for guiding antipsychotic prescription were included in the used pharmacogenetic test, such as 

). Besides considering which genes are tested, it is also important that the laboratory performing the test has a clinical certification that guarantees good analytical and clinical validity.

Pharmacogenetic testing can provide helpful guidance in the choice of treatment when applied in accordance to the available guidelines (

). The current evidence suggests that testing can be helpful in patients who have experienced an adverse drug reaction or inadequate response to at least one previous treatment, including patients with treatment-resistant disorders.

Pharmacogenetic testing should be interpreted as a decision-support tool to assist in thoughtful implementation of good clinical care, and prescriptions should not be based exclusively on the pharmacogenetic results. Clinical-demographic factors (eg, personal and family history, concomitant medications) and lifestyle (eg, diet) should be always taken into account when making prescriptive decisions.

Dr Fabbri is a Postdoctoral Research Fellow, Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, UK; Dr Serretti is Professor of Psychiatry, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. Dr Fabbri reports no conflicts of interest concerning the subject matter of this article. Dr Serretti reports that he is/has been a consultant/speaker for Abbot, Abbvie, Angelini, Astra Zaneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, and Servier.

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Articles

Pharmacogenetic testing can provide helpful guidance in the choice of treatment and should be interpreted as a decision-support tool to assist in thoughtful implementation of good clinical care.

Overcoming Treatment Resistance: Can Pharmacogenetics Help?

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What factors predispose patients to TRD and what treatment strategies achieve response? Find out here, with a bonus case vignette.

6 Signs Your Patient Is at Risk for Treatment-Resistant Depression

Decades of research have focused on the identification of risk factors associated with treatment-resistant depression (TRD). The most reliable include:

• Duration of the episode: the longer the episode of depression, the greater the atrophy in specific brain regions (eg, hippocampus); the cognitive and behavioral changes that take place during long episodes make a return to previous well-being difficult

• Severity of the episode: both ends of the depression spectrum (most severe, mildest) are hypothesized to increase the risk of poor response-severe depression is associated with biological unbalances; mild depression, with lower drug versus placebo response

• Melancholic features: TRD is more prevalent in bipolar depression than in MDD; the specific investigation of subthreshold manic symptoms is pivotal

• Lack of symptomatic improvement within the first couple of weeks since the start of treatment

• Comorbidity: anxious symptoms and full anxiety disorders (especially generalized anxiety disorder) were found to be predictors of lower rates of response and remission; personality disorders, especially avoidant and borderline, are negative prognostic factors

Biological factors have also been studied as possible predictors of TRD. Genetic variants within the serotonin transporter-serotonin receptors and genes involved in neurodevelopment-have been found to modulate the risk of TRD.

 Although this very promising predictive tool is still under development, a number of research centers worldwide are currently using gene-targeted antidepressant prescription (eg, the Canadian Centre for Addiction and Mental Health Pharmacogenetics Program). A further development is the identification of peripheral blood biomarkers or imaging predictors.

Before treating TRD, however, due diligence is advised. A number of conditions are possible causes of relative or “pseudo” TRD:

• Subtherapeutic doses of antidepressants (approximately 20%)

• Patient nonadherence (approximately 40%)

• Intolerable adverse effects (20% to 30%)

• Wrong diagnosis (10% to 15%) (such as, thyroid disease, nutritional deficiencies, sleep apnea, “latent” bipolarity)

Once TRD is established on the basis of one or more of the risk factors and the exclusion of other conditions, the question arises: what to do next? Unfortunately the answer is not clear, but a number of options are available. The 

A combination of 2 antidepressants or augmentation with another drug, such as lithium, a thyroid hormone, or an atypical antipsychotic, can be tried. The most robust evidence is augmentation of conventional antidepressant therapy with atypical antipsychotics.

 Switching to another antidepressant may also help. However, there is no clear evidence to guide the choice between augmentation and switching. Clinical experience and preliminary scientific evidence support the option of augmenting when partial symptomatic improvement is observed during the current antidepressant treatment.

Vortioxetine is an FDA-approved pharmacological option for the treatment of MDD. It is a serotonin modulator and stimulator that blocks the serotonin transporter, a partial agonist of serotonin receptor 1B and antagonist of serotonin receptors 3A and 7. Vortioxetine demonstrated good tolerability and a beneficial effect on cognition that appears largely independent from the effect on depressive symptoms.

The combination of antidepressant pharmacotherapy and psychotherapy (usually cognitive-behavioral therapy) is an effective option; however, the cost-effectiveness of this strategy has not been evaluated.

 Other nonpharmacological treatments have been widely studied. The use of light therapy, possibly in combination with physical exercise, has demonstrated a considerable antidepressant and anxiolytic effect.

Neurostimulation represents a more invasive option that can be helpful in highly refractory patients. Repetitive transcranial magnetic stimulation (rTMS) provided promising results in the treatment of TRD after 2 or more antidepressant treatment trials failed.

 Moreover, rTMS reduced cognitive impairment and improved patient acceptability compared with electroconvulsive therapy. Vagus nerve stimulation was shown to be effective in chronic TRD, with a 12-month response of 30% or more.

 The evidence for deep brain stimulation is compelling as a promising but still experimental treatment strategy in highly resistant patients. Findings indicate a response rate of 40% to 70%.

Ketamine has gained particular interest because of its marked and immediate antidepressant action (substantial improvement is evident within 24 hours).

 ketamine has also been found to be effective in severe TRD and bipolar depression. However, ketamine tolerability is poor, especially for dissociative symptoms, which commonly emerge. Intranasal administration of ketamine has demonstrated rapid antidepressant effects that appeared comparable to those achieved with the intravenous route but with minimal adverse effects.

 Despite the possible benefits of this novel approach, a major issue with ketamine is its brief antidepressant effect, which lasts no more than a few days, even with repeated administrations. A number of studies are under way worldwide to identify compounds that are similar to ketamine in the manner in which they target the 

-methyl-D-aspartate receptor but with acceptable tolerability and persistence of effect.

Other antidepressants with an innovative mechanism of action are those modulating the inflammatory-immune system. Besides augmentation with NSAIDs such as celecoxib, the tumor necrosis factor antagonist infliximab was recently suggested as another possible effective option for patients with increased C-reactive protein concentration at baseline.

The evidence for the use of molecules with stimulant-like properties is ambiguous. The most compelling evidence available is for lisdexamfetamine as augmentation to escitalopram.

 The effect of this combination was estimated to be similar to that obtained through atypical antipsychotic augmentation.

A more conservative line of research is the development of multitarget monoamine antidepressants. Triple monoamine uptake blockers were developed with the idea of directly modifying different symptomatic domains of MDD, including anhedonia (hypothesized to be a consequence of dopaminergic deficits). A nicotinic acetylcholine receptor agonist and triple monoamine uptake block is a further evolution that demonstrated procognitive effect besides antidepressant-like and anxiolytic-like effects in preclinical studies.

Emma is 67 years old with major depression. Her first major depressive episode occurred when she was 23; she was given amitriptyline and had rapid symptom resolution. She was well until age 56, when the depression recurred after a stressful event. Symptom remission followed 2 months of treatment with 40 mg/d of amitriptyline and 600 mg/d of lithium.

After receiving maintenance treatment and being healthy for 4 years, her depression returned after the death of a close relative. Emma was hospitalized and treated with 20 mg/d of citalopram for 4 weeks without symptom improvement. A switch to 70 mg/d of amitriptyline with lithium augmentation (600 mg/d) allowed a relevant improvement. After 8 months, treatment with amitriptyline and lithium was suspended and 100 mg/d of fluvoxamine was introduced as maintenance therapy.However, because of GI adverse effects, Emma stopped taking the fluvoxamine.

She missed follow-up visits but returned after 7 months, complaining of depressed mood, loss of interest, psychomotor retardation, social withdrawal, feelings of guilt, anxiety, and suicidal ideation. She received 100 mg/d of amitriptyline and 600 mg/d of lithium. After 1 month, the depressive symptoms had not improved; thus, amitriptyline was titrated to 125 mg/d. Symptoms persisted and she was hospitalized after another month. She was given 200 mg/d of fluvoxamine.

Symptom improvement was seen at discharge, but Emma complained about the persistence of inner suffering. She saw her general practitioner, who prescribed 100 mg/d of clomipramine and 600 mg/d of lithium; after 2 months, symptoms persisted. Soon after, she presented to the emergency department complaining of depression and suicidal ideation and was hospitalized. She received 300 mg/d of venlafaxine for 7 weeks, with no symptom improvement; thus, treatment with amitriptyline, 60 mg/d, was restarted, and she was discharged after mild improvement. During follow-up, amitriptyline was increased to 150 mg/d and 600 mg/d of lithium was added; a few days later, the patient attempted suicide. During the following hospitalization, Emma was treated with 160 mg/d of amitriptyline, 600 mg/d of lithium, and 50 Î¼g/d of levothyroxine, resulting in slow but complete symptom remission.

Emma’s case is emblematic of melancholic recurrent MDD with a selective response to the antidepressant amitriptyline, which blocks the serotonin transporter and has a lower affinity for the noradrenaline transporter than other TCAs. Several attempts of replacing amitriptyline with better-tolerated antidepressants (citalopram, fluvoxamine, venlafaxine) failed, possibly because of their selectivity for the serotonin transporter or the noradrenaline transporter. On the other hand, clomipramine was not effective, possibly because of its highly prevalent serotonergic activity compared with amitriptyline. The lack of efficacy of these antidepressants was accompanied by reduced treatment adherence.

Julia is 75 years old. The first episode of depression occurred when she was 47-after a major life event. During that time, she began using alcohol with detrimental social and occupational consequences. The alcohol-related disorder remitted 8 years later, but during that period, Julia experienced depressive mood, loss of interest, social withdrawal, and insomnia. She was treated with several TCAs (clomipramine, imipramine, amitriptyline) without clinical benefit. Partial improvement was seen after a year, but without her previous level of functioning.

After another major life event at age 57, she again became severely depressed with psychomotor retardation, appetite and weight loss, psychic and somatic anxiety, feelings of guilt, and suicidal ideation. Treatment was started with 75 mg/d of amitriptyline, titrated to 125 mg/d, with 600 mg/d of lithium augmentation. After symptoms remitted, amitriptyline was reduced to 25 mg/d. But several months later, mild depressive symptoms recurred and did not improve after an increase to 75 mg/d of amitriptyline. A switch to 50 mg/d of nortriptyline was made; however, an increase of anxiety required a return to 50 mg/d of amitriptyline. Symptom remission occurred a few months later.

Julia had 2 more episodes of depression in her late 60s. Both were treated with 300 mg/d of fluvoxamine, with response within 4 weeks. She was well on fluvoxamine (100 mg/d) maintenance therapy until age 73, when she was hospitalized after another depressive episode. An increase in fluvoxamine to 200 mg/d provided slow improvement and eventual symptom remission. After discharge, there was rapid recurrence of depressive symptoms with marked anxiety. Trials of mirtazapine 30 mg/d and clomipramine 20 mg/d provided poor clinical benefits. There were 4 further hospitalizations, with rapid recurrence of symptoms after initial improvement with various combinations of psychotropics. During the last hospitalization, 90 mg/d of amitriptyline was augmented with 1 mg/d of risperidone, which resulted in mood and anxiety improvement but with episodes of disorientation and confusion. Amitriptyline was replaced with 10 mg/d of escitalopram, with initial improvement.

Julia has a severe form of recurrent MDD, with a middle-age onset that occurred after a stressful life event. Later episodes developed without external events. Amitriptyline was most effective throughout illness, but it was not tolerated as she grew older because of the emergence of anticholinergic adverse effects. Old age, long duration of an episode, and anxiety symptoms were all present and contributed to TRD. The combination of escitalopram and risperidone was appropriate given the marked anxiety that characterized the last phase of the disease.

Dr Serretti is Associate Professor and Dr Fabbri is a Resident in the department of biomedical and neuromotor sciences at the Institute of Psychiatry, University of Bologna, Bologna, Italy. They report no conflicts of interest concerning the subject matter of this article.

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What to do once treatment-resistant depression is established based on risk factors and exclusion of other conditions? Insights here-and a treatment algorithm.

Alessandro Serretti, MD, PhD

Articles

Overcoming Treatment Resistance: Can Pharmacogenetics Help?

6 Signs Your Patient Is at Risk for Treatment-Resistant Depression

Factors That Predispose Patients to Treatment-Resistant Depression