Treatment of Mental Health in Patients With Chronic Liver Disease

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Abbreviations

CBT

cognitive behavioral therapy

CLD

chronic liver disease

ECT

electroconvulsive therapy

GAD

generalized anxiety disorder

HE

hepatic encephalopathy

MDD

major depressive disorder

PHQ‐9

9‐item patient health questionnaire

SGA

second‐generation antidepressant

SNRI

serotonin norepinephrine reuptake inhibitor

SSRI

selective serotonin reuptake inhibitor

TCA

tricyclic antidepressant

Vd

volume of distribution

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Depression

The term depression represents a constellation of symptoms that are largely nonspecific in respect to diagnosis. At one extreme is an "everyday depression," a person's experience in the face of a specific challenge, such as paying one’s taxes. At the opposite extreme is major depressive disorder (MDD) described by profound subjective hopelessness, helplessness, and worthlessness. Biological symptoms occur, including sleep continuity disorder with early‐morning awakening, a diurnal variation of mood, and anhedonia. Because of their nonspecificity, other conditions may easily mimic depression, including symptoms of chronic liver disease (CLD), such as hepatic encephalopathy (HE) and delirium. The key therefore is to apply careful, psychiatric differential diagnoses, especially in CLD. Notably, this article focuses on depression and anxiety, while important coexisting or independent mental health conditions, such as bipolar disorder, panic disorder, obsessive‐compulsive disorder, posttraumatic stress disorder, and substance abuse, are not discussed. In any evaluation of a patient with depression and/or anxiety, the aforementioned mental health disorders should be evaluated for and managed appropriately.

Pharmacotherapy

Patients with CLD can have profoundly altered pharmacokinetics resulting in higher systemic drug levels. Portosystemic shunting in cirrhosis reduces the first‐pass metabolism of high‐extraction medications. ¹ The volume of distribution (Vd) is further impacted by decreased transport proteins and ascites and peripheral edema. In addition, drugs eliminated by hepatic metabolism or biliary excretion can have dramatically reduced clearance. The stage of cirrhosis and location of pathology also affect drug metabolism, with glucuronidation often preserved in early cirrhosis compared with cytochrome P450 enzymatic activity, while entities affecting the centrilobular region, such as alcohol‐related liver disease, where oxidative functions are focused, impact enzymatic activity to a different degree to a disease affecting the portal region. ¹ There are additional complexities to consider in CLD, including HE and benzodiazepine sensitivity.

In patients with severe MDD (9‐item patient health questionnaire [PHQ‐9] ≥ 20), the preferred initial treatment is pharmacotherapy plus psychotherapy, which is more efficacious than either treatment modality alone (Fig. 1). ² Electroconvulsive therapy (ECT) may be considered for severe suicidality. For mild‐to‐moderate MDD (PHQ‐9 < 20), initial monotherapy with either second‐generation antidepressants (SGAs), such as selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) (Table 1), or psychotherapy is reasonable. ³ SGAs and psychotherapy have each shown efficacy as monotherapies and have comparable efficacy and tolerability. ³

FIG 1.

Management of depression and anxiety in CLD. *Normal loading dose, half the standard maintenance dosing. Consider atypical antidepressants in certain circumstances: bupropion for comorbid tobacco dependence or reducing risk for sexual dysfunction; mirtazapine for anorexia; trazodone or mirtazapine for insomnia (all medications at half of the standard dosing). **Hydroxyzine is useful for short‐term control of anxiety symptoms, in lieu of benzodiazepines.

TABLE 1.

Overview of the Medications Used in the Treatment of Depression and Anxiety Disorders

Class	Drug
SSRIs	Citalopram
	Escitalopram
	Fluoxetine
	Paroxetine
	Sertraline
Serotonin and norepinephrine reuptake inhibitors	Duloxetine
	Venlafaxine
Norepinephrine and specific serotonergic antidepressant	Mirtazapine
Serotonin antagonist and reuptake inhibitor	Trazodone
Atypical antidepressant	Bupropion
Tricyclic antidepressant	Amitriptyline
Nonbenzodiazepine anxiolytics	Buspirone
	Pregabalin
	Hydroxyzine

SGAs are the first‐line pharmacological agents due to their efficacy and safety (remission rate of 43% versus 29% in placebo) ⁴ and are comparable across and within respective categories. ⁵ The seminal STAR*D study, which captured a broadly “real‐world” representative patient sample with both medical and psychiatric comorbidities, reported a 37% remission rate with citalopram as first‐line therapy. ⁶ Given the comparable efficacy among SGAs, drug selection is based on symptoms, adverse effects, comorbidities, patient preference, affordability, and prior medication experiences. Importantly, SGAs are low‐risk hepatotoxic medications with only rare asymptomatic mild elevation of serum aminotransferases (0.5‐1%). A specific concern for SSRIs in CLD is their association with gastrointestinal bleeding partly attributed to serotonin transporter inhibition on platelets affecting platelet aggregation after vascular injury. ¹ Although the clinical evidence is mixed, caution should still be used with coprescribing of nonsteroidal anti‐inflammatory drugs and antiplatelets. ¹ Concomitant proton pump inhibitors can be considered to mitigate the risk for bleeding in the more vulnerable patients who have thrombocytopenia or additional risk factors for bleeding. The atypical antidepressant, bupropion, is useful in mitigating sexual dysfunction given the lower rate versus SSRIs/SNRIs (6% versus 16%) or for treating comorbid tobacco dependence, whereas mirtazapine should be avoided in patients with features of metabolic syndrome (~3 kg weight gain after 8 weeks). ⁷ Trazodone is useful for insomnia given its higher rate of somnolence versus SGAs, including mirtazapine (42% versus 25%), and can be considered as first‐line therapy if insomnia is a large component of the somatic symptoms, with mirtazapine as an alternative. ⁷ The adverse effects of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors limit their routine use.

Antidepressants should be initiated with low doses. ¹ In CLD, no change is required in the initial dose for SSRIs/SNRIs; however, a target maintenance dose of half of standard dosing is recommended. ¹ Subsequent titration is based on the balance of response and adverse effects. The dosing principles of SSRIs/SNRIs are the same for TCA use in CLD; however, the risk for HE precipitation needs consideration. It is also recommended to reduce the bupropion and mirtazapine dose by 50%. ¹

Time to improvement is around 2 weeks; however, most patients do not achieve remission after initial treatment, ⁷ necessitating therapy switch or augmentation with additional interventions. Should patients display minimal improvement after 4 to 6 weeks, the next treatment step is titration to the maximum tolerated dose, an early switch to an alternative SGA, ⁸ or augmentation with psychotherapy. ⁹ The previously referenced STAR*D experience reported 31%, 14%, and 13% remission rates for second, third, and fourth acute pharmacotherapy treatment steps, respectively. ⁶

Behavioral Therapy

No one psychotherapy is clearly superior in MDD; however, cognitive behavioral therapy (CBT) or interpersonal psychotherapy are first line because they have been more widely studied. ¹⁰ CBT involves identifying and changing maladaptive beliefs, improving emotional regulation, and developing personal coping strategies. CBT is effective as monotherapy with higher remission rates achieved versus controls (waiting list or usual care) (41% versus 21%). ¹⁰ Interpersonal psychotherapy is an attachment‐focused psychotherapy that centers on resolving interpersonal problems and symptomatic recovery. ¹⁰ An important consideration is a patient’s willingness to engage fully in psychotherapy, which is crucial in optimizing behavioral intervention efficacy. There are additional behavioral therapies that can be considered, including family therapy, problem‐solving therapy, and relaxation techniques. Exercise programs can also be considered depending on tolerability and illness extent. ¹¹

Anxiety

Anxiety symptoms are likewise nonspecific and require careful differential diagnosis. Treatment can be deferred with clinical follow‐up in mild generalized anxiety disorder (GAD; GAD‐7 < 10) if symptoms do not interfere significantly with functioning. For patients who warrant treatment, SSRIs/SNRIs and/or CBT are the established first‐line interventions (Fig. 1). ¹² The benefit of medication and CBT are similar, and the choice of which to use, if not using both, is determined by patient preference, availability, affordability, and adverse effects.

There are no differences in the efficacy between SSRIs/SNRIs, and their dosing in CLD is the same as for MDD. ¹² Patients who have a suboptimal response to a SSRI/SNRI after 4 to 6 weeks should be reassessed for co‐occurring untreated conditions or ongoing stressors requiring greater problem‐solving focus. If no co‐occurring exacerbating factors are elicited, then a different SSRI/SNRI should be initiated. If no response occurs after two SSRI/SNRI trials, then augmentation with either a nonaddictive second‐line medication (e.g., buspirone, pregabalin, or hydroxyzine) or CBT should be initiated. Hydroxyzine is useful for short‐term control of anxiety symptoms, in lieu of benzodiazepines. If benzodiazepines are being considered in CLD, then short‐acting benzodiazepines such as lorazepam (which has no active metabolites) should be prescribed to mitigate the risk for drug accumulation. However, the risk for benzodiazepine dependence, whereby patients develop various behavioral and physical symptoms, including tolerance (loss of efficacy over time) and a withdrawal syndrome with medication cessation, limits their utility. Moreover, patients with CLD treated with at least 3 days of benzodiazepines are at a high risk for developing first‐time HE possibly related to increased cerebral benzodiazepine receptor availability in CLD, particularly among patients with alcohol use disorder. Notably, pregabalin (through its agonism of GABA) and hydroxyzine (via its anticholinergic effects) can also increase the risk for HE, and thus patients with CLD who are taking these medications should be monitored carefully. Aerobic exercise, mindfulness‐based stress reduction, and yoga may also be worthwhile adjunctive treatments. ¹³ In addition, web‐based and telehealth interventions will continue to be incorporated into patient management in the near future. ¹⁴

If effective, medication for GAD should be continued for at least 12 months given the lower relapse rate versus 6 months of therapy (8.8% versus 53.7%). ¹⁵ If the patient relapses after cessation of an effective medication, the same medication can be restarted and the treatment course extended.