Management of Psychiatric Disorders in Patients with Cardiovascular Diseases.

INTRODUCTION

Psychiatric illnesses and cardiovascular disorders (CVDs) are the leading causes of morbidity and mortality among the global population. CVDs are the leading cause of death according to the World Health Organization, representing 32% of all deaths globally.[1] About 970 million people are affected with mental illness (MI) throughout the world. Psychiatric disorders are one of the leading causes of morbidity across the globe.[2]

The relationship between MI and CVD is a complex one, with no clear cause and effect. Both have many similarities. Like cardiovascular diseases, mental illnesses also run a chronic course. Both have higher rates of morbidity, mortality, and impaired quality of life when compared to the general population [Table 1].

Table 1

Salient points about the relationship between coronary artery disease and psychiatric disorder[123]

• CVDs are the leading cause of death globally (17.7 million, 31% of all deaths worldwide)

• 300 million people are suffering from mental illnesses and CVD will be the leading cause of disability worldwide by 2030 (14.3 millions of all deaths)

• Depression is an independent risk factor of CAD and carries a bidirectional relationship

• Post MI depression has a 1.6-2.7 fold increased risk of mortality

• The cardiovascular mortality gets almost doubled in persons suffering from bipolar disorder (RR 1.5-2) when compared to the general population

• Stress, anxiety, panic disorder, posttraumatic stress disorders etc., increase mortality in persons having cardiovascular disorder (RR 2.0-4.0)

• Development of PTSD in persons having ACS increases the risk of relapse of ACS (RR=2.0) in 1-3 years time

• HPA axis dysregulation, raised serum cortisol and failure of nonsuppression in DST have been found in PTSD and other anxiety disorders which substantiate the causal relationship

CVDs – Cardiovascular disorders; CAD – Coronary artery disease; MI – Mental illness; PTSD – Posttraumatic stress disorders; ACS – Acute coronary syndrome; DST – Dexamethasone suppression test; RR – Relative risk; HPA – Hypothalamic pituitary adrenal

Cardiovascular disease has been found to be approximately 1.5–2 times higher in people having severe mental disorders like schizophrenia and bipolar disorder (BPAD).[3] Individuals with psychiatric disorders are also at risk for chronic obstructive airway diseases, tuberculosis, respiratory tract infections and other respiratory illnesses, obesity, diabetes and other lifestyle diseases compounded by psychoactive substance abuse, especially nicotine. Poor insight, poor access to healthcare services, lack of social support, stigma about psychiatric illness even amongst physicians often lead to insufficient screening for physical health in these patients. Commonly used psychiatric medications such as lithium, sodium valproate, olanzapine, clozapine, risperidone are known to cause weight gain and also increase the risk of metabolic syndrome and consequences thereof.[4]

The cardiovascular risk factors (CVRF) are on rise in general population and poor control of these CVRF are responsible for poor health related quality of life. The self and perceived stigma is high among both mentally ill patients and their clinicians (both liaison physicians and psychiatrists). The integration of mental health care with other specialties and screening of cardiovascular risk factors starting from primary care level should be the call for the day. Many a time the treating doctor doesn’t pay due attention to their patients suffering from CVD as they are underdiagnosed which is a finding in literature. Pharmacoeconomics also contributes as a key factor for poorer management of cardiovascular risk factors among mentally ill persons.[4]

From the cardiological point of view, it has been consistently found that the prevalence of psychiatric disorders in liaison psychiatry is very high ranging from 48% to 87% across cardiovascular, musculoskeletal and orthopedic patients.[5] Following adverse coronary events, many people do suffer from depression, anxiety, acute and posttraumatic stress disorders (PTSD) which can have a negative impact and further consequences leading to heart failure (HF), stroke and acute myocardial infarction (MI) thus increasing the cardiological morbidity and contributing to the mortality as added risk of psychiatric morbidity.[6]

We will now look at individual psychiatric disorders and their relationship with CVDs. Management AND suggested guidelines will run along the lines of safety and efficacy profiles in this population of patients.

It has been consistently shown that the chronic psychotic disorder Schizophrenia patients have higher risk of hypertension (HTN), coronary vascular disorders, MI and higher incidences of sudden unexplained death due to cardiac reasons when compared to the general population. The causes are attributable to multifactorial genetics, metabolic parameters prominently such as insulin resistance, obesity, less physical activity, and due to medication used in management of chronic psychotic disorders.

In our clinical practice, we often see patients with physical disorders such as HTN or coronary artery disease (CAD). There might be some significant drug-drug interactions between the medications given for psychiatric illnesses and CVDs. For example when antihypertensives and antipsychotics are given together, there is a high chance of the individual having severe hypotension due to their synergistic effects. Many psychotropic medicines alter the cardiac conduction such as prolongation of PR, QRS and QTc intervals, ST segment depression, decreased T wave amplitude and large U waves in ECG. This effect can be potentiated by synergistic effects of antiarrhythmic drugs when given together. SSRIs can displace other protein bound drugs and may lead to toxicity. Hence patients with both cardiovascular and psychiatric morbidities need to be monitored as suggested by the guidelines for drug-drug interactions and pharmacokinetics. Prudent decisions should be made to give such medications which are both efficacious and with side effect profile and drug interactions not harmful to the patient.

MOOD DISORDERS AND CARDIOVASCULAR DISORDERS

Depressive disorders

Depression and cardiovascular disease have a bidirectional relationship. Depression has been consistently linked to CVD as a risk factor.[7] Depression is seen in 15%–20% of patients with CAD. These rates are higher in patients with MI, with up to two-thirds of the patients having some form of depression either during hospitalization or in follow-up.[8] 15% of patients undergoing CABG have depression meeting diagnostic criteria. Women have a higher risk, almost two fold, when compared to men especially in those younger than 60 years.[9] It is also found in 20% of patients with congestive HF with higher rates in more severe patients and as well as peripheral artery disease.[81011] Around 30% of implanted cardioverter defibrillator recipients have been found to have anxiety.[12]

DEPRESSION AND CARDIOVASCULAR DISORDERS

Depression is often found to be persistent and recurrent in these patients [Table 2]. Studies have found that depression is often present before the incident cardiovascular disease presentation and is a major factor for poor outcome.[16] It was also seen that during follow-up following a cardiovascular episode, depression was found to be chronic or relapsing in almost half the patients diagnosed with major depression at the incident episode. 40% of the patients who had minor depressive symptoms progressed to have major depressive episodes within 1 year.[1718] At least 65% of patients with MI report depressive symptoms while 20% of them fulfill criteria for a major depressive episode.[192021]

Table 2

Several biological mechanisms have been suggested to explain the underlying relation between depression and cardiological disorders[8131415]

Biological mechanisms
• Autonomic dysfunction - Depression has been found to be associated with decreased heart rate variability, resting tachycardia, HTN, left ventricular hypertrophy, arrhythmias, mismatch in myocardial supply and demand, reduced baroreceptor sensitivity
• Inflammation and impaired immunity - Depressed patients have been found to have higher production of interleukins 1 and 6, TNF-alpha, alpha interferon, CRP which may heighten risk for CVDs
• Neuroendocrine homeostasis - Both internal and external environmental stressors have been found to have an effect on the neuroendocrine system leading to changes in synthesis and use of serotonin, dopamine, norepinephrine. Abnormal activation and feedback of the HPA axis leads to dysregulated response of CRF and ACTH thus leading to hypercortisolemia
• Endothelial dysfunction - There are increased levels of soluble VCAM-1, VWF and circulating CEC leading to endothelial damage and reduced endothelial NO synthase– and COX-independent relaxation leading to atherosclerotic changes in the vessels
• Impaired platelet functioning - Increased platelet reactivity is seen due to increased platelet aggregation, elevated platelet thrombin response, and elevated levels of platelet factors. Increased platelet reactivity in depression can also be seen due to exaggerated serotonin response, reduced serotonin transporter binding, decreased platelet serotonin levels, and high platelet serotonin density
• Insulin resistance - Depression may lead to immune regulated destruction of the pancreatic beta islet cells leading to increased insulin resistance which is a risk factor for CVD
• Genetic factors - Family history plays a major role in both depressive and cardiac illnesses. Genes identified to have a common link between the two disorders include BDNF, MTHFR, CACNA1D, CACNB2, GNAS, ADRB1, NCAN, TLR4, REST, FTO, POMC, CREB, ITIH4, LEP, GSK3B, SLC18A1, ADRA2A, PPP1R1B, APOE, CRY2, HTR1A, TCF7L2, MTNR1B and IGF1. These genes have been implicated in neuroendocrine and HPA axis systems
• Lifestyle and behavioral factors - Decreased physical exercise, poor nutrition, substance use, noncompliance to medication play a role in worsening cardiovascular status

TNF – Tumor necrosis factor; CVDs – Cardiovascular disorders; HPA – Hypothalamic-pituitary-adrenal; CRF – corticotropin releasing factor; ACTH – adrenocorticotropic hormone; HTN – Hypertension; CRP – C-reactive protein; VCAM 1 – Vascular cell adhesion molecule 1; VWF – von Willebrand factor; CEC – Circulating endothelial cells; NO – Nitrous oxide; COX - Cyclooxygenase

Co-morbid anxiety disorders have been found to co-exist with depressive disorders in at least 40% of the patients diagnosed with depression. Most common anxiety disorders include generalized anxiety disorder (GAD) and PTSD. These worsen the outcome of both depression and cardiac disease.[22]

Screening for depression can be done using scales such as Public Health Questionnaire-9,[23] Beck Depression Inventory,[24] Hamilton Rating Scale for Depression.[25] Cardiac Depression Scale[26] has been developed for screening and measurement of severity of depression in cardiac patients specifically,[1927] hence practically whenever it is possible to use the rating scales is advisable.

TREATMENT OF DEPRESSION IN COEXISTING CARDIOVASCULAR DISORDERS

Many studies have been done which have looked at treatment of depression in cardiac patients. The prominent and significant among them are the following studies SADHART[28] and UPBEAT[29] studies that have looked at the efficacy of sertraline while MIND-IT[30] studied the effects of mirtazapine and citalopram. ENRICHD[31] and CREATE[32] studies looked at the efficacy of CBT and IPT along with pharmacological treatment. Most studies have found only a small to modest effect in cardiac outcomes in patients treated with proper antidepressants or psychological therapies. However, outcomes related to depression were significant, i.e., patients improved significantly following the interventions. Reduced morbidity and mortality in psychiatric patients has been documented to some extent in these studies [Table 3].

Table 3

Summary of evidence of pharmacological management of depression[33343536]

Class of antidepressants	Safety and efficacy profile
SSRIs	These have better safety profiles than other classes. Sertraline, escitalopram, fluoxetine have been found to be safe and efficacious. Citalopram can cause prolonged QT interval and should be preferably avoided
SNRIs	They have a small but definite risk of HTN, tachycardia, and orthostatic hypotension. To be used with slight caution
Newer/atypical antidepressants (fewer studies, so data should be interpreted with caution)	Bupropion - No significant adverse effects
	Mirtazapine - Increased appetite may lead to obesity and hyperlipidemia which is a risk factor for CVD. Otherwise, Mirtazapine is found to be efficacious. Risk of TdP is not found to be significant
	Vilazodone - Research reports of palpitations but no other significant cardiac adverse effects
	Agomelatine - No significant adverse effects
	Vortioxetine - No significant adverse effects found yet
	Buspirone - No significant adverse effects at therapeutic doses
	Nefazodone, Trazodone - May cause prolonged QT interval, orthostatic hypotension to be avoided
TCAs	May cause prolonged QT interval, arrhythmias, severe orthostatic hypotension, sinus tachycardia, may predispose to heart blocks. To be avoided/used with extreme caution. To be avoided
MAOIs	Tachycardia, hypotension, hypertensive crisis with tyramine rich foods, prolonged QT interval are seen with administration of MAOIs. To be avoided

Adapted from ENHANCE, SADHART and CREATE studies. CVD – Cardiovascular disorders; HTN – Hypertension; MAOIs – Monoamine oxidase inhibitors; SSRIs – Selective serotonin reuptake inhibitors ; TCAs – Tricyclic antidepressants

PSYCHOLOGICAL TREATMENT IN DEPRESSION WITH CARDIOVASCULAR PATIENTS

Quality studies are by far less and in between. Stress management techniques, relaxation techniques, CBT have been found to be beneficial when compared to placebo in these patients though the sample size and methodology in these studies are not very rich and sound. They have been found to improve the quality of life. ENRICHD[31] and CREATE[32] studies looked at the efficacy of CBT and IPT along with pharmacological treatment. It is thus suggested that in patients with cardiovascular disorders, psychotherapies should be included in the guidelines.[37]

BIPOLAR DISORDER AND CARDIOVASCULAR DISORDERS

CVD is the leading cause of death in patients with BPAD, with 35%–40% of deaths accountable to it.[38] The rates of bipolar patients having CVD is 2–3 times more than compared to the general population.[39] This decreases the life-span of patients by 10–15 years when compared to the general population. The elevated risk of CVD has been found even in the absence of poor lifestyle factors, substance use, and use of medication. The risk is higher in the younger subset of patients when compared to other age groups and the population. Meta-analytic studies showed a hazard risk ratio of 1.54 for CAD and 2.1 for CHF in bipolar patients when compared to control subjects.[4041]

The medications used to treat BPAD include mood stabilizers such as lithium, divalproex, and antipsychotics, especially second generation antipsychotics, namely Olanzapine, Clozapine, Risperidone, etc., which have a propensity to cause weight gain, impaired glucose tolerance, hyperlipidemia, obesity and metabolic syndrome which are independent risk factors for CVD.[42] Behavioral factors such as poor nutrition, substance use, poor compliance to treatment, impaired sleep also play a role in elevating the risk for CVD. All these factors need to be taken into the picture while planning the management of CVD in bipolar patients.

There are many biological theories existing to explain the basis of both cardiological disorders and depression. Some of the theories are found to have a commonality for both disorders [Table 4].[4344]

Table 4

The suggested biological basis for cardiovascular and bipolar disorder[4344]

Biological mechanisms
Inflammation - Inflammatory markers such as IL-6, CRP, TNF-alpha have been found to be raised during symptomatic episodes of the disorder and also are implicated in atherosclerosis
Oxidative stress - Oxidative stress has been seen in BPAD in frontal regions of the brain especially during the mood episodes. Mitochondrial dysfunction has also been implicated. Oxidative stress has a role in endothelial dysfunction, thus creating a link between BPAD and CVD
Neuroendocrine factors - BDNF levels are found to be decreased during mood episodes. BDNF helps in maintaining the endothelial integrity as well. BDNF levels have been found to be reduced during acute coronary episodes while high serum BDNF levels are associated with decreased risk of CVD
Autonomic dysfunction - Increased carotid intimal thickness has been found in BPAD which has been associated with higher systolic blood pressure
Multisystem microvascular factors - Microvascular changes seen in cerebral, retinal, cardiac and peripheral blood vessels have been found to be risk factors for both BPAD and CVD, especially in the younger population (adolescents)
Hyperhomocysteinemia - Homocysteine levels have been found to be elevated in patients with BPAD and is a risk factor for development of CVD
Genetic factors - Studies have found extensive genetic overlap between BPAD and CVD, with 129 shared loci though this needs further research

IL-6 – Interleukin-6; CRP – C-reactive protein; TNF – Tumor necrosis factor; BPAD – Bipolar disorder; CVD – Cardiovascular disorders; BDNF – Brain derived neurotropic factor; BDNF – Brain derived neurotrophic factor

Commonly found comorbid psychiatric conditions in BPAD include substance use disorders (SUD), anxiety disorders, personality disorders, attention deficit hyperactivity disorders, conduct disorders and eating disorders. The comorbid conditions often make the treatment challenging and the course and prognosis of the illness is also affected.[45]

BPAD is a chronic relapsing illness and often the treatment is lifelong. Scales such as Young Mania Rating Scale,[46] Bipolar Depression Rating Scale,[47] Bipolar Affective Disorder Dimension Scale[48] can be used to supplement and document the illness and management.

TREATMENT OF BIPOLAR DISORDER AND CARDIOVASCULAR DISORDERS

Pharmacological management is the mainstay of treatment.[4950] Baseline examination and investigations are a must and frequent monitoring is needed to assess if patients are at risk for CVD and other physical comorbidities. Common medications used are given in the Table 5.

Table 5

The pharmacological and cardiovascular management in comorbid patients

Class of medication	Safety profile in CVD
Mood stabilizers	Lithium - Causes weight gain. May cause sinus bradycardia, AV block, T wave changes, sinus node dysfunction. Contraindicated in sick sinus syndrome
	Valproic acid - Associated with abnormal platelet function. But no direct significant cardiac adverse effects
	Carbamazepine - Slows cardiac conduction and may cause high grade AV block. Should be avoided in patients with sick sinus syndrome and AV block
	Oxcarbazepine - No significant adverse effects
	Lamotrigine - No significant side effects
Typical antipsychotics	Can cause prolonged QTc interval and predispose to TdP. Tachycardia and orthostatic hypotension are prominent side effects. Low potency antipsychotics (like chlorpromazine and thioridazine) cause more cardiac adverse effects when compared to high potency antipsychotics (like haloperidol) though risk is there with both. Thioridazine is cardiotoxic and is to be avoided
Atypical antipsychotics	Clozapine, risperidone, quetiapine have been more commonly associated with orthostatic hypotension
	Tachycardia is common, especially with clozapine
	Ziprasidone, iloperidone, paliperidone have been associated with prolonged QTc interval
	To be watched
	Metabolic side effects such as obesity, hyperglycemia and dyslipidemia are more with clozapine, olanzapine, risperidone and quetiapine
	Clozapine has been associated with myocarditis. To be watched
	Atypical antipsychotics have been associated with sudden cardiac death
	Aripiprazole is the antipsychotic with the safest cardiac profile

CVD – Cardiovascular disorders; TdP – Torsade de pointes; AV – Atrioventricular

These guidelines recommend to optimize the management of bipolar mood disorders as detailed by Indian psychiatric clinical practice guidelines.

The following guidelines are suggested to watch for the PHARMACOLOGICAL MANAGEMENT OF COMORBID issues of cardiovascular related side effects of the medications commonly used for mood disorders. PLEASE REFER to the guidelines suggested by Indian psychiatry for clinical practice guidelines for management of mood disorders.

Following an acute episode MANAGEMENT, psychotherapies such as individual psychoeducation, CBT, IPSRT and family therapy have been found to be helpful in preventing relapses or worsening of mood episodes.[51] Hence recommended.

SCHIZOPHRENIA

Patients with schizophrenia often have poor physical health due to various factors including sedentary lifestyle, poor nutrition, poor access to healthcare services, smoking etc. Their life expectancy is reduced when compared to the general population. Cardiovascular disease has been found to be the leading cause of death in this population. It is reported to be 2–3 times more in patients with psychosis when compared to control population. The predicted risk ratio of CVD in these patients is 1.3–1.64 though this might be underestimated. MI has been found in at least 30% of the patients with schizophrenia. CAD has been found to be around 27% in these patients while metabolic syndrome ranges from 36% to 52%. The prevalence rates of arrhythmias, acute coronary syndromes, HTN, stroke and HF have been found to range from 1.43 to 2.17.[525354]

Mechanisms underlying the common link between schizophrenia and CVD include behavioral factors, effects of antipsychotics, biological factors such as inflammation, autonomic dysfunction, deficiency of long chain fatty acids, shared genetic loci between the two illnesses that have an effect on cholesterol levels, systolic blood pressure, and BMI.[5556]

Schizophrenia can be diagnosed using standard diagnostic criteria and its course can be objectively documented using scales such as positive and negative syndrome scale[57] and brief psychiatric rating scale.[58]

Mainstay of treatment is the use of antipsychotics. The efficacy and the safety profile of the same in CVD have already been discussed [Table 5]. Regular monitoring of the physical attributes such as weight, HTN, glucose levels, lipid levels, renal and liver function, and cardiac profile is absolutely needed in these patients [Table 6]. Psychological therapies also play a role in the prognosis of the illness.

Table 6

Suggested cardiovascular considerations for prescribing psychotropic medicines

1. Check for underlying cardiac illnesses like ischemic heart diseases, acute coronary syndrome, uncontrolled hypertension, myocarditis, cardiomyopathy, heart failure etc.

2. Check for the presence of congenital long QT syndrome

3. Concurrent use of digoxin or other medicines that can prolong QT interval

4. Consumption of alcohol, nicotine dependence or dependence to any psychoactive substance

5. Elderly, malnourished patients having multiple medical comorbidities

6. Dose adjustments in patients having severe hepatic and renal impairments

7. Special vigilance for patients having electrolyte imbalance, thyroid disorders, other chronic medical illnesses and terminal illnesses

8. Proper training for CPR and availability of emergency medicines for resuscitation especially while using IV medications

CPR – Cardiopulmonary resuscitation; IV – Intravenous

The life expectancy of persons with Schizophrenia and other severe mental disorders is reduced by 10 years due to adverse coronary outcomes when compared to general population.

Psychotropic drugs can cause cardiological adverse effects either by themselves or if given in conjunction with other medication. Thioridazine, Chlorpromazine, Pimozide can prolong QT and QTc intervals (>450 ms) and Pimozide can also lead to ultrastructural changes in cardiac muscles resulting in toxic cardiomyopathy. Clozapine can also cause cardiomyopathy and sudden cardiac death which is rare but is TO BE KEPT IN MIND.

ANXIETY DISORDERS AS COMORBIDITY WITH CARDIOVASCULAR DISORDERS

Anxiety disorders are common in patients with CVD and often affect the outcome of the cardiac illness. Many symptoms overlap between anxiety disorders and CVD such as chest pain, heaviness of chest, palpitations, dizziness, nausea, vomiting etc. This overlap of symptoms often makes diagnosis challenging.

Hence more often than not, patients with anxiety disorder present to emergency and get investigated for cardiac disorders.[5253] 20%–30% of patients experience increased levels of anxiety following an acute coronary episode, the transient nature of which becomes chronic in at least half of the patients. Similar rates are seen in patients prior to CABG procedures. 13% of patients with HF have been found to have anxiety disorder while 20%–40% of patients with implantable cardioverter defibrillator have elevated anxiety levels.[52]

When the relationship between specific types of anxiety and CVD was assessed, it was found that patients suffering from GAD had a hazard ratio of 1.62 for CVD.[54] Prevalence of GAD is 26% in patients with CAD and 14% in patients with HF. Prevalence of PTSD in CVD patients ranges from 6% to 24% while patients suffering from PTSD are found to develop CVD symptoms 20%–65% more than controls.[55] Prevalence of panic disorder varies from 5% to 8% in patients with CVD though some studies show higher prevalence. Anxiety, especially chronic illness, has been found to affect the mortality rate of patients in CVD, with poorer quality of life when compared to patients with CVD with no anxiety.[56]

Biological mechanisms underlying anxiety disorder and CVD include autonomic dysfunction such as decreased heart rate variability, endothelial dysfunction, impaired HPA axis function and hypercortisolemia, inflammation, genetic factors such as pleiotropy.

Scales such as Hamilton Anxiety Rating Scale[57] and Hospital Anxiety and Depression Scale[58] can be used to assess the severity of anxiety symptoms.[59]

TREATMENT OF ANXIETY DISORDERS AND CO EXISTING CARDIOVASCULAR DISORDERS

SSRIs and SNRIs are the common classes of drugs used to treat anxiety disorders. Benzodiazepines (BZDs) are often used for short term for symptomatic relief of anxiety symptoms. Studies have shown BZDs to have beneficial effects in patients with CVD with no anxiety symptoms as well.[60] Short acting BZDs like midazolam and triazolam, and intermediate acting BZDs like lorazepam and oxazepam are preferred over long acting preparations of BZDS to reduce drug-drug interactions and additive effects of other CNS depressants used in CVD. No significant cardiac adverse effects have been found. Drugs like quetiapine and gabapentin can be considered second line medications as they have some efficacy in managing anxiety disorders.

Relaxation techniques, CBT, systemic desensitization, flooding therapies and other appropriate behavior and other psychotherapies including group therapies and family therapies are recommended. Psychoeducation goes a long way in reassuring the patients. They are commonly used as psychological treatments for various forms of anxiety disorders.[61] The evidence though exists is not robust but still recommended.

SUBSTANCE USE DISORDERS AND CARDIOVASCULAR DISORDERS

Non adherence to treatment is very common in patients who are suffering from mental illnesses. The emergence of metabolic syndrome characterized by obesity, diabetes, dyslipidemia, increased waist-hip ratio and insulin resistance has put the persons with MI at an added risk of suffering from cardiovascular disorders.[62] Less than 15% of patients having depression in coronary artery diseases are actually being diagnosed.[345]

SUBSTANCE USE DISORDERS

People with SUD are at a particular risk for both acute and chronic effects of the substances on the cardiovascular system.[6364] This group is very heterogeneous but few common risk factors are often seen. For example, injectable drug use might lead to thrombosis and embolism, infective endocarditis, sepsis, various transmittable illnesses such as HIV/AIDS and hepatitis-B which also contribute to poor vascular health.

CVD is one of the leading causes of mortality in this group. We will be focusing on the most commonly used substances and their effects on the cardiovascular system.

ALCOHOL

Alcohol is one of the most common psychoactive substances used worldwide. There were few studies which reported that moderate levels of alcohol consumption is actually cardio-protective but overall consensus is that there are many harmful physical effects of alcohol though it is not so straight-forward. Alcohol has been shown to have an effect on lipoprotein levels, inflammation, endothelial function, and myocardium.[65] Daily use of 1–2 standard drinks per day has been shown to either be protective or to not have a significant effect on the cardiac system. Higher use of alcohol, binge pattern of drinking, comorbid disorders, older age, and longer duration of use have been shown to increase the morbidity and mortality related to CVD.[66]

HTN is very prevalent among alcohol users and the relationship is dose-dependent on the amount of alcohol use. Incidence odds ratio of HTN in users of alcohol has been found to range from 1.2 to 2.3.[67] HTN itself predisposes an individual to CAD, stroke and HF. According to a longitudinal cohort study in alcohol users, incident increased risk of MI ranged from 1.4 to 1.5, that of atrial fibrillation was 2.08–2-19, and that of HF was 2.29–2.39.[68] The relation between alcohol and peripheral vascular disease was found to be not very clear.

NICOTINE

Nicotine use especially in the form of smoking has been consistently linked with CVD since ages. Along with nicotine, other chemicals in the smoke have been found to be atherogenic, and carcinogenic, and also to increase the thrombogenic activity of platelets, increase cholesterol levels and insulin resistance. The carbon monoxide in the smoke also leads to supply demand mismatch of oxygen.

Nicotine has been found to cause dyslipidemia, HTN, and diabetes which are risk factors for CVD. Mortality due to CVD is 60 percent higher in those who use nicotine as compared to nonusers.[69] The INTERHEART study showed that smoking increased the risk of MI three-fold.[70] Smoking is associated with a 60% increase in HF. There is a doubling of risk for arrhythmia in nicotine users. Nicotine use can be attributed as a cause of peripheral vascular disease by almost 50%. Risk of heart disease is almost 13% higher in users of smokeless tobacco when compared to nonusers. E-cigarettes also have negative health consequences, contrary to popular opinion.

CANNABIS

Cannabis is the most widely used illicit drug globally. It is known as the gateway drug and its use is more common in the younger population. Endocannabinoid receptors in the cardiovascular system may have a role in metabolism and vascular functioning. Cannabis consumption has been known to cause tachycardia, orthostatic hypotension, and dizziness.

Various case studies and reports have shown that cannabis can be linked to arrhythmias and sudden death. The annual risk of MI is found to be 1.5%–3% in daily users of cannabis. Cannabis induced myocarditis may be a risk factor for development of peripheral vascular disease. Rarely, cardiomyopathy due to cannabis use has been reported. Overall, more studies are needed to know the chronic effects of cannabis on the cardiovascular system. Synthetic cannabinoids have also been found to cause tachycardia, acute changes in BP and probable MI.[71]

OPIOIDS

Opioid use has slowly been increasing in the Indian subcontinent. It can include both prescription use and recreational use. Infective endocarditis has been consistently linked to use of injectable opioids. However, other cardiac adverse effects have been studied less frequently. Opioid receptors have been discovered in the cardiac system but the biological link between opioids and CVD has been poorly understood. There are studies that report the cardioprotective effects of opioid use while other studies talk about the harmful effects. Opioids have been used in cardiac patients and for cardiovascular thoracic surgeries. Only more research in this area can shed a light on the relation between opioid use and CVD.[7273]

Opioids such as tramadol and methadone have been associated with prolonged QT interval and can predispose to arrhythmias and Torsade de Pointes.[74] Risk ratio of CAD in opioid use ranges greatly from 0.5 to 3.09.[75] It is possible that lifestyle factors and co-morbid substance use might play a contributory role.

TREATMENT

Treatment includes symptomatic management of withdrawal symptoms and use of agents to prevent craving and relapse [Table 7].[76777879]

Table 7

Cardiac safety of pharmacotherapy of alcohol and substance use[7475767778]

Disorder	Safety profile of medications used
Alcohol use disorder	Acamprosate - No significant cardiac side-effects
	Clonidine - Might cause severe hypotension, syncope, bradycardia, AV block, rarely CHF. To be used with caution
	Disulfiram - Adverse effects include tachycardia, dizziness, hypotension, rarely MI and CHF. Not recommended in CVD
	Naltrexone - No significant cardiac side effects
	BZDs - No significant adverse effects
Nicotine use disorder	Bupropion - No significant adverse effects
	Varenicline - Small risk of CAD and PVD.
	Nicotine replacement therapy - Might cause tachycardia, dizziness, elevated BP
Opioid use disorder	Methadone - Prolonged QT interval, TdP, pathological U waves, cardiomyopathy, CAD, Brugada-like syndrome. Not recommended
	Buprenorphine - Might cause orthostatic hypotension, syncope and arrhythmias. To be used with caution
	Tramadol - Might cause arrhythmia, prolonged QT interval, tachycardia. To be used with caution
	Clonidine - Might cause severe hypotension, syncope, bradycardia, AV block, rarely CHF. To be used with caution
	Naltrexone - No significant cardiac side effects
	BZDs - No significant adverse effects

CHF – Congestive heart failure; CVD – Cardiovascular disorders; MI – Mental illness; BZDs – Benzodiazepines; TdP – Torsade de Pointes; CAD – Coronary artery disease; AV – Atrioventricular block

Psychological therapies include psychoeducation, motivational interviewing, motivational enhancement therapy, CBT, relapse prevention strategies, and family therapies. SUD is a chronic and relapsing disorder, hence long term management is needed.[79]

Many people already have some form of physical disorder or the other when they present to a psychiatrist. The following guidelines can help in choosing the appropriate treatment.

ELECTROCONVULSIVE THERAPY

Electroconvulsive therapy (ECT) is one of the most effective treatments in psychiatric practice. Though there are no absolute contraindications for ECT, one of the relative contraindications include recent unstable angina or MI (within 30 days). ECT and the drugs used in it cause both sympathetic and parasympathetic changes leading to changes in cardiac output, blood pressure, and heart rate. Complications include arrhythmias, ischemic changes, and HF. In patients with pre-existing cardiac conditions, these changes may compromise the cardiovascular health in them.[88] Hence, utmost caution is needed when ECT is given in them.

Following steps are recommended.

High risk consent should be taken from the patients and their relatives for ECT procedure

Pre-anesthetic evaluation and pre-ECT cardiac evaluation are needed to assess the fitness of the patient

If seizure duration is more than a minute, then seizure should be aborted to reduce the stress on the myocardium

Oxygen supplementation should be provided continuously

Post ECT, monitoring should continue in the postanesthesia care unit or a high dependency unit.

MANAGEMENT OF PSYCHIATRIC PATIENTS DEVELOPING NEW ONSET CARDIOVASCULAR ILLNESS

It is well known that psychiatric patients, whether secondary to illness, psychotropic use or psychosocial factors, have an increased risk for development of cardiovascular disease. Regular screening for physical illnesses is needed. However, the majority of the patients do not have proper evaluation due to various factors. If and when they develop CVD, the following steps are recommended.

In case of chronic cardiovascular conditions, the cardiologist/primary care physician should consult with the psychiatrist and decide on pharmacological management taking into account the past and present symptomatology of the psychiatric condition, severity of the illness, need to continue the psychotropic and select an efficacious drug which also has a good safety profile in cardiac patients with minimal interactions with the cardiac drugs.

In case of acute cardiac illnesses such as MI or cardiac surgery, psychiatrist should be consulted on an emergency basis regarding the cessation of the drug till the acute illness is treated. The drug should be restarted at the earliest as post MI or cardiac surgery as exacerbation of previous psychiatric illness is often seen. Drugs which have a better safety profile and least drug-drug interactions should be preferred with regular follow up [Table 8].

Table 8

Safety of drugs in specific illness[778081828384858687]

Cardiovascular disorder	Drugs preferred
HTN	Antidepressants: SSRIs, reboxetine, mirtazapine, agomelatine
	Antipsychotics: Quetiapine, risperidone, Olanzapine, paliperidone, iloperidone
	Others: Valproic acid, benzodiazepines, methadone, donepezil, rivastigmine
CAD	Antidepressants: Sertraline, escitalopram, fluoxetine, mirtazapine, vortioxetine, agomelatine, bupropion, buspirone
	Antipsychotics: Aripiprazole, olanzapine, lurasidone
	Others: Valproic acid, topiramate, benzodiazepines, donepezil, rivastigmine, buprenorphine
CHF	Antidepressants: All SSRIs except citalopram, mirtazapine, bupropion, agomelatine
	Antipsychotics: Aripiprazole, lurasidone, olanzapine
	Others: Valproic acid, benzodiazepines, donepezil, methadone, buprenorphine
Arrhythmias (ventricular tachycardia, torsades de pointes, prolonged QT interval etc.)	Antidepressants: Sertraline, fluoxetine, paroxetine, mirtazapine, bupropion
	Antipsychotics: Aripiprazole, lurasidone
	Others: Valproic acid, benzodiazepines, buprenorphine
Valvular heart disease	Antidepressants: SSRIs except citalopram, mirtazapine
	Antipsychotics: Aripiprazole
	Others: Benzodiazepines, buprenorphine

CAD – Coronary artery disease; HTN – Hypertension; CHF – Congestive heart failure; SSRIs – Selective serotonin reuptake inhibitors

HOW TO MANAGE IN THE CASE OF PROLONGED QT INTERVAL AS MANY PSYCHOTROPICS OFTEN ACT AS A CAUSATIVE FACTOR

When should we intervene?

If QTc interval is <440 ms (men) or 470 ms (women)-no need to intervene.

If QTc interval is more than 440 ms (men) or 470 ms (women) but <500 ms:

Repeat ECG

Consider reducing the dose of the drug

Consider switching to a low risk drug

Consider a cardiology review

Review other causes of prolonged QTc interval.

If QTc interval is more than 500 ms:

Stop the suspected causative drug

Switch to a low risk drug

Review with a cardiologist at the earliest

ECG monitoring if patient is showing symptoms such as syncope

Review other causes of prolonged QTc interval [Table 9].

Table 9

Drugs and their risk of causing QT prolongation[89]

Severity of risk of causing QT prolongation	Medication
Drugs with low risk of causing QT prolongation	Aripiprazole
	Olanzapine
	Perphenazine
	Lurasidone
	Sertraline
	Desvenlafaxine
	Bupropion
	Vilazodone
	Reboxetine
	Mirtazapine
	Valproic acid
	Topiramate
	Carbamazepine
	Oxcarbazepine
	Lamotrigine
	Gabapentin
	Pregabalin
	Benzodiazepines
	Trihexyphenidyl and biperiden
	Buprenorphine
Drugs with moderate risk of causing QT prolongation	Amisulpride
	Clozapine
	Quetiapine
	Risperidone
	Paliperidone
	Flupentixol
	Citalopram
	Escitalopram
	Fluoxetine
	Paroxetine
	Venlafaxine
	Duloxetine
	Amitriptyline
	Nortriptyline
	Clomipramine
	Imipramine
	Doxepin
	Moclobemide
	Lithium
	Methadone
Drugs with high risk of causing QT prolongation	Chlorpromazine
	Haloperidol
	Pimozide
	Sertindole
	Ziprasidone

SPECIAL POPULATIONS

Children

Pre-existing cardiac disease in children increases their susceptibility to adverse cardiac side effects due to use of psychotropics, in particular QT prolongation and arrhythmias.[90] Caution is needed when prescribing drugs in these children. Baseline ECG and investigations including extensive physical examination should be done before initiating therapy in them. Careful monitoring of any adverse effects should be done as long as the child is on these medications.

In case of using stimulants such as methylphenidate in children with ADHD, studies have shown an increased relative risk of arrhythmias and MI though absolute risk is low.[91] Monitoring should be done rigorously especially in the early stages of the treatment as risk is high during these periods. The psychiatrist should be in regular and frequent communication with the pediatrician/cardiologist to minimize risks. In children with congenital heart disease, methylphenidate is contraindicated.

Geriatric population

Physical comorbidities are the rule rather than the exception in this population, often multiple in nature. Illnesses, prescription of multiple drugs, and the drug interactions often lead to significant adverse effects in the elderly.

Before starting any psychotropic, complete history of all the physical conditions, careful review of the medications currently in use and extensive physical examination are needed. Drugs with minimal drug interactions should be started at low doses. Oral treatment is preferable to parenteral treatment as rapid introduction of the drug may cause serious side effects. Use of antipsychotics has been shown to cause sudden deaths in patients, especially in those with dementia. Hence, extreme caution needs to be applied.

Anticholinesterases are often used frequently in this population. It has been shown that the regularly used drugs of this class such as donepezil, rivastigmine, and rivastigmine do not have any significant adverse cardiac effects in the patients and hence can be used safely.[92]

IN SUMMARY

The guidelines suggested above are based upon the best evidence available at this point of time. As with the clinical practice guidelines of Indian psychiatry society, it is important to individualize and evaluate the cardiovascular issues in each case of psychiatric illness. It is also important to do a regular work up basically with an electrocardiogram in the day to day practice.

It is also recommended to do regular investigations and to be in liaison with a cardiologist for any CVD in psychiatric patients. The suggested guidelines as detailed in this chapter have to be personalized for every psychiatrically ill patient. These guidelines further emphasize the need to take care of both cardiovascular disorders and psychiatric illnesses simultaneously.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.