Psychiatric disorders are seen at an increasing rate in those diagnosed with cancer. The most common psychiatric disorders that are seen are delirium, depression, adjustment disorders, anxiety, sexual dysfunctions, and sleep disorders, which overall affect 30%–40% of people diagnosed with cancer. The incidence of psychiatric disorders among those in an advanced phase of cancer illness is higher. However, psychiatric disorders are underdiagnosed and under-treated and affect quality of life (QoL) of a person with cancer. The advancement in psychopharmacology, availability of newer and better tolerated drugs with lesser side effect profile has been a boon in the field of clinical psycho-oncology. There has been growing evidence for the use of nonpharmacological interventions in reducing distress and treating psychiatric disorders. Hence, psycho-oncology is becoming a specialized novel area, integrating psychiatry, psychology into the care of oncology. The definition and various aspects of psycho-oncology have been covered in different chapters of a recent book on psycho-oncology.[1] Here, we focus on the most common psychiatric disorders, their assessment, and their treatment focusing on the pharmacological and nonpharmacological aspects. We have looked at literature and guidelines from various countries and made a comprehensive summary of all, which can start as the beginning point for formal guidelines for the Indian setting. These guidelines will enable standard care and uniformity in procedures and practices across hospitals in the country. This is in the hope of also intriguing clinicians and researchers to focus on specific areas of psycho-oncology and develop the guidelines further. In the first part of the chapter, we cover some basics and key areas of pharmacological management in psycho-oncology. The general principles of pharmacological management in Box 1, interaction of anticancer drugs (ACD) and psychotropics in Table 1, anticancer medications induced psychiatric issues in Table 2 and a list of anticancer drugs with no known interactions with psychotropics in Box 2.Box 1: General principles of pharmacological management in psycho-oncologyTable 1: Drug interactions of psychotropics and anticancer medicationsTable 2: Anticancer medication induces psychiatric disorders and their managementBox 2: Anticancer drugs that do not have any known interactions with psychotropicsAt this stage, we have understood some pharmacological aspects of psycho-oncology. Now, we will look at the nuances in the assessment and treatment of individual psychiatric disorders with respect to psycho-oncology. DEPRESSIVE DISORDERS Introduction In cancer patients, depression is one of the most commonly diagnosed psychiatric disorders.[2] The incidence of major depressive disorder can range from 15% to 40%. Depressive disorders can be on a spectrum and can include major depressive disorders, persistent depressive disorders, dysthymia, adjustment disorder, and demoralization syndrome. Diagnostic guidelines such as ICD-10 or DSM-V can be used to make a diagnosis. However, the clinician should be aware that there is overlap in the biological symptoms of depression and symptoms of cancer or adverse effects of the treatment. It is crucial and important to delineate the symptoms and make a correct diagnosis of depression. There are various approaches described below: Inclusive approach – To include all the symptoms of depression, even if some may be attributable to cancer Substitute approach – Somatic symptoms replaced by cognitive and affective symptoms (Endicott’s criteria)[3] Alternative approach – To add some new affective symptoms to the original criteria (Akechi’s criteria)[4] Exclusive approach – Somatic symptoms are excluded in entirety, and only affective symptoms are considered to make a diagnosis (Cavanaugh’s criteria).[5] For more details on the various approaches, readers are encouraged to read the references mentioned. Depressive disorders when identified and treated improve the QoL and decision-making capacity. Assessment A detailed assessment must be done with regard to a good history on independent symptoms and current treatment, past history – psychiatric and medical, detail family history, and also substance use history. Scales that help understand the intensity and severity are: Brief symptoms inventory Hospital anxiety and depression scale. These are widely used to assess psychological distress. These are specifically designed to detect depressive symptoms in medically ill patients. Other scales are as given below: Center for Epidemiological Studies – Depression Beck depression inventory. They have acceptable sensitivity and specificity in cancer patients. Management Treatment of depression in cancer patients with depression should also involve their families. Holistic care encompassed the following components of providing adequate information, support in making appropriate decisions, informed consent for psychotherapy and other management when necessary.All of this should be done while being sensitive and respectful to the patients familial, religious, cultural and ethnic background as well. The liaison between the cancer care physicians and mental health team is important for a well-coordinated care and good outcome of treatment. A list of contributing factors for depression are given in Box 3. NICE guidelines have given a flowchart for step-wise care for depression in people with cancer [Figure 1]. The management of mild, moderate, and severe depression is discussed in the previous IPS Guidelines on Depression and should be referred to for the treatment of depression in cancer as well.Box 3: Contributors for depressionFigure 1: Stepped care model for delivery of care[6] (adapted with permission)Pharmacological management Psychopharmacological studies show evidence that antidepressants are more effective than placebo in both cancer patients with major depressive disorder or depressive symptoms and distress related to cancer.[789] However, considering poor health status and adverse effects, the utility of ADs should be restricted to those with moderate-to-severe depressive episode. Those with mild depression should be started on ADs if psychosocial intervention does not produce desired change in mood or activity. Guidelines for the use of antidepressants in cancer patients[1] Medications are initiated at low dose and titrated very gradually to achieve an optimum individualized response (initial low doses have shown to reduce initial side effects and are better tolerated, particularly in patients with fragile physical conditions) Patients need to be informed about the time taken for titration, time after which medication has effects (latency period), and most common/serious adverse effects and monitoring if required. This helps in reducing medication stoppage, especially if patients are receiving other medications Treat the patient for a minimum period of 4–6 months to avoid relapses or recurrence of depression postremission Regular monitoring of vitals and blood parameters and check on the concomitant use of medications for cancer (e.g., steroids, antiemetics, antibiotics, antiestrogen, and chemotherapy agents) The process of stopping ADs should be a slow process and the clinician should keep in mind to reduce 25-50% of the dose once in 2-4 weeks. This reduces the risk of possible withdrawal symptoms that can be distressing for a patient. Sometimes, withdrawal may be mistaken for relapse of depression or worsening of symptoms of cancer Psychoeducation and reassurance are extremely important in oncology settings. Most of the evidence comes from case studies or open trials, and as per current research and guidelines practiced, selective serotonin reuptake inhibitors (SSRIs) are the first line of treatment as they have a lesser side effect profile. SSRIs – The most commonly used medications including citalopram, escitalopram, and sertraline are useful to treat depression in patients with cancer and also are found to be beneficial for anxiety and hot flashes. Duloxetine, an antidepressant along with treating depression, also has benefits in chronic musculoskeletal pain, chemotherapy-induced peripheral neuropathy, and neuropathic pain Serotonin norepinephrine reuptake inhibitors (SNRIs) – Venlafaxine and desvenlafaxine are used to treat major depression, anxiety, and neuropathic pain Tricyclic antidepressants (TCAs) – For neuropathic pain, TCAs have to be used judiciously as they can have severe and intolerable side effects such as constipation, dry mouth, and sedation Noradrenergic and specific serotonergic antidepressants (NaSSAs) – Mirtazapine can be used to treat sleep disturbances and nausea; the metabolic adverse effects have to be kept in mind. Nonpharmacological management The type of therapeutic intervention must be given due to thought considering symptoms and factors that contribute to depression. Recently diagnosed patients with cancer with mild-to-moderate depression may benefit from psychoeducation, cognitive-behavioral therapy (CBT), relaxation strategies, and problem-solving approaches.[10] Patients who have more advanced disease may benefit from supportive-expressive psychotherapy that focuses on processing fears associated with death and other existential concerns.[10] Recent development of manualized targeted psychotherapies for those with advanced illness includes Meaning-Centered Group Therapy,[11] Dignity Therapy,[12] Mindfulness-Based Meditation Therapy,[13] and a brief supportive-expressive intervention referred to as CALM[14] (Managing Cancer and Living Meaningfully). Table 3 gives a list of psychotherapeutic interventions.Table 3: Description of psychological interventionsDemoralization The term demoralization was first described by Frank Jerome in 1970s. Demoralization is considered as a normal reaction to a particular situation. Usually, the situation is a medical illness, such as cancer, treatment for their condition, etc. It can coexist with other psychiatric disorders such as depression, anxiety, and adjustment disorder. Table 4[15] enumerates the ways to distinguish demoralization from other psychiatric disorders.Table 4: Differentiating points for various psychiatric conditions seen in cancer[15]ANXIETY DISORDERS Introduction Among those diagnosed with cancer, anxiety is commonly seen as a response to threat or fear of uncertainty, suffering, and mortality. In cancer centers, anxiety to a mild degree is seen in almost everyone with fluctuating levels, and anxiety is highest at times of evaluation, surgery, and other treatment/interventions. However, anxiety at a disorder level[16] is seen in approximately 35% of cancer patients; this is higher than what is seen in general population. Anxiety can result in effective medical decision-making ability, can worsen existing medical symptoms, and can interfere with cancer care.[17] Anxiety and depression are seen to coexist in a lot of people diagnosed with cancer. Anxiety when assessed is associated with poorer QoL. Anxiety can be mild to severe in intensity. Among anxiety spectrum disorders, we can find generalized anxiety, social anxiety, specific phobias, obsessive–compulsive disorder, acute stress reaction, and posttraumatic stress disorder. The clinical symptoms and diagnosis usually made on the criteria as per the ICD-10 or DSM-V. The assessment scales used to assess are the same as those that are used in depressive disorders. It is important to note less-discussed diagnostic criteria, mixed anxiety depression, where the symptoms do not complete anxiety/depressive disorder. This can be managed on the lines of mild depression/mild anxiety disorder. Management In mild anxiety disorders, the first line of management is psychosocial management; in cases with poor response to treatment, pharmacological management should be considered. In moderate-to-severe cases, pharmacological management is combined with psychosocial treatment for adequate treatment. Pharmacological management The guidelines to start and treat with SSRIs in anxiety are like those in depression. SSRIs, benzodiazepines and nonbenzodiazepine anxiolytics can be used to treat anxiety.[17] Benzodiazepine and nonbenzodiazepine analogs can be used to treat anxiety acutely. They should be tapered and stopped at the earliest possible time. Clinicians should be aware of the potential of dependence and complications in those with alcohol abuse/dependence; paradoxical reactions in the elderly; and disturbance in concentration, drowsiness, and possibility of falls in the frail and elderly patients. The dosage should be given at a minimum and titrated based on improvements, tolerability, and adverse effect profile. SSRIs that are used in cancer patients are citalopram, escitalopram, and sertraline, while SNRIs, i.e., venlafaxine and desvenlafaxine, can be used to treat anxiety as they have less interaction with other drugs. Clinicians should try and avoid fluoxetine, fluvoxamine, and paroxetine as they can alter the levels of chemotherapeutic, hormonal therapy and can worsen nausea in cancer patients. Antidepressants can be used for longer duration as required. Other anxiolytics are buspirone, mirtazapine, and atypical antipsychotics (APs) at low doses. Buspirone is an anxiolytic with no addictive potential but has 2–3 weeks for onset of action. Mirtazapine is a good drug of choice when anxiety is associated with insomnia and anorexia as sedation and possible weight gain, which are common adverse effects, are seen to be beneficial here. Low-dose atypical AP, e.g., olanzapine/quetiapine, and anticonvulsants, such as gabapentin, are also used in our routine clinical practice to treat symptoms of anxiety. The drugs with off-label use are not FDA approved and have not been adequately studied in patients with cancer. Nonpharmacological management A nonpharmacological approach to address anxiety and related symptoms has shown to be effective. The various intervention techniques include psychoeducation, CBT, problem-solving therapy, mindfulness, and supportive-expressive group therapy.[18] Conventionally, CBT focuses on restructuring cognitive distortions and negative automatic thoughts and changing intermediate and core beliefs to help the person break the vicious thought process of anxiety. Basic behavioral strategies such as gradual exposure and systematic desensitization can help reduce avoidance and fear in anxiety-provoking situations.[19] The above-mentioned interventions would not be applicable to people in advanced or terminal stages of their illness where existential concerns, increased disability, reduced functioning capacity; perceived burden posed to family caregivers; physical symptoms; and adverse treatment effects are the issues addressed in those receiving palliative care.[20] Acceptance and commitment therapy Acceptance and commitment therapy (ACT) is an amalgamation of cognitive and behavioral strategies; it involves various processes such as acceptance, commitment, mindfulness, and behavior change, to enable the process of psychological flexibility.[21] The six processes of ACT are being in contact with the present moment, defusion, self as a context, acceptance, values and committed action.[22] ACT can be used in individual and group settings. It is shown to have moderate-to-large improvements in cancer-specific QoL outcomes.[23] Mindfulness-based cognitive therapy Mindfulness -based cognitive therapy aims to help a person be mindful, nonjudgmental, and acceptant of their thoughts, emotions, experiences, and bodily sensations. The skills of mindfulness learnt help to achieve a state of self-acceptance, decrease the focus on thoughts and to look at them as transient events occurring in the mind and not as the accurate reflections of reality.[24] DELIRIUM Introduction Among neuropsychiatric disorders, delirium is most commonly associated with cancer. Delirium is associated with high rates of mortality, morbidity, increased burden on caregivers, increased duration of hospital stay, and health-care cost.[2526] Delirium is usually undiagnosed, untreated, or undertreated. Delirium is seen in 20%–30% of people diagnosed with cancer, and the incidence is 85% in those with terminal illness.[27] It can be caused due to various treatable and reversible causes and can also be caused due to irreversible causes, as in terminal delirium. Those at higher risk of developing delirium are given in Box 4, The medications implicated in causing delirium are outlined in Box 5 and reversible causes of delirium are listed in Box 6, Risk factors for delirium in Box 7, clinical signs of delirium in Box 8 and subtypes of delirium in Box 9.[1]Box 4: Those at higher risk of developing depressionBox 5: Medications that can cause depressionBox 6: Reversible causes of deliriumBox 7: Risk factors of deliriumBox 8: Clinical signs in deliriumBox 9: Subtypes of deliriumClinical signs Delirium is characterized by an abrupt onset of disturbances of consciousness (i.e., arousal), attention, cognition, and perception that fluctuate over the course of the day.[2527] Subtypes of delirium There are three types of delirium based on clinical signs, hypoactive subtype, hyperactive subtype, and mixed type of delirium. Hypoactive delirium is characterized by withdrawn behavior, quietened appearance, drowsiness, reduced arousability and low to absent voluntary reporting of experienced distress. Hyperactive delirium characterized by restlessness, agitation, and aggressiveness is more easily recognizable. Mixed delirium is characterized with alterative periods of hyper- and hypo-active delirium. Levels of distress are almost similar in those with hypoactive/hyperactive delirium, and mortality rates are higher in hypoactive delirium as compared to hyperactive delirium. Assessment The assessment should involve focused history of symptoms of delirium, medications, and treatment history; assess systemic comorbidities, signs of infection, and all reversible causes of delirium; and use tools to assess delirium. There are various tools to assess delirium, including: Memorial delirium assessment scale[28] Delirium rating scale-revised 98[29] Confusion assessment method.[30] These scales are validated and can be used in cancer care centers. After assessment and understanding the severity of delirium, we should assess for the causes of delirium as mentioned in Box 4. Management After screening and assessment of delirium, any treatable causes must be addressed, and periodically, delirium should be re-assessed to observe any improvements in the delirious state. The aim of treating delirium is to see a person alert, conscious, calm, comfortable, intact cognitions, not psychotic, pain-free, and coherently communicating.[27] Pharmacological management As a first step, look for the current ongoing medications, and stop any drug with potential to precipitate or worsen delirium. The management of delirium is mentioned briefly here; we recommend the readers refer to IPS Guidelines on Management of Delirium and adopt the same here. Pharmacological treatment of delirium Antipsychotics Haloperidol is the gold standard drug currently used to manage delirium. Haloperidol at doses of 0.5–1 mg can be given intravenous (IV) or intramuscular (IM) route hourly with baseline and regular ECG monitoring for risk of QTc prolongation. Haloperidol should be used with great caution in those sensitive to EPS and those with preexisting dementia. Low-dose chlorpromazine is an acceptable alternative. Second-generation APs – olanzapine, risperidone, and quetiapine – can be tried in hyperactive delirium and aripiprazole in hypoactive delirium. The evidence for the use of second-generation APs is limited. Benzodiazepines Benzodiazepines can be used in patients with agitation and distress. Midazolam and lorazepam can be used as subcutaneous/IV/IM routes. It should be used with caution in the elderly and may cause falls, increased sedation, and respiratory depression. They can also cause paradoxical worsening of agitation. Should start at the lowest dose, around 0.5 mg/h or 1 mg can be repeated every 2 h until the patient is sedated. Psychostimulants The role of Psychostimulants in delirium has been less studied. There is one open-label study showed good efficacy of using modafinil with antipsychotics in hypoactive delirium. There are case reports to give evidence for use of methylphenidate with antipsychotics in hypoactive delirium as well. Modafinil and methylphenidate have shown some positive efficacy in terminally ill patients. However, due consideration should be given to the possibility of drug-induced exacerbation of psychotic symptoms or precipitation of agitation. Cholinesterase inhibitors Rivastigmine and donepezil have been theoretically implicated in correcting the cholinergic imbalance seen in delirium. However, they have not shown evidence to be beneficial in delirium. There have not been any studies done specifically on cancer. Hence, use of these is not recommended in cancer patients with delirium. There have been various studies looking at preventing delirium in acute care setting, specifically in the elderly. Various pharmacological agents such as APs, melatonin, dexmedetomidine, rivastigmine, and donepezil have been tried, but the evidence is sparse and requires more robust clinical trials. Terminal delirium[31] The role of sedation in terminal delirium is debatable. However, in some cases, palliative sedation may be required. Physicians should make this decision in discussion with the family, and there should be documented informed consent. First line: Midazolam and haloperidol as a combination –Titrate midazolam gradually to maximum dose of 20 mg/24 h, very rarely up to 25–30 mg/24 h evaluating the level of agitation. Low doses of haloperidol can be injected If midazolam is ineffective, IV infusion of propofol, phenobarbitone, or pentobarbitone can be used. Dose is gradually titrated up until desired symptom control is achieved. Nonpharmacological management The role of nonpharmacological interventions is limited and is used as a supportive intervention to the primary medical management. The key aspects of identifying the contributing and comorbid conditions and treating them are primary. Nonpharmacological and supportive therapies do not have direct effect on mortality or QoL. Nonpharmacological interventions can help in a faster recovery in delirium.[32] Nonpharmacological strategies including psychoeducational, cognitive retraining help reduce distress in caregivers. Although they directly are not effective in controlling delirium symptoms, they do not pose any harm or risk. Richeimer explains two levels of intervention – cognitive interventions and emotional interventions,[33] which the caregivers can be trained to do regularly. The cognitive interventions aim to restore cognitive functioning, while the emotional intervention aims to cope with overwhelming emotions. Tables 5 and 6 illustrate the application of the two psychological interventions in delirium and their components.Table 5: Cognitive interventions in deliriumTable 6: Emotional interventions in deliriumDelirium in patients of advanced stages of cancer can contribute to high distress levels for family members. One crucial component that must be emphasized within the multidisciplinary intervention is psychoeducation of family members/caregivers and improved their knowledge, emotional state, and response toward the delirious patient. Caregivers who are educated about delirium are seen to be more confident and able to make good decisions. CANCER-RELATED FATIGUE Introduction NCCN guidelines define cancer-related fatigue (CRF) as a “persistent, distressing, subjective feeling of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment” and when severe does not improve with rest (Fatigue, 2018). CRF is also disproportionate to the activity levels and interferes with routine activities. CRF is seen in 40%–100% of people with cancer.[34] CRF can be associated at any stage of illness (at diagnosis, during treatment, or end-of-life care) and can even persist for prolonged durations sometimes years posttreatment. CRF impacts the QoL, and its effect is pervasive and profound. This reduces the capacity to work and to participate in activities (social/leisure) and may interfere with sustaining relationships that are meaningful.[34] The mechanism of CRF remains elusive to date; however, the implication of cytokines, interleukin, tryptophan degradation, and other physiological and biochemical mechanisms has a role to play.[35] Assessment The most important thing to understand in CRF is that it is a subjective experience, usually underdiagnosed and undertreated.[36] Hence, we stress the need for screening and evaluation of CRF and re-evaluation at regular intervals to understand its burden on QoL and cancer care. MD Anderson symptom Inventory can be used to score the severity of CRF.[37] Similarly, other scales that can be used are 10-point numeric rating scale for fatigue[38] and brief fatigue inventory.[39] The first and foremost step is to take a detailed history and focus on the symptom of fatigue and its associated symptoms. A comprehensive and focused diagnostic assessment should be done aiming at identifying contributing and comorbid conditions.[35] In the evaluation of fatigue, a history should assess the onset, course, duration, exacerbating and alleviating factors. Along-side that, the assessment should also include looking for emotional distress, weight gain/loss, nutritional status, sleep, activity levels, ongoing medications, substance use and comorbid conditions. A detailed physical examination focuses on signs of anemia, dehydration, edema, jaundice, and any other physical abnormalities. The brief investigation panel should include complete blood count, serum electrolytes, thyroid panel, blood and urine culture to rule out any active infections and gonadal hormones when necessary. A list of treatable causes and contributing causes of CRF is given in Table 7.Table 7: Enlisting the treatable causes and contributing factors for cancer-related fatigue[40]Management After screening and assessment of CRF, any treatable causes have to be addressed, and periodically, the CRF should be re-evaluated to note for any improvements. There has been improvement noted in cases where anemia, electrolyte imbalance, or other treatable causes have been addressed. In cases where there are no identifiable treatable causes, one should evaluate the severity of CRF and stage of disease, and for mild and mild–moderate cases, nonpharmacological management is recommended; for moderate-to-severe and severe cases of CRF, a combination of pharmacological and nonpharmacological management is recommended. Pharmacological management We should be aware that there are not enough clinical trials or consensuses on the applicability of pharmacological management of CRF. Clinicians and researchers have tried to look at the utility of psychostimulants, antidepressants, corticosteroids, and nutraceutical agents in the treatment of CRF. Here, we describe a summary of the existing guidelines. Psychostimulants The class of psychostimulants includes amphetamines such as methylphenidate, dexamphetamine, and modafinil. Methylphenidate has shown to have some efficacy over placebo in clinical trials. Methylphenidate can be used in cases where there is no other identifiable cause for fatigue. It can be used in treatment, posttreatment, and end-of-life care.[4041] Dexamphetamine in clinical trials so far has not shown any positive results. Modafinil, a nonamphetamine psychostimulant, has shown positive results in those with severe fatigue but not in those with mild-to-moderate levels of fatigue.[42] Modafinil has also shown benefits in patients with advanced disease in small trials but has not been replicated in larger trials. Antidepressants No antidepressant has been approved or shown to have high efficacy in targeting CRF. Corticosteroids Methylprednisolone and its derivative dexamethasone are noted to improve CRF in people with terminal or advanced illness and receiving end-of-life care. One study also reported improvement in fatigue, general condition, and absence/control of fluid retention.[43] A progestational agent, megestrol acetate has shown efficacy in cancer cachexia but not in cancer fatigue.[44] Physicians must give due consideration to the adverse effects and toxicity of long-term use of steroids and should restrict its use in terminally ill patients with cachexia and also in those with brain and bone metastasis with pain. Benzodiazepines Eszopiclone is a sedative-hypnotic which has been tried and has not shown improvement in fatigue scores.[45] Nutraceuticals L-carnitine supplementation at dosages of 1 g b.i.d. reduced fatigue symptoms.[46] Coenzyme Q10, Wisconsin Ginseng, Astragalus, Guarana, and mistletoe have also been under experimentation and need more evidence toward its efficacy and benefits in treating CRF. Research is currently focused on the utility of modafinil, buspirone, American ginseng, L-carnitine, and coenzyme Q10 in CRF.[34] Nonpharmacological management Psychoeducation to the patients about CRF giving adequate information, symptoms, and what to expect can help them understand the condition and reduce uncertainty and anxiety associated.[47] A review looked at nonpharmacological treatment for CRF showed benefits with CBT, physical exercise, massage therapy, hypnosis, acupuncture, muscle relaxation, and psychoeducation for fatigue.[3448] Interventions such as behavioral activation/activity scheduling that leads to gradual increase in physical activity are beneficial to their QoL. The interventions can be done at individual or group levels. SLEEP DISORDER