People living with human immunodeficiency virus (HIV) infection suffer high rates of mental illness. Epidemiological studies indicate that the prevalence of mental illness in this population may be as high as 47.9%. Common diagnoses are depressive disorders, anxiety disorders and substance-related disorders. Rates of mental disorder are also reported to be high in resource-limited settings. Why do people living with HIV suffer such high rates of mental illness? Firstly, there is an association between sexual risk-taking behaviours linked to HIV transmission, and mental illness. Secondly, HIV infection impacts on a person’s life and functioning, both directly through neurological injury producing cognitive and behavioural changes and indirectly though the impact of chronic illness on psychological function. Living with a mental disorder has a signiﬁcant impact on a person’s sense of wellbeing and quality of life which may be worsened by the multiple burdens and stigma of living with a mental illness associated with HIV infection. Untreated mental illness can affect people’s ability to care for themselves and others, maintain accommodation and employment and to comply with HIV treatment.
People with pre-existing mental illnesses are at a higher risk of contracting HIV infection. The type of predisposing mental disorders can range from cognitive disorders (intellectual disability, dementia and acquired brain injury) to mood disorders (depression and mania), psychotic disorders (especially schizophrenia) and personality disorder (particularly borderline and antisocial personality disorder). In younger people, severe mental illness may be associated with an increased frequency of sexual risk behaviours (higher partner numbers, lower condom use), higher rates of substance use, and an association with social networks that have a higher risk of HIV infection. It is thought that adequately identifying and treating mental illness in young people is likely to reduce HIV acquisition risk behaviours.
In people living with HIV infection, different types of mental disorders occur with various stages of the infection. There are signiﬁcant illness milestones that can occur, related to phases of disease progression such as: the time of initial diagnosis; commencement of antiretroviral therapy (ART); onset of symptomatic illness; ART failure and the need for antiretroviral salvage therapy. The later stages of illness may be associated with the increasing loss of physical functioning combined with the cognitive manifestations of HIV infection. These illness milestones may be associated with periods of stress or normal psychological adjustment. However, if severe they can manifest with psychological symptoms such as anxiety or mood symptoms that may be better described as an adjustment disorder or if more severe, a major depressive disorder or an anxiety disorder. People with a prior history of mental illness and substance abuse, and those with low social support, are more at risk of suffering from major adjustment difficulties, and more likely to come to the attention of clinicians during these periods of change.
In the Australian context, the majority of people currently living with HIV are men who contracted the infection through sexual contact with other men. A large percentage of men who have sex with men present unique psychological issues that come from living in a society that is often hostile to gender non-conformity, resulting in personal stigma and shame. While societal attitudes to homosexuality have evolved, the developmental impact of this sense of difference, coupled not infrequently with a history of discrimination and abuse can manifest in adulthood with higher rates of mental illness and substance abuse than in the community in general. Among heterosexuals in Australia diagnosed with HIV infection, migrants, especially those from high-prevalence regions are signiﬁcantly over-represented. This group also presents unique challenges and often has suffered difficult developmental and migration histories, coupled with the challenges of adapting to a new culture and lifestyle. These individuals are thus at high risk of developing mental disorder which can manifest in differing ways due to the effects of cultural differences. Equally, a diagnosis of HIV infection is often highly stigmatised in these communities, resulting in secrecy and social isolation for those with the infection. There is a need for culturally sensitive and appropriate practice in order to better engage, educate and treat patients from migrant communities who present with mental illness and HIV infection.
The later stages of HIV infection are commonly associated with the neurocognitive complications of HIV infection and less commonly with severe episodes of psychiatric illness such as manic episodes, psychotic illness and episodes of delirium. These later episodes, though less common, are important to identify and treat early to prevent risks to the patient and potentially others. Antiretroviral medications have also been associated with reported neuropsychiatric symptoms in patients. These can range from mood disturbance to anxiety, sleep disturbance and confusion. The non-nucleoside reverse transcriptase inhibitor (NNRTI), efavirenz, is the antiretroviral agent most frequently associated with neuropsychiatric symptoms including sleep disturbance, vivid dreams, anxiety, agitation, abnormal thinking and, less commonly, frank manic or psychotic symptoms.
The broad principles of management in this population include a focus on engagement of the person with HIV infection and identiﬁcation and containment of immediate risks. These may be immediate risks to the person (e.g. self harm and suicidal behaviours), or less directly via self-neglect or disturbed behaviour, and also risks to others through direct violence, neglect (e.g. of children) or problem behaviours (e.g. through unsafe sexual practices). All states and territories of Australia have mental health legislation that allows for involuntary treatment of people if there are immediate safety concerns and the person is unable or unwilling to consent to treatment. It is important to have some knowledge of the legal structures involved. Treatment of mental illness involves a multifaceted bio-psycho-social approach and often requires the resources of a multidisciplinary team (e.g. psychiatrist, mental health trained nurse, psychologist, social worker and occupational therapist) to adequately assess and deliver treatment. Access to such resources are obviously more difficult in rural and remote regions where many of these functions may be provided by a sole clinician such as a general practitioner or nurse practitioner.
People living with HIV suffer high rates of major depression. A meta-analysis found rates of major depression in HIV-positive people to be twice that of matched HIV-negative controls. Rates may increase with disease progression and symptomatic illness. Certain risk factors are associated with an increased risk of depression: a personal or family history of mood disorders, substance use, anxiety disorders, suicidal episodes, being female, low social support, and current medical illness. Suicidal thoughts and acts are a common reason for psychiatric referral and can occur at times of crisis such as at the time of HIV diagnosis and in the late stages of illness. Depression may adversely affect the outcome of treating HIV infection. There is evidence to support an association between depression and self-neglect, with implications for treatment adherence.
It can be difficult to identify depression in patients with severe medical illness. Depressive symptoms may represent a normal reaction to physical illness, a manifestation of the underlying physical illness (e.g. symptoms of fatigue and anorexia) or a component of a depressive syndrome. As such, depression can be easily missed. Untreated depression in patients is associated with a worse prognosis. Cognitive-affective symptoms (as opposed to somatic symptoms) may be more discriminating in identifying depression in this population. Examples of these symptoms would be: a sense of failure, a sense of being punished, indecisiveness, reduced social interest, suicidal ideation, frequent crying and dissatisfaction. In patients with HIV infection it is always important to consider an organic basis to the depression, especially when there is no personal or family history of a mood disorder, there are no obvious precipitants, when the presentation is atypical, when cognitive symptoms appear severe, if the patient is severely immunocompromised or when the patient had failed to respond to treatment. Assessment needs to include a thorough physical examination and medical workup to exclude organic pathology (Table 1).
|Psychosocial history||Living environment, employment, ﬁnances, relationships|
|Level of functioning||Activities of daily living Presenting symptoms and relationships to psychosocial factors|
|HIV status||Duration of illness, recent CD4 cell count, viral load, CD4 cell nadir (Indicates likelihood of CNS involvement, and indicates stage of illness) HIV complications and opportunistic infections Current antiretroviral treatment, recent changes and compliance|
|Medical and psychiatric history||Other active medical problems and medications Personal and family past psychiatric history Comprehensive drug and alcohol use assessment|
|Examination||Mental state assessment with focus on cognition and risk assessment Physical examination as indicated to identify and exclude organic illness|
|Investigations||HIV status (CD4 cell count, HIV viral load if not recently determined) CNS investigation if CD4 cell count < 200 cells/μL and clinically indicated, e.g. CSF (viral load and cryptococcal antigen) and neuroimaging Metabolic screen (renal and liver function), vitamin B12/folate, blood glucose Full blood examination, inflammatory markers. Endocrine (thyroid function tests, consider pituitary function, testosterone) Urine drug screen Review past serology (including syphilis)|
|CNS = central nervous system; CSF = cerebrospinal ﬂuid.|
The appropriate treatment approach in the patient with HIV infection with depression depends on the type and severity of the depression (Table 2). Once organic illness is excluded or reversed, for mild depression, treatment with short-term psychotherapy alone is usually appropriate and there is evidence to suggest efficacy. This treatment could be supportive, cognitive behavioural or interpersonal psychotherapy and needs to be provided by trained clinicians. For moderate-to-severe depression, antidepressant medications are recommended, often in combination with psychological therapies. The choice of antidepressant depends on the patient’s symptom proﬁle and history of prior response. Though there is evidence for good effect with tricyclic antidepressants, given their side-effect proﬁle and risk in overdose, current ﬁrst-line therapy would be a selective serotonin reuptake inhibitor (SSRI) antidepressant. It is better to choose an agent with less drug-drug interactions such as citalopram, escitalopram or sertraline. Second-line agents include mirtazapine, which aids insomnia and poor appetite, or venlafaxine. For more severe depression associated with melancholic or psychotic symptoms it is advisable to seek advice from a trained psychiatrist as treatment may require the use of augmentation with antipsychotic drugs or mood stabilisers, and, rarely, electroconvulsive therapy.
Anxiety symptoms are common in patients with HIV infection, and are likely to be more prominent at times of signiﬁcant life stresses and at stages of disease progression. Anxiety disorders where anxiety is severe and persistent are also common: surveys have estimated the prevalence of generalised anxiety disorder to be up to 15% of patients and the prevalence of panic disorder to be 10% of patients. Agoraphobia and social phobia are also common and high rates of post traumatic stress disorder and acute stress disorder have been described. The presentation of these disorders is often clouded by comorbid mood disorder, substance use and personality disorders making diagnosis more complicated. Effective treatment requires a comprehensive assessment of the presenting symptoms, life stresses and coping style.
Treatment approaches include brief psychological interventions and medication. Psychological approaches that may be helpful include behavioural techniques such as progressive muscular relaxation, breathing exercises and systematic desensitisation. These may be incorporated within a cognitive behavioural therapy approach and medications are often used concurrently. Benzodiazepines may be helpful for short-term symptom relief, and are usually best used with antidepressant agents and tapered as symptoms improve. Shorter-acting agents with fewer metabolites are preferred such as oxazepam, lorazepam and temazepam, with consideration given to risks such as abuse and dependence. Antidepressants are effective for the longer-term treatment of anxiety, with SSRIs being the first-line choice, again choosing agents that have less hepatic cytochrome p450 interactions. Mirtazapine and venlafaxine can also be effective.
Manic episodes are more common in people with HIV infection than in the general population. An episode of mania is often associated with poor impulse control, impaired judgment and greater risk-taking behaviours, increasing the chance of contracting or spreading HIV infection.
A manic episode may be primary (related to a bipolar disorder) or secondary to a range of other causes. Possible secondary causes are substance-induced mania related to either illicit or prescription medications including antiretroviral agents, mania due to a medical condition such as central nervous system opportunistic infection, a manifestation of a hyperactive delirium, or related to primary HIV infection.
Important clinical features to consider on history taking include a past or family history of a mood disorder, current HIV clinical parameters and stage, current medications and recent changes, substance abuse history and a cognitive assessment. Speciﬁc enquiry regarding increased libido or sexual activity should also be made as previously insightful patients may lose their usual judgment, e.g. occasionally develop delusions and believe their HIV is cured. A comprehensive medical examination is required and investigations such as neuroimaging and cerebrospinal ﬂuid analysis undertaken to elucidate central nervous system involvement with HIV.
Manic episodes related to HIV infection tend to be a late manifestation of illness associated with a low CD4 T-lymphocyte (CD4) cell count, high HIV viral load and evidence of structural brain damage demonstrable on magnetic resonance image (MRI) or computed tomography (CT) scans. These episodes classically have been associated with cognitive impairment and a poor clinical prognosis, as they have been linked to the development of an HIV-associated dementia. Clinically, patients may present with more irritability, talkativeness and cognitive slowing and impairment than those with primary bipolar illness. Treatment must be provided in a safe and secure environment. This recommendation may mean hospitalisation and involuntary treatment.
Evidence suggests the most effective treatment for HIV-associated mania is ART that penetrates the central nervous system. Symptoms may also be controlled with psychotropic medications including mood stabilisers, antipsychotic and anxiolytic drugs. All mood stabilisers have the potential for side effects and drug interactions. Lithium is reported to be effective but has higher rates of neurotoxicity in this population. Sodium valproate is frequently used but care must be taken to monitor for liver toxicity and the theoretical risk of elevation of HIV viral load. Mood stabilisers are often combined with antipsychotic drugs to treat acute episodes. Current practice suggests that olanzapine, risperidone and quetiapine can be effective in this population though there is an increased rate of extrapyramidal side effects. Benzodiazepines are also used for short-term sedation.
Acute changes in cognition – delirium
Sudden changes in cognitive function raise the possibility of a diagnosis of delirium. The cardinal signs of delirium are ﬂuctuating conscious state, impaired concentration and disorientation in time or place. As the course of illness is variable there may be periods of lucidity. There may also be associated psychotic symptoms (hallucinations in any sensory modality or delusional ideas) that can be distinguished from other forms of psychotic illness on a temporal basis. Delirium is more likely to occur in the later stages of HIV infection but is not exclusively limited to this period. It is also common in hospitalised patients with rates of up to 22% described in inpatients with HIV infection. A thorough medical assessment including corroborative history of substance abuse or withdrawal may help to clarify the aetiology.
The assessment of delirium includes documentation of cognitive changes both for diagnosis and monitoring progress (Table3). Physical examination and investigation should be targeted towards likely causes. 
|Physical examination||Vital signs Focal neurological signs Signs of focal infection Tremor, asterixis Ophthalmological examination Evidence of head trauma|
|Initial screen||FBE, ESR, CRP, liver function, renal function, thyroid function, blood sugar Urine/serum drug screen: illicit drugs Medication level monitoring: lithium, anticonvulsants Urinalysis Chest X-ray|
|Investigation of HIV- associated conditions||Serology: toxoplasma, Cryptococcus, cytomegalovirus, herpes simplex virus, syphilis|
|Further investigation||Nutritional deﬁciency: B12, folate Pulse oximetry and blood gas analysis if hypoxic Sputum culture Blood culture Lumbar puncture: CSF analysis for HIV and opportunistic infections Cerebral imaging: CT, MRI EEG|
|FBE = full blood examination; ESR = erythrocyte sedimentation rate; CT = computer tomography; MRI = magnetic resonance imaging; EEG = Electroencephalography; CSF = cerebrospinal ﬂuid.|
Treatment will be directed by the ﬁndings on investigation, but it is not uncommon to fail to discover a speciﬁc cause. General management includes environmental measures to increase the familiarity of the person’s environment such as adequate lighting, orientation cues and limiting the number of staff involved in patient interaction. Medication can be used to decrease agitation and maintain a regular sleep cycle. It is common practice to use antipsychotic medication in these circumstances initially at low doses and titrated accordingly. Occasionally parenteral medication may be required and it should be used judiciously. Benzodiazepine medication is indicated in delirium secondary to alcohol withdrawal but should be used cautiously in other circumstances. Benzodiazepines can cause signiﬁcant interactions with antiretroviral medications and they have been associated with increased confusion, excessive sedation and ataxia.
Chronic cognitive disorders in HIV
Cognitive difficulties are often associated with chronic HIV infection. HIV enters the central nervous system early in the course of acute infection, infecting predominantly microglia and perivascular macrophages. Over time progressive neuronal dysfunction and apoptosis occurs, producing evident deficits especially in the subcortical regions and frontostriatal pathways. The exact mechanism of this damage is not fully understood but it may occur either due to the direct effect of viral replication and release of viral proteins by infected macrophages and microglia, or possibly secondary to inﬂammatory mediators released by activated macrophages and microglia over time.
Clinical assessment of cognitive impairment in people with HIV infection should consider the range of common comorbidities that can affect cognitive performance, in addition to the direct effects of chronic HIV infection. Common physical comorbidities that require consideration include ageing, previous acquired brain injuries, cardiovascular disease, diabetes, co-infection with hepatitis C and sleep disorders. Consideration should also be given to psychiatric factors such as substance abuse and mental illnesses including high prevalence disorders such as depression, and low prevalence disorders such as schizophrenia. A history of previous HIV-related CNS disorders (HIV-associated neurocognitive disorder [HAND] and CNS opportunistic infections) before commencing combination antiretroviral therapy (cART) also increases the likelihood of HAND being present on assessment. 
The cognitive domains most typically involved in HAND are working memory, speed of information processing, attention and active retrieval. People with mild impairments may report some difficulties performing complex cognitive tasks in everyday life. In more moderate to severe cognitive impairment, clinically evident slowness and apathy may be present. In advanced cognitive impairment, people may exhibit disinhibited behaviour, apathy, slowness and grossly disturbed motor functioning.
cART has had a significant impact on reducing the mortality and the morbidity associated with both HIV infection and HAND. In spite of this effect, HIV infection continues to be associated with varying degrees of cognitive impairment. The Frascati criteria are the current standard for describing the categories of impairment as based on a clinical assessment. These criteria divide impairment into three levels of severity based on a neuropsychological assessment:
- HIV-associated neurocognitive impairment (ANI)
- HIV-associated mild neurocognitive disorder (MND)
- HIV-associated dementia (HAD).
All three categories require impairments in cognitive function across two domains, with performance at least 1 standard deviation below the mean compared to a normal population sample. They differ on their level of impact on daily function with no impact in those with ANI, mild interference in function in those with MND and a marked impairment in daily functioning in people with HAD (see section on neurological disorders).
With the widespread adoption of cART for HIV infection in developed countries, there has been a shift in the presentation of HAND. There has been a decline in the appearance of the more severe forms of impairments such as HAD, however more mild forms of HAND such as ANI and MND persist. The CHARTER study revealed that over half of cART-treated adults with HIV infection showed evidence of neuropsychological impairments. Most of these showed evidence of mild impairments consistent with ANI (33%) and MND (12%). Only 2% had severe impairments consistent with HAD.
Treatment considerations should be sensitive to the patient’s care requirements and available community supports. Consideration of competence to make medical and lifestyle decisions and discussion of an appropriate proxy should be part of an overall treatment plan. It is thought that ART which better penetrates the central nervous system (NeurocART) may improve some of the cognitive deﬁcits associated with this pathology. However, these improvements may only be modest and some patients remain severely impaired despite instigation of treatment.
Substance abuse disorders
Substance abuse is a signiﬁcant risk factor for the acquisition of HIV infection by direct means, such as sharing of injecting equipment, and indirect means such as risk behaviour associated with impaired judgment while intoxicated. Substance abuse is especially prevalent in people with HIV infection with reported rates ranging from 50-75%. It is important to note that there is a common comorbidity between substance abuse disorders and other psychiatric diagnoses and patients will beneﬁt from a coordinated assessment approach. The general approach is to: take a comprehensive history of substance use in an empathic and accepting manner; provide education about harm reduction strategies associated with drug use; and make an assessment of a person’s commitment to changing behaviour. A commitment to changing behaviour has been classiﬁed according to a Stages of Change Model that includes stages of pre-contemplation, contemplation, preparation, action and maintenance. There are speciﬁc psychological therapies that have been shown to be effective in helping people make and maintain changes in behaviour. Psychosocial interventions aimed at stabilising a person’s living circumstances can assist and have beneﬁcial effects on maintaining health. There are pharmacological strategies that have been shown to be beneﬁcial particularly when combined with psychological interventions. Initiating some of these pharmacological therapies may require specialist assessment. A person considering abruptly ceasing use, especially of alcohol, should consider a speciﬁc detoxiﬁcation program to prevent the potential complications of withdrawal.
There is a complex association between the diagnosis of HIV infection and psychotic disorders, each potentially adversely affecting the other. The nature of a psychotic illness is such that it may signiﬁcantly impair a patient’s capacity to participate in treatment. The diagnosis of a chronic psychosis is complex with symptoms divided into disorders of thought, perception, cognition and volition. Deﬁcits in reasoning, impulsivity and impaired capacity to process complex information are often associated with the primary symptoms of psychosis. There is frequently deterioration in psychosocial function that further complicates the provision of effective HIV care. Chronic psychotic symptoms are associated with a diagnosis of schizophrenia and schizo-affective disorder but may also be associated with dementia. Episodic psychotic symptoms may be associated with acute episodes of depression and mania in bipolar affective disorder. The abrupt onset of psychotic symptoms may be secondary to the acute effects of substance use or may be part of a syndrome of delirium.
Any treatment plan for HIV patients with psychotic illness should involve a risk assessment and consideration of the appropriate treatment environment. This is facilitated by a close working relationship between HIV and psychiatric services. Support to encourage compliance with oral medications will have beneﬁts both for psychiatric symptom relief and adherence to ART. Most antipsychotic medications can be safely combined with ART but the potential for interactions should be considered. Due to the effects of HIV infection on the central nervous system, patients may be more susceptible to extrapyramidal side effects and monitoring should be undertaken. For this reason, the atypical antipsychotic medications are usually preferred. However some atypical antipsychotic medications (e.g. olanzapine, quetiapine) have been associated with hyperlipidaemia and abnormalities of blood sugar metabolism, so periodic investigation is warranted in this already susceptible population.
Principles of pharmacotherapy for mental illness
Clinicians require a good understanding of the role of psycho-active medications in the treatment of mental illness and also the high risk of potential drug-drug interactions and side effects in the population with HIV infection. Certain antiretroviral drugs, in particular protease inhibitors and NNRTIs, are metabolised primarily by the cytochrome P450 3A4 and 2D6 hepatic microsomal isoenzymes, which can in turn inhibit or enhance their activity. Most psychotropic medications are also metabolised by, and can affect the activity of, these isoenzymes. Patients may also have serum protein anomalies resulting in an altered free fraction of protein-bound drugs. There is, thus, a high potential for drug interactions when psychotropic agents are used in the setting of cART making it important to use care and consult up-to-date drug information or an informed pharmacist before prescribing. Commonly used agents in this population include antidepressant medications such as SSRIs that are used to treat depression and anxiety disorders. These agents directly affect the CYP 450 enzymes and, thus, SSRIs that have less interaction with these enzymes (e.g. citalopram, escitalopram and sertraline) are preferred for use. Benzodiazepines are commonly prescribed for short-term use in anxiety disorders. However their half lives can be signiﬁcantly prolonged by treatments: thus agents with shorter half lives (e.g. oxazepam, temazepam and lorazepam) are preferred. Similarly mood stabilisers and antipsychotics can interact with certain antiretroviral drugs and care is required when prescribing.