Hydroxychloroquine (HCQ) is a disease-modifying anti-rheumatic drug (DMARD) widely prescribed for the long-term management of autoimmune conditions like Systemic Lupus Erythematosus and Rheumatoid Arthritis. HCQ modulates the immune system to reduce inflammation and prevent tissue damage. It works by accumulating in cellular compartments called lysosomes, increasing the pH level, and interfering with antigen processing by immune cells. This action dampens the overactive immune response by reducing pro-inflammatory signaling molecules, which drive the disease process.
The Direct Connection: Hydroxychloroquine and Anxiety
Anxiety is a documented adverse effect associated with hydroxychloroquine, though it is considered a relatively uncommon side effect. Psychiatric reactions are listed in the prescribing information, indicating a potential impact on mental health. These adverse events cover a spectrum of symptoms, including depression, sleep disturbances, and generalized anxiety.
Case studies and systematic reviews confirm the occurrence of anxiety, which can manifest as nervousness, persistent worry, or, in rare instances, panic attacks or agitation. Healthcare providers are advised to be vigilant for these psychiatric changes, especially during the initial phase of treatment. Drug-related anxiety symptoms frequently occur within the first month of starting the medication or following a dosage increase.
How Hydroxychloroquine Affects the Central Nervous System
Hydroxychloroquine’s ability to affect mood stems from its capacity to interact with the central nervous system. As a lipophilic molecule, HCQ can cross the blood-brain barrier. Once inside the brain, the drug accumulates in tissue, sometimes reaching concentrations significantly higher than those found in the bloodstream due to its long half-life.
A primary mechanism involves the drug’s interaction with neurotransmitter systems that regulate mood and stress. Studies suggest that HCQ can influence the activity of brain-resident immune cells called microglia and alter the expression of molecules involved in the stress response. For instance, HCQ has been shown to decrease the expression of corticotropin-releasing hormone (CRH), a peptide central to the body’s reaction to stress.
Furthermore, HCQ may impact the expression of brain-derived neurotrophic factor (BDNF), a protein that supports the survival and growth of neurons. Low BDNF levels are implicated in anxiety and depression. The drug may also interfere with the serotonin transporter, potentially causing dysregulation of this major mood-regulating pathway. These molecular changes provide a biological explanation for the observed anxiety reactions.
Distinguishing Drug Side Effects from Underlying Disease Symptoms
One of the greatest challenges in assessing anxiety in patients taking HCQ is that anxiety is already a highly prevalent symptom of the underlying autoimmune diseases themselves. Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis experience chronic inflammation, pain, and life stress, which significantly increase the risk of developing anxiety disorder.
Anxiety directly related to the autoimmune disease often correlates with disease activity, meaning symptoms worsen during a flare-up of pain or systemic inflammation. This is commonly seen in neuropsychiatric lupus. In contrast, anxiety that is a direct side effect of hydroxychloroquine tends to manifest soon after the drug is initiated or the dose is adjusted, often without a corresponding increase in joint pain or other systemic disease markers.
The timing of symptom onset is therefore a crucial factor for differentiation. If anxiety is a new experience that appears within weeks of starting the medication, it is more likely to be drug-induced. If the anxiety has been a long-standing issue that fluctuates with pain levels and overall disease activity, it is more likely a manifestation of the underlying rheumatic condition. Accurate distinction requires a careful medical evaluation to determine the cause.
Monitoring and Communicating Psychiatric Changes
Patients experiencing new or worsening mental health symptoms while taking hydroxychloroquine should communicate these changes to their healthcare team immediately. It is important to document specific symptoms, such as new onset of panic, persistent restlessness, changes in sleep patterns, or irrational thoughts. Noting the exact date symptoms began and whether they correlate with the start of the medication or a dosage change provides invaluable information to the prescribing physician.
New or unusual feelings of confusion, agitation, or severe depression, including thoughts of self-harm, require urgent medical consultation. Patients should never abruptly discontinue the medication, as stopping treatment suddenly can lead to a flare-up of the underlying autoimmune disease. Adjustments to the treatment plan, including dosage modification or switching medications, should only be made under the guidance of a physician.