Conrad M. Swartz, MD, PhD

Dr. Swartz is Affiliate Faculty, Oregon Health & Science University, Portland; Emeritus Faculty, Southern Illinois University School of Medicine, Springfield, Illinois; and Medical Director, Lutheran Community Services Northwest, Vancouver, Washington.

Visual Hallucinations Linked to Timolol Eye Drops

The visual hallucinations from timolol eye drops reported in your January cover story apparently resulted from local effects on retinal circulation rather than systemic effects.

 The hallucinations described were of geometric shapes. This resembles phosphenes, an ordinary response to disruption of retinal circulation, as from closing eyelids tightly for 5-10 seconds or from orthostasis. Phosphenes can also result from diseases affecting the retina (eg, MS).

For mechanism, the Psychiatric Times piece hypothesized only similar systemic effects of eye drops and a 10-mg oral dose. A drop of timolol 0.5% in each eye contains just one twentieth of 10 mg, so its systemic effects cannot be compared. Moreover, timolol is hydrophilic, so after systemic absorption, it does not normally enter the brain.

In treating anxiety disorders over 25 years I have given CNS-active beta-blockers to over 2000 patients with clinical benefit. For elderly patients I prefer pindolol, in younger adults betaxolol.

 None of the patients reported visual hallucinations or showed (or mentioned) cognitive impairment. Beta-blockers are well tolerated and safer than antipsychotics in anxiety disorders. The report about timolol should not be understood as stating that timolol causes psychosis. Moreover, changes in color vision are distortions, and your article should not have called them hallucinations.

This article was originally published on February 1, 2018 and has since been updated.

Visual hallucinations linked to timolol eye drops

3. Swartz CM. Sympathy for the sympathetic (nervous system). In series "Clinical Controversies." 

Articles

Timolol Does Not Cause Psychosis

How is it that anti-anxiety drugs can cause anxiety and insomnia, sometimes within the first day or two of treatment? This effect is repeatedly noted in the 

 for most selective serotonin reuptake inhibitors such as fluoxetine (Prozac) and sertraline (Zoloft). Anxiety reactions occurred in 14% of patients given fluoxetine for obsessive-compulsive disorder versus 7% on placebo (PDR, 2003a). Similarly, insomnia occurred in 33% of patients with bulimia treated with fluoxetine versus 13% on placebo (PDR, 2003a). Fluoxetine and sertraline induced tremor in about 10% to 11% of patients with major depression compared to 3% for placebo (PDR, 2003a, 2003b); these are not the soothing qualities we expect for anti-anxiety medications.

A simple explanation is that there are two (or more) separate types of anxiety, and a drug can affect them differently. Specifically, SSRIs reliably decrease psychological anxiety but not somatic anxiety. Somatic anxiety is primarily a tension phenomenon, with restlessness, agitation, impatience, hyperreactivity and irritability. It is largely but not entirely observable. Tension is associated with high epinephrine or norepinephrine activity and activation of the sympathetic nervous system. Drug-induced akathisia is usually described as a tension phenomenon.

In contrast, psychological anxiety is largely comprised of worry, repetitive thoughts and dissatisfaction. Because it is subjective, understanding its presence and severity requires description by the patient. Psychological anxiety is apparently related to low serotonergic activity. The separation between somatic anxiety and psychological anxiety has been observed in symptom cluster analysis (Watson et al., 1995) and suggested by pharmaceutical response (Fogari et al., 1992). This separation implies that the evaluation of anxiety involves specific assessments of somatic anxiety and psychological anxiety. Because pain, dizziness and disassociation can respond to hypnosis therapy, they might be considered additional types of anxiety.

Different types of anxiety can provoke each other in a circular loop, but this does not make them inseparable. Although pain causes anxiety, when pain remits, anxiety can persist if an anxiety disorder has developed. Similarly, worry can induce somatic anxiety, but restless tension can persist after worry has faded. Tension can begin with worry, yet it can eventually be autonomous from worry. This concept resembles phantom pain that persists after the physical cause of the pain is removed.

Somatic anxiety is sometimes mislabeled as psychological disinhibition. Inappropriate conduct that appears when irritability or hyperreactivity overcome self-control does not illustrate psychological disinhibition. Analogously, pain can cause patients to scream; this is bodily discomfort, not psychological disinhibition. The discomfort is the same, with or without the scream. Tension is also a bodily discomfort. Another inconsistency between tension and disinhibition is shown by the effect of benzodiazepines--they diminish tension but actually increase disinhibition.

The DSM formulation of anxiety disorders contains the belief that the mind controls bodily tension. This is done by combining tension and psychological anxiety together in the diagnostic criteria. Surely psychotherapy can relieve psychological anxiety. The problem is that after successful psychotherapy relieves the psychological anxiety, the patient may no longer meet anxiety disorder diagnostic criteria but might still suffer from somatic anxiety. This inconsistency is resolved only by believing that psychotherapy also reliably treats somatic anxiety.

However, besides muscle movement, body control by the mind is indirect, incomplete, highly variable and largely speculative. It is not right to base our professional diagnosis and treatment on the assumption that psychotherapy can control bodily function. The alternative to this belief is once tension has become persistent and intrusive, it no longer depends on worry in order to continue. Worry provokes bodily tension, and it also predisposes to infections, injuries and substance abuse. The bodily consequences of these problems are not reasonably curable by psychotherapy alone, but require medical treatment of the body.

Psychiatrists might be able to occasionally decrease persistent tension or other somatic conditions with psychotherapy. Still, it is not appropriate for DSM to require the belief that psychotherapy (or pharmacotherapy) reliably relieves somatic anxiety as it diminishes psychological anxiety. The myth that psychological anxiety and somatic anxiety are the same condition probably pervades DSM because it is a widely accepted belief. This belief may predispose to violent consequences from not treating somatic anxiety in patients on SSRIs.

In 1991, several news reports mentioned individuals in whom suicidality became problematic after starting an SSRI (e.g., Masand and Dewan, 1991). However, that same year, an ad hoc U.S. Food and Drug Administration panel found no connection between SSRIs and suicide (Harris, 2003). Nevertheless, in 2003 the United Kingdom Committee on Safety of Medicines recommended that physicians avoid most SSRIs for treating major depression in patients under age 18 (Duff, 2003). Similarly, the U.K. Medicines and Healthcare products Regulatory Agency warned doctors against prescribing paroxetine (Paxil) for children (Vedantam, 2003). This year a "healthy" participant given duloxetine (Cymbalta) committed suicide four days after discontinuation and was the fifth suicide in premarket trials of duloxetine (Harris, 2004). Both sides of the suicide/violence issue are represented by a variety of publications.

Healy (2003) claimed an excess of suicides and suicide attempts in participants taking SSRIs compared to a placebo group. A National Institute of Mental Health-sponsored analysis found no significant difference between fluoxetine and placebo for suicide attempts and completions (Leon et al., 1999). However, violence should theoretically be less prevalent in the treatment group because it is a symptom of the illness that is being treated. The lack of a decline in suicidality with drug treatment implies that the therapeutic effect is incomplete, at least for a group whose symptoms include suicidality.

On one side of the debate are reports of suicide in patients given SSRIs (The Guardian, 2003). On the other side are reports about patient groups for whom average instances of violence and suicide are not increased with SSRIs (Leon et al., 1999). If SSRI-induced violence is genuine but rare, a study of patient group averages will not reflect it. Rather, it will be hidden by patients who respond to SSRIs.

To illustrate, suppose that 30% of patients show decreased irritability with treatment, 65% hardly change and 5% show increased irritability, while average irritability falls significantly. If the consequences of increased irritability are clinically unacceptable, the statistical significance is irrelevant. A more effective treatment might add a drug that reliably decreases irritability.

Rather than group averages of violence-related behaviors, the incidence of violent acts must be described. Indeed, the reported decrease in suicides since SSRIs were first introduced suggested that these drugs diminish more violence than they might provoke (Walsh and Dinan, 2001). On the other hand, violent methods of completed suicides in patients with detectable fluoxetine levels were about three times the incidence of violent suicides of patients with tricyclic antidepressant levels (65% versus 23%) (Frankenfield et al., 1994).

The fact that patients on SSRIs may commit more violent acts does not mean that the SSRIs caused them. A simpler explanation is that violence becomes worse by leaving somatic tension unrelieved. Tension does provoke violent acts such as suicide (Busch et al., 2003), and symptoms left untreated can make themselves worse. However, the sedative properties of some TCAs (e.g., amitriptyline [Elavil, Endep]) can actually decrease tension. That is, there may be more frequent violent suicides of patients on SSRIs such as fluoxetine than on TCAs, because TCAs may offer greater tension relief. Another explanation is that physicians are more reluctant to give TCAs to patients who appear suicidal because of the toxic overdose potential (Warshaw and Keller, 1996). Both explanations presumably contribute to the finding that more violent suicides may be seen with SSRIs than with TCAs.

Studies that do not reflect positively on SSRIs are unlikely to be published, and this undermines the proper understanding of these drugs. GlaxoSmithKline acknowledged that eight of its nine studies of paroxetine in children and adolescents were not published, and the FDA assessed the overall result to be that paroxetine was not effective for depression in patients under age 18 (Harris, 2003). This nonpublication is a deliberate bias in favor of SSRIs. It obstructs us from making an impartial assessment of positive and negative effects of SSRIs by considering collections of published results, including meta-analyses. The professional ethics of withholding publication are questionable. We are left to make only impressionistic judgments. We psychiatrists seem to be overly comfortable doing so, to such an extreme that DSM expects us to overlook evidence and apply subjective impressions instead (see 

On the opposite side, biases against SSRIs are notorious, specifically those propagated by antipsychiatry organizations. When we dismiss these groups for their wrongful predation of the mentally ill or for posing as a religion, it is easy to also dismiss the issues they raise. This is not logically correct.

It is clear that SSRIs induce somatic tension in the form of akathisia (Hamilton and Opler, 1992). From what I have seen, patients who already have observable tension have the most problematic SSRI-induced akathisia. Figuratively, adding the SSRI was salting an open wound. These patients ended up discontinuing the SSRI on their own within days. Patients who can tolerate an SSRI for months seem unlikely to have problematic akathisia from it. So, it is implausible to attribute substantial violence or suicidality to akathisia, because these patients will not tolerate the drug long enough to commit violence or suicide. Nevertheless, the possibility of SSRI-induced akathisia is an additional reason to monitor for and treat somatic anxiety symptoms. As with antipsychotic-induced akathisia, patients with akathisia from SSRIs should tolerate medication better when the akathisia is relieved.

Of note, patients who do not achieve remission on fluoxetine have substantially more somatic anxiety than patients who remit (Fava, 2003). This meshes with my experience that patients referred by primary care physicians after inadequate SSRI responses show prominent restlessness. That buspirone (BuSpar) does not decrease tension as benzodiazepines do probably explains why patients do not accept it (Rickels et al., 2000) or SSRIs as substitutes. Similarly, the sedative action of clomipramine (Anafranil) presumably explains its superiority over SSRIs for tension relief in OCD (e.g., Geller et al., 2003). In addition, tension mitigation surely underlies the mushrooming use of antipsychotics for nonpsychotic patients, and their recent concurrent use with SSRIs (Corya et al., 2003).

This discussion focuses on disorders that are treated by SSRIs: primarily anxiety disorders, atypical major depression and bipolar II disorder. Differences among them are unclear because they are subjective (see 

 December 2003, p75), and there is close overlap in symptoms, co-occurrence and treatment approaches (see PT April 2003, p30). All are dominated by hyperreactivity, assertive dissatisfaction and tension. Their psychological anxiety tends to decrease with SSRIs but their tension does not.

Suicidal behavior varies across these disorders. Attributing suicidality or violence to undertreated major depression is not supported by the literature. Undertreated tension is just as plausible a cause. Dishonor-related tension apparently underlies hara-kiri, stock market crash jumping and post office revenge. Adding SSRIs to the association between tension and violent behavior (i.e., suicide) produces an explanation for suicidal behavior in patients on SSRIs. The problem is resolved by adding treatment of somatic anxiety to treatment with SSRIs or buspirone.

Tension, as hyperarousal of the sympathetic nervous system, is diminished by calming drugs (see 

 March 2003, p48). The fine details are everyday topics in my clinical teaching of psychiatry residents. Calming drugs are generally ß-blockers, α-blockers, anticonvulsants, sedating TCAs, low-potency antipsychotics or benzodiazepines; thus, we need to know when other doctors give these medications to our patients. Drugs with consistent efficacy and only rare side effects have a smooth, gradual action without rebound, tolerance, rapid elimination (short half-life) or psychological impairment. This excludes benzodiazepines, some sympatholytics (e.g., propranolol [Inderal]) and more than minimal doses of antipsychotics (see 

In summary, suicidal and violent acts occur in patients with anxiety because somatic anxiety is undertreated. There is a mistaken impression that SSRIs or buspirone reliably treat somatic anxiety.

SSRIs treat anxiety but also induce anxiety--why does this happen?

Worry causes tension, so why doesn't relieving worry always relieve tension?

Is chronic hyperarousal a thought problem or a physical problem?

 Busch KA, Fawcett J, Jacobs DG (2003), Clinical correlates of inpatient suicide. J Clin Psychiatry 64(1):14-19 [see comments].
 

 Corya SA, Andersen SW, Detke HC et al. (2003), Long-term antidepressant efficacy and safety of olanzapine/fluoxetine combination: a 76-week open-label study. J Clin Psychiatry 64(11):1349-1356. 
 

 Duff G (2003), Selective serotonin reuptake inhibitors- Use in children and adolescents with major depressive disorder. Committee on Safety of Medicines, Medicines and Healthcare products Regulatory Agency. Available at:

medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/cemssri_101203.pdf

 Fava M (2003), The role of the serotonergic and noradrenergic neurotransmitter systems in the treatment of psychological and physical symptoms of depression. J Clin Psychiatry 64(suppl 13):26-29.
 

 Fogari R, Zoppi A, Corradi L et al. (1992), Comparison of bisoprolol and diazepam in the treatment of cardiac neurosis. Cardiovasc Drugs Ther 6(3):249-253.
 

 Frankenfield DL, Baker SP, Lange WR et al. (1994), Fluoxetine and violent death in Maryland. Forensic Sci Int 64(2-3):107-117.
 

 Geller DA, Biederman J, Stewart SE et al. (2003), Which SSRI? A meta-analysis of pharmacotherapy trials in pediatric obsessive-compulsive disorder. Am J Psychiatry 160(11):1919-1928.
 

 Hamilton MS, Opler LA (1992), Akathisia, suicid-ality, and fluoxetine. J Clin Psychiatry 53(11):401-406 [see comments].
 

 Harris G (2003), Debate resumes on the safety of depression's wonder drugs. New York Times. Aug. 7, A1.
 

 Harris G (2004), Student, 19, in trial of new antidepressant commits suicide. New York Times. Feb. 12, A22.
 

 Healy DI (2002), Conflicting interests in Toronto: anatomy of a controversy at the interface of academia and industry. Perspect Biol Med 45(2):250-263.
 

 Leon AC, Keller MB, Warshaw MG et al. (1999), Prospective study of fluoxetine treatment and suicidal behavior in affectively ill subjects. Am J Psychiatry 156(2):195-201.
 

 Masand P, Dewan M (1991), Association of fluoxetine with suicidal ideation. Am J Psychiatry 148(11):1603-1604 [letter].
 

 PDR (2003a), Prozac (fluoxetine hydrochloride). Montvale, N.J.: Medical Economics Company Inc., pp1232-1237.
 

 PDR (2003b), Zoloft (sertraline hydrochloride). Montvale, N.J.: Medical Economics Company Inc., pp2675-2681.
 

 Rickels K, DeMartinis N, Garcia-Espana F et al. (2000), Imipramine and buspirone in treatment of patients with generalized anxiety disorder who are discontinuing long-term benzodiazepine therapy. Am J Psychiatry 157(12):1973-1979 [see comment].
 

 The Guardian (2003), Prozac killed my wife. Available at: www.guardian.co.uk/g2/story/0,3604,969789,00.html.
 Accessed Jan. 21, 2004.
 

 Vedantam S (2003), Britain warns of Paxil's risk to children. Washington Post. June 11, A14.
 

 Walsh MT, Dinan TG (2001), Selective serotonin reuptake inhibitors and violence: a review of the available evidence. Acta Psychiatr Scand 104(2):84-91.
 

 Warshaw MG, Keller MB (1996), The relationship between fluoxetine use and suicidal behavior in 654 subjects with anxiety disorders. J Clin Psychiatry 57(4):158-166.
 

 Watson D, Clark LA, Weber K et al. (1995), Testing a tripartite model: II. Exploring the symptom structure of anxiety and depression in student, adult, and patient samples. J Abnorm Psychol 104(1):15-25.

How is it that anti-anxiety drugs can cause anxiety and insomnia, sometimes within the first day or two of treatment? These are not the soothing qualities we expect for anti-anxiety medications.

Author | Conrad M. Swartz, MD, PhD

Articles

Timolol Does Not Cause Psychosis

Less Anxiety But More Violence?